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Sample records for adjuvant trastuzumab herceptin

  1. Deconstructing media coverage of trastuzumab (Herceptin): an analysis of national newspaper coverage

    PubMed Central

    Wilson, Paul M; Booth, Alison M; Eastwood, Alison; Watt, Ian S

    2008-01-01

    Summary Objective To explore and critically describe the content and main narratives of UK national daily newspaper coverage of trastuzumab (Herceptin®). Design We used the NewsBank database to search eight national daily newspapers, and their Sunday equivalents, retrospectively from 19 February 2006 back to the earliest mention of trastuzumab or Herceptin (19 May 1998). Setting UK national newspapers. Main outcome measures To be eligible for inclusion, articles had to contain at least three sentences about trastuzumab. Articles that focused on the financial performance of companies associated with the drug were excluded from the analysis. For each included article, we extracted bibliographic details and data, and independently rated the reporting slant towards trastuzumab and, where relevant, the reporting slant towards access to treatment. Results We identified 361 articles that met the study inclusion criteria. The proprietary name of Herceptin was always used, with only eight articles mentioning the generic alternative. 294/361 included articles (81.5%) were rated as being positive towards trastuzumab, the remainder rated as neutral. Access to trastuzumab treatment was the main narrative running across included articles and reports of individual patients seeking treatment featured prominently throughout. In 208/361 of included articles (57%) the reporting slant towards access to trastuzumab treatment was rated as negative. 178/361 of included articles (49.3%) mentioned licensing, but rarely mentioned that licensing processes can only occur when the manufacturer applies for a licence. Only a minority of articles mentioned that the drug had to be licensed before it could be subject to the NICE approval process. Conclusions Newspaper coverage of trastuzumab has been characterized by uncritical reporting. Journalists (and consumers) should be more questioning when confronted with information about new drugs and of the motives of those who seek to set the news

  2. Trastuzumab re-treatment following adjuvant trastuzumab and the importance of distant disease-free interval: the HERA trial experience.

    PubMed

    Metzger-Filho, Otto; de Azambuja, Evandro; Procter, Marion; Krieguer, Magalie; Smith, Ian; Baselga, Jose; Cameron, David; Untch, Michael; Jackisch, Christian; Bell, Richard; Gianni, Luca; Goldhirsch, Aron; Piccart, Martine; Gelber, Richard D

    2016-01-01

    This retrospective analysis conducted using data from patients enrolled onto the Herceptin Adjuvant has two objectives: The first is to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI) upon overall survival (OS). The second is to describe the duration of trastuzumab-based regimens in the metastatic setting for patients previously treated with adjuvant trastuzumab. The first objective included 187 patients treated with adjuvant trastuzumab and diagnosed with distant recurrence at 4-year median follow-up. The second objective included data from questionnaires sent to investigators retreating patients with trastuzumab upon distant recurrence: 144 of 156 questionnaires were returned (93 %), and 90 patients were selected based on available clinical information and consent for subsequent studies. There was no statistically significant relationship between TDRI following 1 year of adjuvant trastuzumab and OS from distant recurrence: hazard ratio 0.991, p = 0.46. The median OS from distant recurrence was numerically longer among patients with a TDRI of ≥12 months (n = 103) than <12 months (n = 84) but not statistically significant (23.7 vs. 17.8 months, p = 0.47). The median duration of first-line trastuzumab-based regimens for patients previously treated with adjuvant trastuzumab and diagnosed with distant disease recurrence was 8.8 months (n = 88). This retrospective, exploratory study suggests that TDRI did not impact on OS measured from distant recurrence. We argue that prospective collection of treatment information beyond disease progression should be included in future clinical studies. PMID:26708471

  3. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice

    PubMed Central

    2011-01-01

    Background Cardiac inflammation and generation of oxidative stress are known to contribute to trastuzumab (herceptin) induced cardiac toxicity. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signaling, we investigated whether or not TLR4 is involved in trastuzumab induced cardiotoxicity. Methods Seven days after a single injection of herceptin (2 mg/kg; i.p.), left ventricular pressure volume loops were measured in HeN compotent (TLR4+/+) and HeJ mutant (TLR4-/-) treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs) for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α), Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker. Results Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN), in contrast TLR4-/- trastuzumab mice showed improved left ventricular function EF%, CO; p < 0.05, attenuation of mononuclear cell infiltration in TLR4 -/-; p < 0.05 vs.TLR-4 competent (HeN), reduced level of cytokines TNF-α, MCP-1 and ICAM-1 expression in TLR4-/-, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p < 0.05 vs.TLR-4 competent (HeN). Conclusions Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1), so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy. PMID:21999911

  4. The ErbB2 inhibitor Herceptin (Trastuzumab) promotes axonal outgrowth four weeks after acute nerve transection and repair.

    PubMed

    Placheta, Eva; Hendry, J Michael; Wood, Matthew D; Lafontaine, Christine W; Liu, Edward H; Cecilia Alvarez Veronesi, M; Frey, Manfred; Gordon, Tessa; Borschel, Gregory H

    2014-10-17

    Accumulating evidence suggests that neuregulin, a potent Schwann cell mitogen, and its receptor, ErbB2, have an important role in regulating peripheral nerve regeneration. We hypothesized that Herceptin (Trastuzumab), a monoclonal antibody that binds ErbB2, would disrupt ErbB2 signaling, allowing us to evaluate ErbB2's importance in peripheral nerve regeneration. In this study, the extent of peripheral motor and sensory nerve regeneration and distal axonal outgrowth was analyzed two and four weeks after common peroneal (CP) nerve injury in rats. Outcomes analyzed included neuron counts after retrograde labeling, histomorphometry, and protein analysis. The data analysis revealed that there was no impact of Herceptin administration on either the numbers of motor or sensory neurons that regenerated their axons but histomorphometry revealed that Herceptin significantly increased the number of regenerated axons in the distal repaired nerve after 4 weeks. Protein analysis with Western blotting revealed no difference in either expression levels of ErbB2 or the amount of activated, phosphorylated ErbB2 in injured nerves. In conclusion, administration of the ErbB2 receptor inhibitor after nerve transection and surgical repair did not alter the number of regenerating neurons but markedly increased the number of regenerated axons per neuron in the distal nerve stump. Enhanced axon outgrowth in the presence of this ErbB2 inhibitor indicates that ErbB2 signaling may limit the numbers of axons that are emitted from each regenerating neuron. PMID:25220708

  5. Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report.

    PubMed

    Stemmler, Hans-Joachim; Mengele, Karin; Schmitt, Manfred; Harbeck, Nadia; Laessig, Dorit; Herrmann, Karin A; Schaffer, Pamela; Heinemann, Volker

    2008-09-01

    Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC. PMID:18690096

  6. In silico design, construction and cloning of Trastuzumab humanized monoclonal antibody: A possible biosimilar for Herceptin

    PubMed Central

    Akbarzadeh-Sharbaf, Soudabeh; Yakhchali, Bagher; Minuchehr, Zarrin; Shokrgozar, Mohammad Ali; Zeinali, Sirous

    2012-01-01

    Background: There is a novel hypothesis in that antibodies may have specificity for two distinct antigens that have been named “dual specificity”. This hypothesis was evaluated for some defined therapeutic monoclonal antibodies (mAbs) such as Trastuzumab, Pertuzumab, Bevacizumab, and Cetuximab. In silico design and construction of expression vectors for trastuzumab monoclonal antibody also in this work were performed. Materials and Methods: First, in bioinformatics studies the 3D structures of concerned mAbs were obtained from the Protein Data Bank (PDB). Three-dimensional structural alignments were performed with SIM and MUSTANG softwares. AutoDock4.2 software also was used for the docking analysis. Second, the suitable genes for trastuzumab heavy and light chains were designed, synthesized, and cloned in the prokaryotic vector. These fragments individually were PCR amplified and cloned into pcDNA™ 3.3-TOPO® and pOptiVEC™ TOPO® shuttle vectors, using standard methods. Results: First, many bioinformatics tools and softwares were applied but we did not meet any new dual specificity in the selected antibodies. In the following step, the suitable expression cascade for the heavy and light chains of Trastuzumab therapeutic mAb were designed and constructed. Gene cloning was successfully performed and created constructs were confirmed using gene mapping and sequencing. Conclusions: This study was based on a recently developed technology for mAb expression in mammalian cells. The obtained constructs could be successfully used for biosimilar recombinant mAb production in CHO DG44 dihydrofolate reductase (DHFR) gene deficient cell line in the suspension culture medium. PMID:23210080

  7. [Is Herceptin(®) (trastuzumab) by subcutaneous a mini revolution? Pharmaco-economic study].

    PubMed

    Lieutenant, Vincent; Toulza, Émilie; Pommier, Martine; Lortal-Canguilhem, Barbara

    2015-03-01

    Herceptin(®) injected by intravenous (IV) is one of the key treatment of breast cancer HER2+. The improvement of galenic form allowed a new way of administration, the sub-cutaneous way (SC), authorized by EMEA in 2013. This new way enables a 5-minute infusion, a fixed dose and a fixed volume of preparation. On 2012, saving-time and financial impacts were calculated by extrapolation of the IV way in a cancer treatment center. The study showed a preparing time-saving of 7.5min/loading dose and of 6.5min/maintenance dose, and a nurse time-saving of 4.5min/loading dose and 4.25min/maintenance dose. Moreover, it can be added a saving of consumable of 13,31€ per injection in case of monotherapy. The SC leads to a new adaptation and reorganization in the preparation of monoclonal antibodies and day hospitals. PMID:25725921

  8. Trastuzumab improves locoregional control in HER2-positive breast cancer patients following adjuvant radiotherapy

    PubMed Central

    Cao, Lu; Cai, Gang; Xu, Fei; Yang, Zhao-Zhi; Yu, Xiao-Li; Ma, Jin-Li; Zhang, Qian; Wu, Jiong; Guo, Xiao-Mao; Chen, Jia-Yi

    2016-01-01

    Abstract The benefit of adjuvant trastuzumab in disease-free and overall survival for human epidermal receptor 2–positive (HER2+) breast cancer patients is well established. However, the effect of trastuzumab on locoregional control remains unclear, particularly in patients treated with adjuvant radiotherapy (RT). In this study, we investigated the locoregional benefit of trastuzumab in patients with HER2+ breast cancer after adjuvant RT. Using a single institutional database, we identified 278 patients with stage II/III invasive HER2+ breast tumors receiving adjuvant RT between January 2008 and July 2011. We compared the locoregional outcomes of 134 patients who received trastuzumab to 144 patients without trastuzumab within the same period. Clinical and biological factors that might impact on the locoregional benefit of trastuzumab were also assessed. At the median follow-up of 45 months, trastuzumab significantly lowered the risk of locoregional recurrence (LRR) with a 3-year LRR rate of 2.4% versus 7.5% for the cohort with and without trastuzumab (P = 0.019). Trastuzumab was associated with a more significant locoregional benefit in the hormone receptor–positive (HR+)/HER2+ subgroup, with a 3-year LRR of 0% versus 6.7% in the cohort with and without trastuzumab (P = 0.027). For HR−/HER2+ breast tumor patients, the 3-year LRR rate was still lower for the cohort with trastuzumab (4.7% vs 8.6%). However, statistical significance was not found (P = 0.179). Both univariate and multivariate analyses confirmed that trastuzumab treatment was the only significant predictive factor for LRR (hazard ratio, 4.05; 95% confidence interval, 1.07–15.35; P = 0.039). Adjuvant trastuzumab in addition to RT is associated with significant reduced LRR risk in HER2+ breast cancer. PMID:27512838

  9. Kit for the preparation of (111)In-labeled pertuzumab injection for imaging response of HER2-positive breast cancer to trastuzumab (Herceptin).

    PubMed

    Lam, Karen; Scollard, Deborah A; Chan, Conrad; Levine, Mark N; Reilly, Raymond M

    2014-10-23

    We previously reported that (111)In-labeled pertuzumab imaged trastuzumab (Herceptin)-mediated changes in HER2 expression preclinically in breast cancer tumors. To advance (111)In-labeled pertuzumab to a Phase I/II clinical trial, a kit was designed for preparing this agent in a form suitable for human administration. Unit-dose kits containing pertuzumab modified with 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (BzDTPA) were prepared that labeled to high efficiency (>90%) with (111)In and met specifications for pharmaceutical quality. The kits were stable for 4 months and the final radiopharmaceutical was stable for 24h. Imaging studies demonstrated high and specific uptake in HER2-positive tumors in mice using this clinical kit formulation. PMID:25464190

  10. Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas.

    PubMed

    Martin-Castillo, Begoña; Lopez-Bonet, Eugeni; Cuyàs, Elisabet; Viñas, Gemma; Pernas, Sonia; Dorca, Joan; Menendez, Javier A

    2015-10-20

    Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24-/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24-/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24-/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24-/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of "Trojan horse" approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes

  11. Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas

    PubMed Central

    Martin-Castillo, Begoña; Lopez-Bonet, Eugeni; Cuyàs, Elisabet; Viñas, Gemma; Pernas, Sonia; Dorca, Joan; Menendez, Javier A.

    2015-01-01

    Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24−/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24−/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24−/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24−/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of “Trojan horse” approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC

  12. Trastuzumab after Chemotherapy Is Effective in HER2-Positive Breast Cancer

    Cancer.gov

    Treatment with trastuzumab for 1 year following standard chemotherapy improved disease-free survival in women with HER2-positive early breast cancer, according to 4-year follow-up results of the Herceptin Adjuvant (HERA) trial reported February 25, 2011,

  13. Enhancement of radiosensitivity by dual inhibition of the HER family with ZD1839 ('Iressa') and trastuzumab ('Herceptin')

    SciTech Connect

    Fukutome, Mika . E-mail: fukutome@rad.twmu.ac.jp; Maebayashi, Katsuya; Nasu, Sachiko; Seki, Kaori; Mitsuhashi, Norio

    2006-10-01

    Purpose: The aims of this study were twofold: (1) to examine the effects of dual inhibition of 2 members of the HER family, the epidermoid growth factor receptor (EGFR) and HER2/neu, by gefitinib (ZD1839) and trastuzumab on radiosensitivity; and (2) to explore the molecular mechanism of radiosensitization especially focusing on the survival signal transduction pathways by using A431 human vulvar squamous carcinoma cells expressing EGFR and HER2/neu. Methods and Materials: The effects of inhibitors on Radiation-induced activation of EGFR and/or HER2/neu, and the intracellular proteins that are involved in their downstream signaling, were quantified by the Western blot. Radiosensitizing effects by the blockage of EGFR and/or HER2/neu were determined by a clonogenic assay. Results: Radiation-induced activation of the EGFR and HER2/neu was inhibited with ZD1839 and/or trastuzumab. ZD1839 also inhibited Radiation-induced phosphorylation of HER2/neu. Radiation in combination with the HER family inhibitors inhibited the activation of Akt and MEK1/2, the downstream survival signaling of the HER family. ZD1839 enhanced radiosensitivity with a dose-modifying factor (DMF) (SF3) of 1.45 and trastuzumab did so with a DMF (SF3) of 1.11. Simultaneous blockade of EGFR and HER2/neu induced a synergistic radiosensitizing effect with a DMF (SF3) of 2.29. Conclusions: The present data suggest that a dual EGFR and HER2/neu targeting may have potential for radiosensitization in tumors in which both of these pathways are active.

  14. A Prospective Cohort Study on Cardiotoxicity of Adjuvant Trastuzumab Therapy in Breast Cancer Patients

    PubMed Central

    Matos, Erika; Jug, Borut; Blagus, Rok; Zakotnik, Branko

    2016-01-01

    Background Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. Objectives The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. Methods In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). Results 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. Conclusions Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant. PMID:27305108

  15. Trastuzumab Benefits Women with Locally Advanced or Inflammatory

    Cancer.gov

    Women treated with trastuzumab (Herceptin) and chemotherapy before surgery and trastuzumab again after surgery had a reduced risk of the disease recurring or progressing compared with women who received pre-surgical chemotherapy but no trastuzumab, accord

  16. Cardiac Monitoring During Adjuvant Trastuzumab-Based Chemotherapy Among Older Patients With Breast Cancer

    PubMed Central

    Chavez-MacGregor, Mariana; Niu, Jiangong; Zhang, Ning; Elting, Linda S.; Smith, Benjamin D.; Banchs, Jose; Hortobagyi, Gabriel N.; Giordano, Sharon H.

    2015-01-01

    Purpose Patients treated with adjuvant trastuzumab require adequate cardiac monitoring. We describe the patterns of cardiac monitoring and evaluate factors associated with adequate monitoring in a large population-based study of older patients with breast cancer. Patients and Methods Patients age 66 years or older with full Medicare coverage, diagnosed with stage I to III breast cancer between 2005 and 2009, and treated with adjuvant trastuzumab-based chemotherapy were identified in the SEER-Medicare and the Texas Cancer Registry-Medicare databases. The adequacy of cardiac monitoring was determined. Chemotherapy, trastuzumab use, cardiac monitoring, and comorbidities were identified by using International Classification of Diseases, 9th revision and Healthcare Common Procedure Coding System codes. Prescribing physician characteristics were also evaluated. Analyses included descriptive statistics and multilevel logistic regression models. Results In all, 2,203 patients were identified; median age was 72 years. Adequate monitoring was identified in only 36.0% of the patients (n = 793). In the multivariable model, factors associated with optimal cardiac monitoring included a more recent year of diagnosis (hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54), anthracycline use (HR, 1.39; 95% CI, 1.14 to 1.71), female prescribing physician (HR, 1.37; 95% CI, 1.10 to 1.70), and physician graduating after 1990 (HR, 1.66; 95% CI, 1.29 to 2.12). The presence of cardiac comorbidities was not a determinant for cardiac monitoring. Of the variance in the adequacy of cardiac monitoring, 15.3% was attributable to physician factors and 5.2% to measured patient factors. Conclusion A large proportion of patients had suboptimal cardiac monitoring. Physician characteristics had more influence than measured patient-level factors in the adequacy of cardiac monitoring. Because trastuzumab-related cardiotoxicity is reversible, efforts to improve the adequacy of cardiac monitoring are needed

  17. Early cardiac toxicity following adjuvant radiotherapy of left-sided breast cancer with or without concurrent trastuzumab

    PubMed Central

    Cao, Lu; Cai, Gang; Chang, Cai; Yang, Zhao-Zhi; Feng, Yan; Yu, Xiao-Li; Ma, Jin-Li; Wu, Jiong; Guo, Xiao-Mao; Chen, Jia-Yi

    2016-01-01

    Purpose To evaluate the influence of concurrent trastuzumab on the cardiotoxicity in patients receiving left-sided adjuvant radiotherapy. Materials and Methods Medical records of stage I-III left-sided breast cancer patients, including 64 receiving concurrent trastuzumab with radiotherapy and 73 receiving radiotherapy alone were retrospectively reviewed. All of the patients had normal LVEF after adjuvant chemotherapy. Information of doses volume to cardiac structures was collected. Cardiac events were assessed according to CTC 2.0. Results Median follow-up of LVEF and clinical assessment of cardiac function from the initiation of radiotherapy was 6.7 months (range 3–60.9) and 26 months (range 6.4–60.9), respectively. Grade 1 LVEF dysfunction occurred in 5 (7.8%) and 3 (4.1%) patients of the concurrent-trastuzumab and radiotherapy alone cohort, respectively. Trastuzumab was the only significant factor influencing absolute LVEF decrease in univariate analysis. In multivariate analysis of concurrent-trastuzumab cohort, IMC radiotherapy and start trastuzumab during radiotherapy were independent risk factors. For concurrent cohort, mean heart dose, as well as D10-D30, D50-D55, V5-V20 of the heart and D30-D45, D65-D75, V6-V15 of the LV were significantly higher in patients developing LVEF dysfunction. Conclusions Concurrent trastuzumab and left-sided radiotherapy is well tolerated in terms of cardiotoxicity in patients with normal baseline cardiac function after adjuvant chemotherapy. However, increases in mean dose and low–dose volume of cardiac structures are associated with a higher risk of acute LVEF dysfunction. PMID:26460956

  18. Delay in initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free survival in patients with HER2-positive non-metastatic breast cancer.

    PubMed

    Gallagher, Christopher M; More, Kenneth; Kamath, Tripthi; Masaquel, Anthony; Guerin, Annie; Ionescu-Ittu, Raluca; Gauthier-Loiselle, Marjolaine; Nitulescu, Roy; Sicignano, Nicholas; Butts, Elizabeth; Wu, Eric Q; Barnett, Brian

    2016-05-01

    Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6 months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6 months and ≤6 months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9 % initiated adjuvant trastuzumab within ≤6 months of diagnosis and 20.1 % initiated adjuvant trastuzumab >6 months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6 months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within ≤6 months of diagnosis (hazard ratios [95 % CIs]: 1.51 [1.22-1.87], 1.54 [1.12-2.12], and 1.43 [1.16-1.75]; respectively). The results of this population-based study suggest that delays of >6 months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS. PMID:27107569

  19. Outcome of patients with HER2-positive breast cancer treated with or without adjuvant trastuzumab in the Finland Capecitabine Trial (FinXX)

    PubMed Central

    2014-01-01

    Background. Little information is available about survival outcomes of patients with HER2-positive early breast cancer treated with adjuvant capecitabine-containing chemotherapy with or without trastuzumab. Patients and methods. One thousand and five hundred patients with early breast cancer were entered to the Finland Capecitabine trial (FinXX) between January 2004 and May 2007, and were randomly assigned to receive either three cycles of adjuvant TX (docetaxel, capecitabine) followed by three cycles of CEX (cyclophosphamide, epirubicin, capecitabine; TX-CEX) or three cycles of docetaxel followed by three cycles of CEF (cyclophosphamide, epirubicin, fluorouracil; T-CEF). The primary endpoint was recurrence-free survival (RFS). The study protocol was amended in May 2005 while study accrual was ongoing to allow adjuvant trastuzumab for patients with HER2-positive cancer. Of the 284 patients with HER2-positive cancer accrued to FinXX, 176 (62.0%) received trastuzumab after amending the study protocol, 131 for 12 months and 45 for nine weeks. The median follow-up time was 6.7 years. Results. Patients with HER2-positive cancer who received trastuzumab had better RFS than those who did not (five-year RFS 89.2% vs. 75.9%; HR 0.41, 95% CI 0.23–0.72; p = 0.001). Patients treated with trastuzumab for 12 months or nine weeks had similar RFS. There was no significant interaction between trastuzumab administration and the type of chemotherapy. Four (2.3%) patients treated with trastuzumab had heart failure or left ventricular dysfunction, three of these received capecitabine. Conclusion. Adjuvant trastuzumab improves RFS of patients treated with TX-CEX or T-CEF. Few patients had cardiac failure. PMID:23957715

  20. Cardiac Tolerability of Concurrent Administration of Trastuzumab and Anthracycline-Based Regimen as Adjuvant Chemotherapy for Breast Cancer

    PubMed Central

    Watanabe, Naoki; Otsuka, Shoko; Sasaki, Yoko; Shimojima, Reiko; Wani, Yoji; Uchino, Kaori

    2014-01-01

    Summary Background Retrospective analysis suggests that anthracycline-containing regimens may be superior to non-anthracycline-containing regimens in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, both trastuzumab and anthracycline have cardiotoxicity, and it remains unclear how to use trastuzumab in combination with an anthracycline to curtail their cardiotoxicity. Patients and Methods From 2010 to 2013, we administered weekly (q1w) paclitaxel (wP) followed by 75 mg/m2 epirubicin, fluorouracil, and cyclophosphamide (FEC) every third week (q3w) and concurrent q1w trastuzumab (H) to 41 patients with HER2-positive breast cancer (H+ group), and wP followed by FEC100 without trastuzumab to 57 patients who were HER2-negative (H– group). We routinely assessed the left ventricular ejection fraction (LVEF) by echocardiography, at the time of initiation, after wP, and after FEC, and compared them between these 2 groups. Results LVEF decreased from 63.2 to 60.9% (p = 0.030) in the H+ group and from 63.9 to 61.9% (p = 0.009) in the H– group. These 2 groups showed no significant difference in the reduction rate of LVEF over the period of chemotherapy (0.968 vs. 0.978: NS, p = 0.6457). There was no severe cardiotoxicity or congestive heart failure in either group. Conclusion Concurrent administration of epirubicin (q3w, 75 mg/m2) and trastuzumab showed no less cardiac tolerability in an adjuvant setting. PMID:24803887

  1. Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial

    PubMed Central

    Pogue-Geile, Katherine L.; Song, Nan; Jeong, Jong-Hyeon; Gavin, Patrick G.; Kim, Seong-Rim; Blackmon, Nicole L.; Finnigan, Melanie; Rastogi, Priya; Fehrenbacher, Louis; Mamounas, Eleftherios P.; Swain, Sandra M.; Wickerham, D. Lawrence; Geyer, Charles E.; Costantino, Joseph P.; Wolmark, Norman; Paik, Soonmyung

    2015-01-01

    Purpose Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) –positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31. Patients and Methods Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point. Results Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64). Conclusion Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting. PMID:25559813

  2. Real-Life Use and Effectiveness of Adjuvant Trastuzumab in Early Breast Cancer Patients: A Study of the Southeast Netherlands Breast Cancer Consortium

    PubMed Central

    Seferina, Shanly C.; Lobbezoo, Dorien J.A.; de Boer, Maaike; Dercksen, M. Wouter; van den Berkmortel, Franchette; van Kampen, Roel J.W.; van de Wouw, Agnès J.; de Vries, Bart; Joore, Manuela A.; Peer, Petronella G.M.; Voogd, Adri C.

    2015-01-01

    Background. The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials. Methods. We included all patients with stage I–III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005–2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice. Results. Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37–1.06) for trastuzumab when adjusting for potential confounders. Conclusion. This study shows that in real life, patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment. PMID:26099745

  3. External influences and priority-setting for anti-cancer agents: a case study of media coverage in adjuvant trastuzumab for breast cancer

    PubMed Central

    Booth, Christopher M; Dranitsaris, George; Gainford, M Corona; Berry, Scott; Fralick, Michael; Fralick, John; Sue, Joanna; Clemons, Mark

    2007-01-01

    Background Setting priorities for the funding of new anti-cancer agents is becoming increasingly complex. The funding of adjuvant trastuzumab for breast cancer has brought this dilemma to the fore. In this paper we review external factors that may influence decision-making bodies and present a case study of media response in Ontario, Canada to adjuvant trastuzumab for breast cancer. Methods A comprehensive search of the databases of Canadian national and local newspapers and television was performed. Articles pertaining to trastuzumab in adjuvant breast cancer as well as 17 other anti-cancer drugs and indications were retrieved. The search period was from the date when individual trial results were announced to the date funding was made available in Ontario. Results During the 2.6 months between the release of the trastuzumab results to funding approval in Ontario, we identified 51 episodes of media coverage. For the 17 other drugs/indications (7 breast and 10 non-breast), the median time to funding approval was 31 months (range 14–46). Other recent major advances in oncology such as adjuvant vinorelbine/cisplatin for resected NSCLC and docetaxel for advanced prostate cancer received considerably less media attention (17 media reports for each) than trastuzumab. The median number of media reports for breast cancer drugs was 4.5 compared to 2.5 for non-breast cancer drugs (p = 0.56). Conclusion Priority-setting for novel anti-cancer agents is a complex process that tries to ensure fair use of constrained resources to fund therapies with the best evidence of clinical benefit. However, this process is subject to external factors including the influence of media, patient advocates, politicians, and industry. The data in this case study serve to illustrate the significant involvement one (or all) of these external factors may play in the debate over priority-setting. PMID:17598896

  4. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients

    PubMed Central

    2013-01-01

    Background Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena. Methods We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS). Results ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells. Conclusion The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab

  5. The effect of trastuzumab/docatexel combination on breast cancer angiogenesis: dichotomus effect predictable by the HIFI alpha/VEGF pre-treatment status?

    PubMed

    Koukourakis, Michael I; Simopoulos, Constantinos; Polychronidis, Alexandros; Perente, Sebach; Botaitis, Sotirios; Giatromanolaki, Alexandra; Sivridis, Efthimios

    2003-01-01

    In this study we describe and discuss the dichotomous effects of docetaxel trastuzumab (Herceptin)/docetaxel therapy on the angiogenic molecular profile in two patients with her-2 + chemo-resistant recurrent breast carcinoma. In the first case, an intensification of angiogenesis occurred following therapy, accompanied by an impressive increase of the cancer cell proliferation index. This tumor did not express HIF1 alpha and shared a HIF-independent VEGF overexpression, which remained unaffected by therapy. An intensified formation of thymidine phosphorylase (TP)-rich stroma, presumably a response to docetaxel, shows a TP-dependent angiogenic response. In the second patient, VEGF and HIF1 alpha were down-regulated in post-treatment biopsies and this was accompanied by a sharp reduction of the vascular density and of the cancer cell proliferation rate. In both cases, c-erbB-2 expression was abrogated by Herceptin. Taking into account that Herceptin down-regulates VEGF through reduction of HIF1 alpha synthesis, this clinical study provides evidence that an anti-angiogenic effect from Herceptin/Docetaxel therapy is expected only in tumors with HIF1 alpha-dependent VEGF overexpression. In contrast, HIF1 alpha-independent VEGF angiogenic activity cannot be abrogated by Herceptin. Docetaxel mediated up-regulation of TP in the tumoral stroma may, on the contrary, result in angiogenesis intersification and rapid tumor relapse. Such an effect should be of clinical importance since Herceptin/Docetaxel-based regimens are currently evaluated for the adjuvant therapy of her-2 + breast cancer patients. Studying the Herceptin-induced phenotypic changes of tumors could lead to the identification of specific molecular profiles that bring about diverging angiogenic responses. Adjustment of the chemotherapy regimen accordingly would prove of clinical importance. PMID:12820439

  6. Factors affecting disease-free survival in patients with human epidermal growth factor receptor 2-positive breast cancer who receive adjuvant trastuzumab

    PubMed Central

    GÜNDÜZ, SEYDA; GÖKSU, SEMA SEZGIN; ARSLAN, DENIZ; TATLI, ALI MURAT; UYSAL, MÜKREMIN; GÜNDÜZ, UMUT RIZA; SEVINÇ, MERT MAHSUNI; COŞKUN, HASAN SENOL; BOZCUK, HAKAN; MUTLU, HASAN; SAVAS, BURHAN

    2015-01-01

    Breast cancer is the most frequently diagnosed cancer in women worldwide and the second cause of cancer-related mortality. A total of 20–30% of patients with early-stage breast cancer develop recurrence within the first 5 years following diagnosis. Trastuzumab significantly improves overall survival and disease-free survival (DFS) in women with human epidermal growth factor receptor 2 (HER2)-positive early and locally advanced breast cancer. This study aimed to determine the factors that affect DFS following adjuvant transtuzumab therapy. A total of 62 patients treated with trastuzumab for early and locally advanced breast cancer were included in our study. Data, including pathology, treatment and treatment outcome, rate of recurrence and laboratory tests, were retrospectively collected. There was no significant association between DFS and age, menopausal status, disease stage and hormone receptor status. The median follow-up was 48.4 months. The median DFS of patients treated with adjuvant trastuzumab was 64.1 months. In addition, the median DFS was 44.3 vs. 66.8 months in patients with platelet-lymphocyte ratio (PLR) ≤200 vs. >200, respectively (log-rank test; P=0.001), and 70 vs. 45 months in patients with eosinophil count ≤70 vs. >70×103/mm3 (log-rank test; P=0.001). Our data revealed the prognostic relevance of a decrease in the peripheral blood eosinophil count and PLR value following trastuzumab therapy in breast cancer. PLR and eosinophil count measurements are cost-effective, readily available worldwide, non-invasive and safe. Combined with other markers, such as patient age, tumor stage and tumor histology, may be effectively used for patients with breast cancer. PMID:26623060

  7. Trastuzumab-induced cardiomyopathy.

    PubMed

    Guglin, Maya; Cutro, Raymond; Mishkin, Joseph D

    2008-06-01

    Trastuzumab is a recombinant humanized monoclonal antibody used for the treatment of advanced breast cancer. It improves survival and increases response to chemotherapy. The major side effect of trastuzumab is cardiotoxicity manifesting as a reduction in left ventricular systolic function, either asymptomatic or with signs and symptoms of heart failure. Although reversible in most cases, cardiotoxicity frequently results in the discontinuation of trastuzumab. The objective of this review is to summarize facts about trastuzumab-induced cardiotoxicity and to highlight the areas of future investigations. We searched PubMed for trials involving trastuzumab used as an adjuvant therapy for breast cancer, including the metastatic breast cancer setting, and focused on cardiotoxicity. PMID:18514938

  8. In vitro antiproliferative effect of trastuzumab (Herceptin(®)) combined with cetuximab (Erbitux(®)) in a model of human non-small cell lung cancer expressing EGFR and HER2.

    PubMed

    Privitera, G; Luca, T; Musso, N; Vancheri, C; Crimi, N; Barresi, V; Condorelli, D; Castorina, S

    2016-05-01

    Lung cancer is the leading cause of cancer death. For this reason, new therapies are needed for the treatment of this devastating disease. In this study, we investigated the effects of combining cetuximab and the trastuzumab on the growth of a model of human non-small cell lung carcinoma cell line (A549). The results were compared with those obtained from a human lung squamous carcinoma cell line (NCI-H226). Both cell lines were treated with cetuximab and trastuzumab, alone or in combination, at various concentrations, for 24, 48 and 72 h. Cell proliferation was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. EGFR and HER-2 mRNA expression was detected by reverse transcription polymerase chain reaction, and the gene amplification status of receptors was evaluated by fluorescence in situ hybridisation. The colorimetric proliferation assay showed that trastuzumab combined with cetuximab significantly inhibited A549 cells at a dose of 40 μg/ml after 72 h of treatment (p < 0.05), while no time-dose dependent inhibition was observed in NCI-H226 cells. The combined treatment influenced both levels of EGFR and HER-2 mRNA in A549 cells and only EGFR mRNA levels in NCI-H226 cells. Fluorescence in situ hybridisation showed that both cell lines were aneuploid for the two genes with equally increased EGFR and CEN7 signals, as well as HER-2 and CEN17 signals, indicating a condition of polysomy without amplification. The preliminary results of this study encourage further investigations to elucidate the downstream events involved and to understand how these mechanisms influence non-small cell lung cancers growth. PMID:25716471

  9. Trastuzumab Injection

    MedlinePlus

    Trastuzumab injection is used along with other medications or after other medications have been used to treat ... has spread to other parts of the body. Trastuzumab injection is also used during and after treatment ...

  10. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis

    PubMed Central

    Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

    2016-01-01

    Background The anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab’s high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. Methods and Findings A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50–54 y; 95% CI 2.29–2.37) for the worst prognosis (ER−/PR−) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25–29 to 90–94 y (0.44 times for the age group 50–54 y; 95% CI 0.43–0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]–adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER−/PR− subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR− cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had

  11. Ablation of breast cancer cells using trastuzumab-functionalized multi-walled carbon nanotubes and trastuzumab-diphtheria toxin conjugate.

    PubMed

    Oraki Kohshour, Mojtaba; Mirzaie, Sako; Zeinali, Majid; Amin, Mansour; Said Hakhamaneshi, Mohammad; Jalili, Ali; Mosaveri, Nader; Jamalan, Mostafa

    2014-03-01

    Trastuzumab (Herceptin(®) ) is a monoclonal antibody (mAb) for specific ablation of HER2-overexpressing malignant breast cancer cells. Intensification of antiproliferative activity of trastuzumab through construction of immunotoxins and nano-immunoconjugates is a promising approach for treatment of cancer. In this study, trastuzumab was directly conjugated to diphtheria toxin (DT). Also, conjugates of trastuzumab and multiwalled carbon nanotubes (MWCNT) were constructed by covalent immobilization of trastuzumab onto MWCNTs. Then, antiproliferative activity of the fusion constructs against HER2-overexpressing SK-BR-3 and also HER2-negative MCF-7 cancer cell lines were examined. Cells treated with trastuzumab-MWCNT conjugates were irradiated with near-infrared (NIR) light. Efficient absorption of NIR radiation and its conversion to heat by MWCNTs can be resulted to thermal ablation of cancerous cells. Our results strongly showed that both trastuzumab-MWCNT and trastuzumab-DT conjugates were significantly efficient in the specific killing of SK-BR-3 cells. Targeting of MWCNTs to cancerous cells using trastuzumab followed by exposure of cells to NIR radiation was more efficient in repression of cell proliferation than treatment for cancer cells with trastuzumab-DT. Our results also showed that conjugation linkers can significantly affect the cytotoxicity of MWCNT-immunoconjugates. In conclusion, our data demonstrated that trastuzumab-MWCNT is a promising nano-immunoconjugate for killing of HER2-overexpressing cancerous cells. PMID:24118702

  12. Effectiveness of Trastuzumab in First-Line HER2+ Metastatic Breast Cancer After Failure in Adjuvant Setting: A Controlled Cohort Study

    PubMed Central

    Negri, Eva; Zambelli, Alberto; Franchi, Matteo; Rossi, Marta; Bonifazi, Martina; Corrao, Giovanni; Moja, Lorenzo; Zocchetti, Carlo

    2014-01-01

    Background. The evidence supporting the use of trastuzumab (T) in a metastatic setting comes from studies that included (almost) only patients who never received prior T. We investigated the effectiveness of T as first-line therapy for metastatic breast cancer (mBC) in women previously treated with T in the adjuvant setting. Materials and Methods. By using record linkage of five administrative health care databases of Lombardy, Italy, we identified 2,046 women treated with T for early breast cancer (eBC) in 2006–2009, 96 of whom developed a metastasis and were retreated with T in first-line treatment for mBC (treatment group). We compared the overall survival (OS) of these women with that of 197 women treated with T in first-line treatment for mBC, who were treated with therapies other than T for early disease (control group). We computed Kaplan-Meier 2-year OS and used a proportional hazard model to estimate the multivariate hazard ratio (HR) of death in the intervention group compared with the control group, adjusted by age, use of endocrine therapy, and site of metastasis. Results. Two-year OS was 60.0% in the treatment group and 59.5% in the control group. The adjusted HR of death in the treatment group compared with the control group was 0.79 (95% confidence interval, 0.50–1.26). Conclusion. Our data provide convincing evidence that the outcome of women receiving first-line T treatment for mBC after T failure in the adjuvant setting is comparable to that of women not receiving T for eBC. These data are of specific interest, given the unavailability of data from randomized clinical trials. PMID:25355843

  13. Darpp-32 and Its Truncated Variant t-Darpp Have Antagonistic Effects on Breast Cancer Cell Growth and Herceptin Resistance

    PubMed Central

    Gu, Long; Waliany, Sarah; Kane, Susan E.

    2009-01-01

    Background Herceptin (trastuzumab) is a humanized monoclonal antibody that is approved for the treatment of metastatic breast cancer patients whose tumors overexpress Her2 (erbB2/neu). Up to 70% of Her2-positive breast cancers demonstrate a response to Herceptin-based therapies, but resistance almost inevitably arises within a year of the initial response. To help understand the mechanism of Herceptin resistance, we isolated clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to Herceptin. These cell lines exhibit sustained PI3K/Akt signaling as an essential component of Herceptin-resistant proliferation. Several genes in the protein kinase A (PKA) signaling network have altered expression in BT/HerR cells, including PPP1R1B, which encodes a 32 kDa protein known as Darpp-32 and its amino-terminal truncated variant, t-Darpp. The purpose of the current work was to determine the role of Darpp-32 and t-Darpp in Herceptin resistance. Methodology and Results We determined expression of Darpp-32 and t-Darpp in BT/HerR cells selected for resistance to Herceptin. Subsequently, cDNAs encoding the two isoforms of Darpp-32 were transfected, separately and together, into Her2-positive SK-Br-3 breast cancer cells. Transfected cells were tested for resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. DNA binding activity by the cAMP response element binding protein (CREB) was also measured. We found that BT/HerR cells overexpressed t-Darpp but not Darpp-32. Moreover, t-Darpp overexpression in SK-Br-3 cells was sufficient for conferring resistance to Herceptin and Herceptin-mediated dephosphorylation of Akt. Darpp-32 co-expression reversed t-Darpp's effects on Herceptin resistance and Akt phosphorylation. t-Darpp overexpression led to increased CREB binding activity, which was also reversible by Darpp-32. Conclusions t-Darpp and Darpp-32 appear to have antagonistic effects on Herceptin resistance. We present a

  14. Characterization of the Native and Denatured Herceptin by ELISA and QCM using a High-Affinity Single Chain Fragment Variable (scFv) Recombinant Antibody

    PubMed Central

    Shang, Yuqin; Mernaugh, Ray

    2012-01-01

    Herceptin/Trastuzumab is a humanized IgG1κ light chain antibody used to treat some forms of breast cancer. A phage-displayed recombinant antibody library was used to obtain an scFv (designated 2B4) to a linear synthetic peptide representing Herceptin’s heavy chain CDR3. ELISAs and piezoimmunosensor/quartz crystal microbalance (QCM) assays were used to characterize 2B4-binding activity to both native and heat denatured Herceptin. The 2B4 scFv specifically bound to heat denatured Herceptin in a concentration dependent manner over a wide (35–220.5 nM) dynamic range. Herceptin denatures and forms significant amount of aggregates when heated. UV-Vis characterization confirms that Herceptin forms aggregates as the temperature used to heat Herceptin increases. QCM affinity assay shows that binding stoichiometry between 2B4 scFv and Herceptin follows a 1:2 relationship proving that 2B4 scFv binds strongly to the dimers of heat denatured Herceptin aggregates and exhibits an affinity constant of 7.17 × 1013 M−2. The 2B4-based QCM assay was more sensitive than the corresponding ELISA. Combining QCM with ELISA can be used to more fully characterize non-specific binding events in assays. The potential theoretical and clinical implications of these results and the advantages of using QCM to characterize human therapeutic antibodies in samples are also discussed. PMID:22934911

  15. Analysis of Regional Timelines To Set Up a Global Phase III Clinical Trial in Breast Cancer: The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Experience

    PubMed Central

    de Azambuja, Evandro; Bradbury, Ian; Saini, Kamal S.; Bines, José; Simon, Sergio D.; Dooren, Veerle Van; Aktan, Gursel; Pritchard, Kathleen I.; Wolff, Antonio C.; Smith, Ian; Jackisch, Christian; Lang, Istvan; Untch, Michael; Boyle, Frances; Xu, Binghe; Baselga, Jose; Perez, Edith A.; Piccart-Gebhart, Martine

    2013-01-01

    Purpose. This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries. Methods. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. Results. South America had a significantly longer time to RA approval (median: 236 days, range: 21–257 days) than Europe (median: 52 days, range: 0–151 days), North America (median: 26 days, range: 22–30 days), and Asia-Pacific (median: 62 days, range: 37–75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21–257 days) than high-income (median: 47 days, range: 0–112 days) and lower-middle income economies (median: 57 days, range: 37–62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0–174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26–412 days). Conclusion. This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research. PMID:23359433

  16. Trastuzumab Injection

    MedlinePlus

    ... are allergic to trastuzumab, medications made from Chinese hamster ovary cell protein, any other medications, or benzyl ... you are allergic to is made from Chinese hamster ovary cell protein or contains benzyl alcohol.tell ...

  17. Breast tumor cells isolated from in vitro resistance to trastuzumab remain sensitive to trastuzumab anti-tumor effects in vivo and to ADCC killing.

    PubMed

    Kute, Timothy E; Savage, Lori; Stehle, John R; Kim-Shapiro, Jung W; Blanks, Michael J; Wood, James; Vaughn, James P

    2009-11-01

    An understanding of model systems of trastuzumab (Herceptin) resistance is of great importance since the humanized monoclonal antibody is now used as first line therapy with paclitaxel in patients with metastatic Her2 overexpressing breast cancer, and the majority of their tumors has innate resistance or develops acquired resistance to the treatment. Previously, we selected trastuzumab-resistant clonal cell lines in vitro from trastuzumab-sensitive parental BT-474 cells and showed that cloned trastuzumab-resistant cell lines maintain similar levels of the extracellular Her2 receptor, bind trastuzumab as efficiently as the parental cells, but continue to grow in the presence of trastuzumab and display cell cycle profiles and growth rates comparable to parental cells grown in the absence of trastuzumab (Kute et al. in Cytometry A 57:86-93, 2004). We now show that trastuzumab-resistant and trastuzumab-sensitive cells both surprisingly display trastuzumab-mediated growth inhibition in athymic nude mice. This demonstrates that resistance developed in vitro is not predictive of resistance in vivo. The observation that in vitro resistant cells are sensitive to trastuzumab in vivo could be explained by antibody dependent cellular cytotoxicity (ADCC). Therefore, both parental and trastuzumab-resistant cells were assayed for ADCC in real time on electroplates with and without trastuzumab in the presence of a natural killer cell line (NK-92), and granulocyte or mononuclear cellular fractions isolated from human peripheral blood. Mononuclear cells and NK-92 cells were more effective in killing both parental and trastuzumab-resistant cells in the presence of trastuzumab. Both trastuzumab-resistant cells and trastuzumab-sensitive cells showed similar susceptibility to ADCC despite displaying divergent growth responses to trastuzumab. The granulocyte fraction was able to kill these cells with equal efficacy in the presence or absence of trastuzumab. These results support a model

  18. Phosphodiesterase Type 5 Inhibitors Increase Herceptin Transport and Treatment Efficacy in Mouse Metastatic Brain Tumor Models

    PubMed Central

    Inoue, Satoshi; Konda, Bindu; Patil, Rameshwar; Ding, Hui; Espinoza, Andres; Wawrowsky, Kolja A.; Patil, Chirag; Ljubimov, Alexander V.; Black, Keith L.

    2010-01-01

    Background Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment. Methodology/Principal Findings We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [14C]dextran and trastuzumab (Herceptin®, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [14C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05). Conclusions

  19. Ado-trastuzumab Emtansine

    MedlinePlus

    Ado-trastuzumab emtansine injection is used to treat a certain type of breast cancer that has spread to other ... has worsened after treatment with other medications. Ado-trastuzumab emtansine is in a class of medications called ...

  20. MicroRNAs Linked to Trastuzumab Resistance, Brain Metastases | Division of Cancer Prevention

    Cancer.gov

    Researchers have tied increased levels of a microRNA (miRNA) to resistance to the targeted therapy trastuzumab (Herceptin) in women with HER2-positive breast cancer. Another research team has discovered a “signature” of miRNAs in brain metastases in patients with melanoma—a signature that is also present in the primary tumor and could identify melanoma patients at increased risk of brain metastases. |

  1. Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial

    PubMed Central

    2014-01-01

    Background Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet. Methods From July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation. Results At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020). Conclusions No significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2

  2. Expression Enhancement in Trastuzumab Therapeutic Monoclonal Antibody Production using Genomic Amplification with Methotrexate

    PubMed Central

    Akbarzadeh-Sharbaf, Soudabeh; Yakhchali, Bagher; Minuchehr, Zarrin; Shokrgozar, Mohammad Ali; Zeinali, Sirous

    2013-01-01

    Background Trastuzumab (Herceptin) is a humanized monoclonal antibody (mAb) which is used for specific treatment of metastatic breast cancer in patients with overexpression of HER2/neu receptor. In this study, we have attempted to develop a biosimilar version of trastuzumab mAb. Methods According to in silico studies, the heavy and light chains of trastuzumab mAb were designed and constructed. The recombinant constructs were co-transfected in CHO DG44 cell line. Stable transformants were selected on a semi solid medium. Genomic amplification with methotrexate was achieved for heavy chain gene amplification. Biological activity of produced antibody in comparison with Herceptin was tested by flow cytometry method. Results Three folds of amplification were obtained after seven rounds of methotrexate treatments. The results indicated the equal expression level of heavy and light chains. The yield of purified mAb was between 50 to 60 mg/l /day. According to the results, the produced mAb had similar affinity to HER2+ tumor cells to that of Herceptin. Conclusion High-level recombinant protein expression can be achieved by amplification of the recombinant gene with a selectable marker, such as Dihydrofolate Reductase (DHFR). It is usually accepted that DHFR gene can be amplified in DHFR- CHO cells, which consequently leads to amplification of the co-linked target gene, and finally amplification of recombinant protein. In this research, with the aim of producing a biosimilar version of herceptin, the effect of genomic amplification was investigated on the increasing the gene copy number using quantitative real-time PCR. PMID:23799177

  3. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption

    NASA Astrophysics Data System (ADS)

    Kinoshita, Manabu; McDannold, Nathan; Jolesz, Ferenc A.; Hynynen, Kullervo

    2006-08-01

    Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system. brain tumor | microbubble

  4. Mild hyperthermia influence on Herceptin® properties

    PubMed Central

    Escoffre, Jean-Michel; Deckers, Roel; Sasaki, Noboru; Bos, Clemens; Moonen, Chrit

    2015-01-01

    Background Mild hyperthermia (mHT) increases the tumor perfusion and vascular permeability, and reduces the interstitial fluid pressure, resulting in better intra-tumoral bioavailability of low molecular weight drugs. This approach is potentially also attractive for delivery of therapeutic macromolecules, such as antibodies. Here, we investigated the effects of mHT on the stability, immunological and pharmacological properties of Herceptin®, a clinically approved antibody, targeting the human epidermal growth factor receptor 2 (HER-2) overexpressed in breast cancer. Results Herceptin® was heated to 37°C (control) and 42°C (mHT) for 1 hour. Formation of Herceptin® aggregates was measured using Nile Red assay. mHT did not result in additional Herceptin® aggregates compared to 37°C, showing the Herceptin® stability is unchanged. Immunological and pharmacological properties of Herceptin® were evaluated following mHT using HER-2 positive breast cancer cells (BT-474). Exposure of Herceptin® to mHT preserved recognition and binding affinity of Herceptin® to HER-2. Western-blot and cell proliferation assays on BT-474 cells showed that mHT left the inhibitory activities of Herceptin® unchanged. Conclusions The stability, and the immunological and pharmacological properties of Herceptin® are not negatively affected by mHT. Further in-vivo studies are required to evaluate the influence of mHT on intra-tumoral bioavailability and therapeutic effectiveness of Herceptin®. PMID:25810700

  5. Cardiotoxicity of concomitant radiotherapy and trastuzumab for early breast cancer

    PubMed Central

    Marinko, Tanja; Dolenc, Jure; Bilban-Jakopin, Cvetka

    2014-01-01

    Background Trastuzumab therapy given in combination with one of several chemotherapy regimens is currently considered the standard of care for the treatment of early-stage, human epidermal growth factor receptor-2 (HER2) -positive breast cancer. The treatment with trastuzumab is due to a significant impact on the survival part of the standard adjuvant treatment of patients with HER2-positive breast cancer. Patients treated with postoperative breast or chest wall irradiation receive trastuzumab concomitant with radiotherapy. In a small proportion of patients trastuzumab causes cardiotoxicity. Preclinical findings indicate a radiosensibilizing effect of trastuzumab in breast cancer cells, but it is not yet clear whether it radiosensibilizes cells of healthy tissues too. Conclusions Special attention is required when left breast or left thoracic wall is irradiated in patient receiving trastuzumab, because long-term effects of the concurrent treatment with trastuzumab and radiotherapy are not yet known. In an era where more patients are surviving a diagnosis of breast cancer, better understanding and earlier detection of therapy-induced cardiac toxicity will be of paramount importance. PMID:24991199

  6. EGFR over-expression and activation in high HER2, ER negative breast cancer cell line induces trastuzumab resistance.

    PubMed

    Dua, Rajiv; Zhang, Jianhuan; Nhonthachit, Phets; Penuel, Elicia; Petropoulos, Chris; Parry, Gordon

    2010-08-01

    HER2 is gene amplified or over-expressed in 20-25% of breast cancers resulting in elevated HER2 activation. Trastuzumab (Herceptin), a humanized monoclonal antibody, targets activated HER2 and is clinically effective in HER2-over-expressing breast cancers. However, despite prolonged survival, treated breast cancer patients develop resistance. Resistance to trastuzumab occurs upon inactivation of HER2 regulatory proteins or upon up-regulation of alternative receptors. In particular, elevated levels of EGFR, present in estrogen receptor (ER) positive, trastuzumab-resistant BT-474 xenografts caused, a trastuzumab-resistant phenotype (Ritter et al. Clin Cancer Res 13:4909-4919, 2007). However, the role of EGFR in acquired trastuzumab resistance in ER negative cell models is not well defined. In this study, SKBR3 cell line clones expressing EGFR were generated to examine the role of EGFR over-expression on trastuzumab sensitivity in an, ER-negative breast carcinoma cell line. A stable clone, SKBR3/EGFR (clone 4) expressing moderate levels of EGFR remained sensitive to trastuzumab, whereas a stable clone, SKBR3/EGFR (clone 5) expressing high levels of EGFR, became resistant to trastuzumab. Depletion of EGFR by EGFR small-interfering RNAs in the SKBR3/EGFR (clone 5) reversed trastuzumab resistance. However, the SKBR3/EGFR (clone 5) cell line remained sensitive to lapatinib, an EGFR/HER2 inhibitor. Biochemical analysis using co-immunoprecipitation and proximity-based quantitative VeraTag assays demonstrated that high levels of EGFR phosphorylation, EGFR/EGFR homo-dimerization, and EGFR/HER2 hetero-dimerization were present in the trastuzumab-resistant cells. We conclude that EGFR over-expression can mediate trastuzumab resistance in both ER positive and ER negative cells and hypothesize that a threshold level of EGFR, in the absence of autocrine ligand production, is required to induce the resistant phenotype. PMID:19859802

  7. Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer

    PubMed Central

    Yu, Anthony F.; Yadav, Nandini U.; Lung, Betty Y.; Eaton, Anne A.; Thaler, Howard T.; Hudis, Clifford A.; Dang, Chau T.; Steingart, Richard M.

    2016-01-01

    Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (n = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p<0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p<0.0001) and trastuzumab (62 vs. 67 %, p<0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients. PMID:25552363

  8. Herceptin-geldanamycin immunoconjugates: pharmacokinetics, biodistribution, and enhanced antitumor activity.

    PubMed

    Mandler, Raya; Kobayashi, Hisataka; Hinson, Ella R; Brechbiel, Martin W; Waldmann, Thomas A

    2004-02-15

    The efficacy of monoclonal antibodies (mAbs) as single agents in targeted cancer therapy has proven to be limited. Arming mAbs with a potent toxic drug could enhance their activity. Here we report that conjugating geldanamycin (GA) to the anti-HER2 mAb Herceptin improved the activity of Herceptin. The IC(50)s of the immunoconjugate H-GA were 10-200-fold lower than that of Herceptin in antiproliferative assays, depending on the cell line. The H-GA mode of action involved HER2 degradation, which was partially lactacystin sensitive and thus proteasome dependent. The linkage between GA and Herceptin remained stable in the circulation, as suggested by the pharmacokinetics of Herceptin and conjugated GA, which were almost identical and significantly different from that of free GA. Tumor uptake of Herceptin and H-GA were similar (52 +/- 7 and 43 +/- 7% of the initial injected dose per gram tissue, respectively; P = 0.077), indicating no apparent damage attributable to conjugation. Therapy experiments in xenograft-bearing mice consisted of weekly i.p. doses, 4 mg/kg for 4 months. H-GA showed a greater antitumor effect than Herceptin because it induced tumor regression in 69% of the recipients compared with 7% by Herceptin alone. Median survival time was 145 days as opposed to 78 days, and 31% of the recipients remained tumor free 2 months after therapy was terminated versus 0% in the Herceptin group. Enhancement of Herceptin activity could be of significant clinical value. In addition, the chemical linkage and the considerations in therapeutic regimen described here could be applied to other immunoconjugates for targeted therapy of a broad spectrum of cancers. PMID:14973048

  9. Ado-trastuzumab Emtansine

    MedlinePlus

    ... following symptoms: nausea, vomiting, extreme tiredness, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, dark-colored urine, or flu-like symptoms.Ado-trastuzumab ...

  10. Quantitative Proteomics with siRNA Screening Identifies Novel Mechanisms of Trastuzumab Resistance in HER2 Amplified Breast Cancers*

    PubMed Central

    Boyer, Alaina P.; Collier, Timothy S.; Vidavsky, Ilan; Bose, Ron

    2013-01-01

    HER2 is a receptor tyrosine kinase that is overexpressed in 20% to 30% of human breast cancers and which affects patient prognosis and survival. Treatment of HER2-positive breast cancer with the monoclonal antibody trastuzumab (Herceptin) has improved patient survival, but the development of trastuzumab resistance is a major medical problem. Many of the known mechanisms of trastuzumab resistance cause changes in protein phosphorylation patterns, and therefore quantitative proteomics was used to examine phosphotyrosine signaling networks in trastuzumab-resistant cells. The model system used in this study was two pairs of trastuzumab-sensitive and -resistant breast cancer cell lines. Using stable isotope labeling, phosphotyrosine immunoprecipitations, and online TiO2 chromatography utilizing a dual trap configuration, ∼1700 proteins were quantified. Comparing quantified proteins between the two cell line pairs showed only a small number of common protein ratio changes, demonstrating heterogeneity in phosphotyrosine signaling networks across different trastuzumab-resistant cancers. Proteins showing significant increases in resistant versus sensitive cells were subjected to a focused siRNA screen to evaluate their functional relevance to trastuzumab resistance. The screen revealed proteins related to the Src kinase pathway, such as CDCP1/Trask, embryonal Fyn substrate, and Paxillin. We also identify several novel proteins that increased trastuzumab sensitivity in resistant cells when targeted by siRNAs, including FAM83A and MAPK1. These proteins may present targets for the development of clinical diagnostics or therapeutic strategies to guide the treatment of HER2+ breast cancer patients who develop trastuzumab resistance. PMID:23105007

  11. Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both HER2 dependence and immune cell infiltration.

    PubMed

    Triulzi, Tiziana; De Cecco, Loris; Sandri, Marco; Prat, Aleix; Giussani, Marta; Paolini, Biagio; Carcangiu, Marialuisa L; Canevari, Silvana; Bottini, Alberto; Balsari, Andrea; Menard, Sylvie; Generali, Daniele; Campiglio, Manuela; Di Cosimo, Serena; Tagliabue, Elda

    2015-09-29

    While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit. The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), with ERBB2 and ESR1 expression as core elements, able to identify patients with high and low risk of relapse. Application of the TRAR model to 24 HER2+ core biopsies from patients treated with neo-adjuvant trastuzumab indicated that it is predictive of trastuzumab response. Examination of TRAR in available whole-transcriptome datasets indicated that this model stratifies patients according to response to trastuzumab-based neo-adjuvant treatment but not to chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed genes of the immune response, with higher numbers of CD8-positive cells detected immunohistochemically compared to TRAR-high tumors. The TRAR model identifies tumors that benefit from trastuzumab-based treatment as those most enriched in CD8-positive immune infiltrating cells and with high ERBB2 and low ESR1 mRNA levels, indicating the requirement for both features in achieving trastuzumab response. PMID:26334217

  12. Efficacy, safety and administration timing of trastuzumab in human epidermal growth factor receptor 2 positive breast cancer patients: A meta-analysis

    PubMed Central

    CHEN, YUAN-YUAN; WANG, LIN-WEI; CHEN, FANG-FANG; WU, BI-BO; XIONG, BIN

    2016-01-01

    Trastuzumab has been demonstrated to be an effective treatment in patients with human epidermal growth factor receptor-2 (HER-2) positive breast cancer (BC); however, inconsistent results with regards to the long-term survival benefits, safety and optimal administration timing of trastuzumab exist. The present meta-analysis investigated these inconsistencies in patients with HER-2 positive BC that received adjuvant or neoadjuvant trastuzumab. Computerized and manual searches were used to identify eligible randomized control trials (RCTs) to include in the analysis. Based on a fixed or random effects model, hazard and risk ratios were calculated and used to assess the survival advantages and risks of trastuzumab. A total of 14,546 patients from 13 RCTs were included in the analysis; 9 RCTs used an adjuvant setting and 4 RCTs used a neoadjuvant setting. Analysis of RCTs with an adjuvant setting demonstrated that treatment with trastuzumab and chemotherapy in patients with HER-2 positive BC, in comparison with patients receiving chemotherapy alone, improved disease-free survival, overall survival and overall response. However, a higher incidence of neutropenia (P<0.0001), leukopenia (P<0.0001), diarrhea (P=0.002), skin/nail change (P=0.02), left ventricular ejection fraction reduction (P=0.007) and congestive heart failure (P<0.00001) was observed. Notably, the incidence of mortality and cardiac toxicity following concurrent and weekly use of trastuzumab was significantly lower compared to treatment with trastuzumab sequentially and every 3 weeks, respectively. Additionally, trastuzumab improved the pathologic complete response with no additional toxicity in the neoadjuvant setting. The present meta-analysis summarizes that trastuzumab is efficacious in patients with HER-2 positive BC in adjuvant and neoadjuvant settings. Thus, concurrent and weekly administration of trastuzumab is preferable to treatment with trastuzumab sequentially and every 3 weeks. These findings

  13. Trastuzumab-Conjugated Liposome-Coated Fluorescent Magnetic Nanoparticles to Target Breast Cancer

    PubMed Central

    Jang, Mijung; Yoon, Young Il; Kwon, Yong Soo; Yoon, Tae-Jong; Lee, Hak Jong; Hwang, Sung Il; Yun, Bo La

    2014-01-01

    Objective To synthesize mesoporous silica-core-shell magnetic nanoparticles (MNPs) encapsulated by liposomes (Lipo [MNP@m-SiO2]) in order to enhance their stability, allow them to be used in any buffer solution, and to produce trastuzumab-conjugated (Lipo[MNP@m-SiO2]-Her2Ab) nanoparticles to be utilized in vitro for the targeting of breast cancer. Materials and Methods The physiochemical characteristics of Lipo[MNP@m-SiO2] were assessed in terms of size, morphological features, and in vitro safety. The multimodal imaging properties of the organic dye incorporated into Lipo[MNP@m-SiO2] were assessed with both in vitro fluorescence and MR imaging. The specific targeting ability of trastuzumab (Her2/neu antibody, Herceptin®)-conjugated Lipo[MNP@m-SiO2] for Her2/neu-positive breast cancer cells was also evaluated with fluorescence and MR imaging. Results We obtained uniformly-sized and evenly distributed Lipo[MNP@m-SiO2] that demonstrated biological stability, while not disrupting cell viability. Her2/neu-positive breast cancer cell targeting by trastuzumab-conjugated Lipo[MNP@m-SiO2] was observed by in vitro fluorescence and MR imaging. Conclusion Trastuzumab-conjugated Lipo[MNP@m-SiO2] is a potential treatment tool for targeted drug delivery in Her2/neu-positive breast cancer. PMID:25053899

  14. Radiosensitization of Chemotherapy-Refractory, Locally Advanced or Locally Recurrent Breast Cancer With Trastuzumab: A Phase II Trial

    SciTech Connect

    Horton, Janet K.; Halle, Jan; Ferraro, Madlyn; Carey, Lisa; Moore, Dominic T.; Ollila, David; Sartor, Carolyn I.

    2010-03-15

    Purpose: Trastuzumab (Herceptin), an anti-human epidermal growth factor receptor 2 (HER2) antibody, has been shown to be an effective radiosensitizer in preclinical studies. The present Phase II trial evaluated trastuzumab plus radiotherapy in patients with HER2-positive, chemotherapy-refractory, locally advanced or locoregionally recurrent breast cancer. Methods and Materials: Eligible patients had measurable disease, normal cardiac function, and biopsy-confirmed residual HER2-positive disease. Patients received weekly trastuzumab (2 mg/kg intravenously), concurrent with radiotherapy (50 Gy) to the breast and regional lymph nodes for 5 weeks. If feasible, surgery followed radiotherapy. The primary endpoint was safety, and the secondary endpoint was efficacy (pathologic response and interval to symptomatic local progression). Results: Of the 19 patients enrolled, 7 were ineligible and received radiotherapy alone and 12 received therapy per protocol. Of these 12 patients, 11 had a Stage T4 diagnosis. Grade 3 toxicities included skin (n = 2) and lymphopenia (n = 1). One patient experienced delayed wound healing after surgery. No patients developed symptomatic cardiac dysfunction. Of the 7 patients who had undergone mastectomy, 3 (43%) had a substantial pathologic response (complete response or microscopic residual disease), significantly more than a comparison cohort (2 of 38 or 5%, p = .02). The median interval to symptomatic local progression was not reached. The median overall survival was 39 months. Conclusion: This is the first prospective trial providing evidence for a radiosensitizing effect of trastuzumab in breast cancer. The combination of trastuzumab and radiotherapy was well tolerated.

  15. Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine (T-DM1)

    PubMed Central

    Diessner, J; Bruttel, V; Stein, R G; Horn, E; Häusler, S F M; Dietl, J; Hönig, A; Wischhusen, J

    2014-01-01

    The antibody trastuzumab (Herceptin) has substantially improved overall survival for patients with aggressive HER2-positive breast cancer. However, about 70% of all treated patients will experience relapse or disease progression. This may be related to an insufficient targeting of the CD44highCD24low breast cancer stem cell subset, which is not only highly resistant to chemotherapy and radiotherapy but also a poor target for trastuzumab due to low HER2 surface expression. Hence, we explored whether the new antibody-drug conjugate T-DM1, which consists of the potent chemotherapeutic DM1 coupled to trastuzumab, could improve the targeting of these tumor-initiating or metastasis-initiating cells. To this aim, primary HER2-overexpressing tumor cells as well as HER2-positive and HER2-negative breast cancer cell lines were treated with T-DM1, and effects on survival, colony formation, gene and protein expression as well as antibody internalization were assessed. This revealed that CD44highCD24lowHER2low stem cell-like breast cancer cells show high endocytic activity and are thus particularly sensitive towards the antibody-drug conjugate T-DM1. Consequently, preexisting CD44highCD24low cancer stem cells were depleted by concentrations of T-DM1 that did not affect the bulk of the tumor cells. Likewise, colony formation was efficiently suppressed. Moreover, when tumor cells were cocultured with natural killer cells, antibody-dependent cell-mediated cytotoxicity was enhanced, and EMT-mediated induction of stem cell-like properties was prevented in differentiated tumor cells. Thus our study reveals an unanticipated targeting of stem cell-like breast cancer cells by T-DM1 that may contribute to the clinical efficacy of this recently approved antibody-drug conjugate. PMID:24675467

  16. The in vitro influences of epidermal growth factor and heregulin-β1 on the efficacy of trastuzumab used in Her-2 positive breast adenocarcinoma

    PubMed Central

    2013-01-01

    Background Human epidermal growth factor receptor-2 (Her-2) is over expressed in approximately 25-30% of all primary breast tumors resulting in a distinctive breast cancer subtype associated with a poor prognosis and a decrease in overall survival. Trastuzumab (Herceptin®), an anti-Her-2 monoclonal antibody, has dramatically altered the prognosis of Her-2 positive breast cancer. Trastuzumab is, however, associated with primary and acquired resistance. Aim and methods To investigate the in-vitro effects of trastuzumab on cell viability (tetrazolium conversion assay), cell cycling (propidium iodide staining), apoptosis (executioner caspases and annexin-V) and relative surface Her-2 receptor expression (anti-Her-2 affibody molecule) in Her-2-positive (SK-Br-3) and oestrogen receptor positive (MCF-7) breast adenocarcinoma cells and to determine potential augmentation of these effects by two endogenous ligands, epidermal growth factor (EGF) and heregulin-β1 (HRG- β1). Results Cell viability was decreased in SK-Br-3 cells by exposure to trastuzumab. This was associated with G1 accumulation and decreased relative surface Her-2 receptor density, supporting the cytostatic nature of trastuzumab in vitro. SK-Br-3 cells exposed to EGF and heregulin-β1 produced differential cell responses alone and in combination with trastuzumab, in some instances augmenting cell viability and cell cycling. Relative surface Her-2 receptor density was reduced substantially by trastuzumab, EGF and heregulin-β1. These reductions were amplified when ligands were used in combination with trastuzumab. Conclusion Cell type specific interactions of endogenous ligands appear to be dependent on absolute Her-receptor expression and cross activation of signaling pathways. This supports the notion that receptor density of Her-family members and multiplicity of growth ligands are of mutual importance in breast cancer cell proliferation and therefore also in resistance associated with trastuzumab. PMID

  17. Pertuzumab and trastuzumab: the rationale way to synergy.

    PubMed

    Richard, Sandrine; Selle, Frédéric; Lotz, Jean-Pierre; Khalil, Ahmed; Gligorov, Joseph; Soares, Daniele G

    2016-01-01

    It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast cancer patients. Despite this achievement, most patients with HER2-positive metastatic breast cancer still show progression of their disease, highlighting the need for new therapies. The continuous interest in novel targeted agents led to the development of pertuzumab, the first in a new class of agents, the HER dimerization inhibitors. Pertuzumab is a novel recombinant humanized antibody directed against extracellular domain II of HER2 protein that is required for the heterodimerization of HER2 with other HER receptors, leading to the activation of downstream signalling pathways. Pertuzumab combined with trastuzumab plus docetaxel was approved for the first-line treatment of patients with HER2-positive metastatic breast cancer and is currently used as a standard of care in this indication. In the neoadjuvant setting, the drug was granted FDA-accelerated approval in 2013. Pertuzumab is also being evaluated in the adjuvant setting. The potential of pertuzumab relies in the dual complete blockade of the HER2/3 axis when administered with trastuzumab. This paper synthetises preclinical and clinical data on pertuzumab and highlights the mechanisms underlying the synergistic activity of the combination pertuzumab-trastuzumab which are essentially due to their complementary mode of action. PMID:27275646

  18. Anthocyanins inhibit trastuzumab-resistant breast cancer in vitro and in vivo.

    PubMed

    Li, Xin; Xu, Jinmei; Tang, Xi; Liu, Yilun; Yu, Xiaoping; Wang, Zhi; Liu, Weihua

    2016-05-01

    Trastuzumab (Herceptin®) is a recombinant humanized monoclonal antibody that is targeted against the human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor. Trastuzumab has been successfully used to treat patients with HER2-positive breast cancer, which accounts for ~25% of invasive breast cancer. However, the majority of patients who initially respond to trastuzumab demonstrate disease progression within 1 year of treatment. Therefore, identifying alternative drugs that overcome trastuzumab resistance and target HER2 may increase the magnitude and duration of response. Through a high‑throughput screening approach, we previously identified numerous anthocyanins that exert activity in HER2‑positive human breast cancer cell lines. The present study aimed to evaluate the anti‑tumor properties of anthocyanins against parental HER2‑positive cells and derivative trastuzumab‑resistant cells in vitro and in vivo. Cell proliferation, western blotting, Annexin V staining, migration and invasion assays were used to determine the effects of anthocyanins in vitro. Cyanidin-3-glucoside and peonidin-3-glucoside were able to inhibit phosphorylation of HER2, induce apoptosis, suppress migration and invasion, and inhibit tumor cell growth. Coupled with the fact that anthocyanins have been used for decades as supplements for the treatment of various types of cancer in Asia, the present study may have established a framework for the development and testing of anthocyanins as a novel treatment paradigm used to overcome classical trastuzumab-resistance and to improve the outcome of this disease. PMID:26985659

  19. Bilateral inflammatory metachronic ERBB2 (HER2/neu)-positive breast carcinoma: prolonged survival with combined chemotherapy and trastuzumab.

    PubMed

    Lázaro, Alicia; Casinello, Javier; Amorós, Almudena; Heredia, Miriam; López-Alfonso, Ana

    2008-09-01

    A patient with inflammatory breast carcinoma (IBC) diagnosed in the left breast responded to cisplatin and was treated with radical mastectomy and adjuvant therapy. Two years later C-erbB2-positive IBC was diagnosed in the right breast, and was treated with mastectomy and radiotherapy. Two years later skin metastases appeared, and trastuzumab was started initially as monotherapy, and later with paclitaxel and capecitabine. More than 12 years after diagnosis and 7 years after trastuzumab was started, the patient remains in complete clinical remission on trastuzumab and capecitabine. PMID:18796377

  20. Tumour biology: Herceptin acts as an anti-angiogenic cocktail

    NASA Astrophysics Data System (ADS)

    Izumi, Yotaro; Xu, Lei; di Tomaso, Emmanuelle; Fukumura, Dai; Jain, Rakesh K.

    2002-03-01

    Malignant tumours secrete factors that enable them to commandeer their own blood supply (angiogenesis), and blocking the action of these factors can inhibit tumour growth. But because tumours may become resistant to treatments that target individual angiogenic factors by switching over to other angiogenic molecules, a cocktail of multiple anti-angiogenic agents should be more effective. Here we show that herceptin, a monoclonal antibody against the cell-surface receptor HER2 (for human epidermal growth factor receptor-2; ref. 4), induces normalization and regression of the vasculature in an experimental human breast tumour that overexpresses HER2 in mice, and that it works by modulating the effects of different pro- and anti-angiogenic factors. As a single agent that acts against multiple targets, herceptin, or drugs like it, may offer a simple alternative to combination anti-angiogenic treatments.

  1. Identification of caveolin-1 as a potential causative factor in the generation of trastuzumab resistance in breast cancer cells.

    PubMed

    Sekhar, Sreeja C; Kasai, Tomonari; Satoh, Ayano; Shigehiro, Tsukasa; Mizutani, Akifumi; Murakami, Hiroshi; El-Aarag, Bishoy Ya; Salomon, David S; Massaguer, Anna; de Llorens, Rafael; Seno, Masaharu

    2013-01-01

    The oncogenic tyrosine kinase receptor ErbB2 is a prognostic factor and target for breast cancer therapeutics. In contrast with the other ErbB receptors, ErbB2 is hardly internalized by ligand induced mechanisms, indicating a prevalent surface expression. Elevated levels of ErbB2 in tumor cells are associated with its defective endocytosis and down regulation. Here we show that caveolin-1 expression in breast cancer derived SKBR-3 cells (SKBR-3/Cav-1) facilitates ligand induced ErbB2 endocytosis using an artificial peptide ligand EC-eGFP. Similarly, stimulation with humanized anti ErbB2 antibody Trastuzumab (Herceptin) was found to be internalized and co-localized with caveolin-1 in SKBR-3/Cav-1 cells. Internalized EC-eGFP and Trastuzumab in SKBR-3/Cav-1 cells were then delivered via caveolae to the caveolin-1 containing early endosomes. Consequently, attenuated Fc receptor mediated ADCC functions were observed when exposed to Trastuzumab and EC-Fc (EC-1 peptide conjugated to Fc part of human IgG). On the other hand, this caveolae dependent endocytic synergy was not observed in parental SKBR-3 cells. Therefore, caveolin-1 expression in breast cancer cells could be a predictive factor to estimate how cancer cells are likely to respond to Trastuzumab treatment. PMID:23833684

  2. The chemomodulatory effects of resveratrol and didox on herceptin cytotoxicity in breast cancer cell lines

    PubMed Central

    Abdel-Latif, Ghada A.; Al-Abd, Ahmed M.; Tadros, Mariane G.; Al-Abbasi, Fahad A.; Khalifa, Amany E.; Abdel-Naim, Ashraf B.

    2015-01-01

    Herceptin is considered an essential treatment option for double negative breast cancer. Resveratrol and didox are known chemopreventive agents with potential anticancer properties. The aim of the current study is to investigate the influence of resveratrol and didox on the cytotoxicity profile of herceptin in HER-2 receptor positive and HER-2 receptor negative breast cancer cell lines (T47D and MCF-7 cell lines, respectively). The IC50’s of herceptin in T47D and MCF-7 were 0.133 ± 0.005 ng/ml and 23.3795 ± 1.99 ng/ml respectively. Equitoxic combination of herceptin with resveratrol or didox in T47D significantly reduced the IC50 to 0.052 ± 0.001 and 0.0365 ± 0.001 ng/ml, respectively and similar results were obtained in MCF-7. The gene expression of BCL-xl was markedly decreased in T47D cells following treatment with herceptin/resveratrol compared to herceptin alone. Immunocytochemical staining of HER-2 receptor in T47D cells showed a significant reduction after treatment with herceptin/resveratrol combination compared to herceptin alone. On the contrary, herceptin/didox combination had no significant effect on HER-2 receptor expression. Cell cycle analysis showed an arrest at G2/M phase for both cell lines following all treatments. In conclusion, herceptin/resveratrol and herceptin/didox combinations improved the cytotoxic profile of herceptin in both T47D and MCF-7 breast cancer cell lines. PMID:26156237

  3. Improving Trastuzumab's Stability Profile by Removing the Two Degradation Hotspots.

    PubMed

    Yang, Yuemei; Zhao, Jian; Geng, Shusheng; Hou, Chunmei; Li, Xingyin; Lang, Xiaoling; Qiao, Chunxia; Li, Yan; Feng, Jiannan; Lv, Ming; Shen, Beifen; Zhang, Boyan

    2015-06-01

    Stability of recombinant monoclonal antibodies (mAbs) is essential for their clinical application. The presence of the two degradation hotspots, namely, LC-Asn30 and HC-Asp102, in its complementary determinant regions prevents trastuzumab (Herceptin®) from being supplied in a drug product format of liquid formulation. To improve the stability, a new antibody was created by replacing the two residues with chemically similar amino acids of LC-Gln30 and HC-Glu102. This new mAb, named as T-mAb2, exhibited a simple and more uniform charge heterogeneity profile than T-mAb1, which is trastuzumab made in our laboratory, as displayed by the difference between their main peak area percentages (82.9% for T-mAb2 vs. 60.5% for T-mAb1). Computer modeling results, physicochemical and biological characterization, and stability profiling studies on T-mAb2 and T-mAb1 demonstrated that stability of T-mAb2 was significantly improved. In comparison with T-mAb1, although its in vitro human epidermal growth factor receptor 2 (HER2)-target binding activities were reduced slightly, in vivo tumor growth inhibiting activity was not affected, as demonstrated by the study results using the SKOV3 xenograft mouse model. Hence, a new anti-HER2 antibody was generated with improved stability that could be used to produce the drug product in liquid formulation for cost saving and more convenient usage. PMID:25820189

  4. SRL172 (killed Mycobacterium vaccae) may augment the efficacy of trastuzumab in metastatic breast cancer patients.

    PubMed

    Altundag, Kadri; Mohamed, Ali-Seyed; Altundag, Ozden; Silay, Yavuz Selim; Gunduz, Esra; Demircan, Kadir

    2005-01-01

    SRL172, non-specific immunological adjuvant downregulates interleukin-4, upregulates interleukin-2 production, switching towards a T-helper-1 response, induces an increase in natural killer cells and activates antigen presenting cells. The human epidermal growth factor receptor 2 gene amplification is frequently observed in a number of primary tumors, suggesting that the overexpression of this growth factor receptor may contribute to transformation and tumorigenesis. Gene amplification occurs in approximately 15-20% of human breast cancers Amplification is associated with aggressive tumor behavior and shortened survival. Trastuzumab, humanized anti-HER-2 antibody targets the HER-2 protein with high affinity. Trastuzumab when used alone or in combination with cytotoxic chemotherapy can induce reasonably durable remissions in a significant percentage of women with metastatic breast cancer whose tumors demonstrate Her-2/neu gene amplification. One of the proposed mechanisms of trastuzumab antitumor action is through antibody dependent cellular cytotoxocity. Pivotal study showed that Trastuzumab+IL-2 resulted in NK cell expansion with enhanced in vitro targeted killing of HER-2-expressing cells. SRL172 by increasing IL-2 production and number of natural killer cells may augment the efficacy of trastuzumab in metastatic breast cancer patients. SRL 172 increases IL-2 production and the number of NK cells in vivo. Based on these data, a clinical trial can be performed to test whether SRL 172 added to trastuzumab is safe and more efficacious. PMID:15607548

  5. IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

    SciTech Connect

    Jia, Yanhan; Zhang, Yan; Qiao, Chunxia; Liu, Guijun; Zhao, Qing; Zhou, Tingting; Chen, Guojiang; Li, Yali; Feng, Jiannan; Li, Yan; Zhang, Qiuping; Peng, Hui

    2013-07-12

    Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer.

  6. Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer.

    PubMed

    Kono, Koji; Takahashi, Akihiro; Ichihara, Fumiko; Sugai, Hidemitsu; Fujii, Hideki; Matsumoto, Yoshirou

    2002-10-15

    The humanized monoclonal antibody Herceptin, which specifically targets HER-2/neu, exhibits growth inhibitory activity against HER-2/neu-overexpressing tumors and is approved for therapeutic use with proved survival benefit in patients with HER-2/neu-positive breast cancer. In the present study, we investigated whether Herceptin could affect the HER-2/neu-overexpressing gastric cancer cells based on antibody-dependent cell-mediated cytotoxicity (ADCC) and compared immune effector cells from gastric cancer patients with normal individuals on ADCC. HER-2/neu-expressing gastric cancer cells could be killed by Herceptin-mediated ADCC and the Herceptin-induced ADCC correlated with the degree of HER-2/neu expression on the gastric cancer cells. However, the Herceptin-mediated ADCC was significantly impaired in peripheral blood mononuclear cells from advanced disease patients (n = 10) compared with that in early disease (n = 12; P = 0.04) or healthy individuals (n = 10, P = 0.02). Moreover, natural killer (NK) cells purified from patients with advanced disease indicated less Herceptin-mediated ADCC in comparison with that from healthy donors (P = 0.04), whereas monocytes purified from the patients showed an almost equal amount of Herceptin-mediated ADCC in comparison with that from healthy individuals, indicating that NK cell dysfunction contributed to the impaired Herceptin-mediated ADCC in gastric cancer patients. Furthermore, the NK-cell dysfunction on Herceptin-mediated ADCC correlated with the down-regulation of CD16zeta expression in the patients, and interleukin 2 ex vivo treatment of NK cells could restore the impairment of Herceptin-mediated ADCC, concomitant to the normalization of the expression of CD16zeta molecules. Thus, some modalities such as interleukin 2 treatment aimed at reversing NK dysfunction may be necessary for successful Herceptin treatment of gastric cancer. PMID:12384543

  7. The Promher Study: An Observational Italian Study on Adjuvant Therapy for HER2-Positive, pT1a-b pN0 Breast Cancer

    PubMed Central

    Gori, Stefania; Inno, Alessandro; Fiorio, Elena; Foglietta, Jennifer; Ferro, Antonella; Gulisano, Marcella; Pinotti, Graziella; Gubiotti, Marta; Cavazzini, Maria Giovanna; Turazza, Monica; Duranti, Simona; De Simone, Valeria; Iezzi, Laura; Bisagni, Giancarlo; Spazzapan, Simon; Cavanna, Luigi; Saggia, Chiara; Bria, Emilio; Cretella, Elisabetta; Vici, Patrizia; Santini, Daniele; Fabi, Alessandra; Garrone, Ornella; Frassoldati, Antonio; Amaducci, Laura; Saracchini, Silvana; Evangelisti, Lucia; Barni, Sandro; Gamucci, Teresa; Mentuccia, Lucia; Laudadio, Lucio; Zoboli, Alessandra; Marchetti, Fabiana; Bogina, Giuseppe; Lunardi, Gianluigi; Boni, Luca

    2015-01-01

    Background The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients. Methods Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted. Results Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p<0.001). Conclusions The majority of patients (66%) with pT1a-b pN0 HER2-positive breast cancer enrolled in this retrospective study received adjuvant systemic therapy with trastuzumab, whereas only 11% patients did not receive any adjuvant systemic therapy. The choice of treatment type seems to be mainly influenced by tumor size, proliferation index, hormone receptor status and age. The 5-year DFS probability was significantly higher for patients receiving adjuvant systemic therapy with trastuzumab compared with patients not receiving adjuvant

  8. Barriers to the Use of Trastuzumab for HER2+ Breast Cancer and the Potential Impact of Biosimilars: A Physician Survey in the United States and Emerging Markets.

    PubMed

    Lammers, Philip; Criscitiello, Carmen; Curigliano, Giuseppe; Jacobs, Ira

    2014-01-01

    Trastuzumab in combination with chemotherapy has become a standard of care for patients with HER2+ breast cancer. The cost of therapy, however, can limit patient access to trastuzumab in areas with limited financial resources for treatment reimbursement. This study examined access to trastuzumab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia and Brazil via physician survey. The study also investigated if the availability of a biosimilar to trastuzumab would improve access to and use of HER2 monoclonal antibody therapy. Across all countries, a subset of oncologists reported barriers to the use of trastuzumab in a neoadjuvant, adjuvant or metastatic setting. Common barriers to the use of trastuzumab included issues related to insurance coverage, drug availability and cost to the patient. Overall, nearly half of oncologists reported that they would increase the use of HER2 monoclonal antibody therapy across all treatment settings if a lower cost biosimilar to trastuzumab were available. We conclude that the introduction of a biosimilar to trastuzumab may alleviate cost-related barriers to treatment and could increase patient access to HER2-directed therapy in all countries examined. PMID:25232798

  9. Treatment of early-stage human epidermal growth factor 2-positive cancers among medicare enrollees: age and race strongly associated with non-use of trastuzumab.

    PubMed

    Vaz-Luis, Ines; Lin, Nancy U; Keating, Nancy L; Barry, William T; Lii, Joyce; Burstein, Harold J; Winer, Eric P; Freedman, Rachel A

    2016-08-01

    Adjuvant trastuzumab for human epidermal growth factor receptor-2 (HER2)-positive breast cancer is highly efficacious regardless of age. Recent data suggested that many older patients with HER2-positive disease do not receive adjuvant trastuzumab. Nevertheless, some of this 'under-treatment' may be clinically appropriate. We used Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify patients aged ≥ 66 with stage ≥ Ib-III, HER2-positive breast cancer diagnosed during 2010-2011 (HER2 status available) who did not have a history of congestive heart failure. We described all systemic treatments received and sociodemographic and clinical characteristics associated with treatment patterns. Among 770 women 44.4 % did not receive trastuzumab, including 21.8 % who received endocrine therapy only, 6.3 % who received chemotherapy (±endocrine therapy) and 16.2 % who did not receive any systemic therapy. In addition to age and grade, race was strongly associated with non-use of trastuzumab (64.4 % of Non-Hispanic blacks vs. 43.6 % of whites did not receive trastuzumab, adjusted ORNon-Hispanic black vs. white = 3.14, 95 %CI = 1.38-7.17), and many patients with stage III disease did not receive trastuzumab. Further, 16.2 % of patients did not receive any systemic treatment and this occurred more frequently for black patients. Over 40 % of older patients with indication to receive adjuvant trastuzumab did not receive it and nearly 20 % of these patients did not receive any other treatment. Although treatment omission may be appropriate in some cases, we observed concerning differences in trastuzumab receipt, particularly for black women. Strategies to optimize care for older patients and to eliminate treatment disparities are urgently needed. PMID:27484879

  10. Trial Validates Biosimilar for Trastuzumab.

    PubMed

    2016-07-01

    Preliminary data from the phase III Heritage trial suggest that a biosimilar to trastuzumab, MYL-14010, is just as safe and effective as its brand-name equivalent for women with HER2-positive advanced breast cancer. The findings, presented during the annual meeting of the American Society of Clinical Oncology in June, may pave the way for the first FDA-approved biosimilar for cancer. PMID:27277256

  11. [A case of HER2-positive metastatic breast cancer responding to trastuzumab plus gemcitabine combination therapy].

    PubMed

    Sugie, Tomoharu; Nagai, Toshihiro; Ohgaki, Kazuhisa

    2008-04-01

    A 60-year-old woman was admitted to the hospital with left thigh pain. She had undergone mastectomy and axillary lymph node dissection for right breast cancer (T3N2M0) five years and two months earlier. The pathological diagnosis then was invasive ductal carcinoma with axillaryly mph node metastases. Hormone receptors and HER2 status were negative and positive (3+), respectively. The patient received adjuvant chemotherapy and radiotherapy, but bone metastases appeared 18 months after surgery. Although trastuzumab-combination chemotherapy with taxane and/or capecitabine was given, bone metastases in thoracic vertebra resulted in incomplete paralysis in both legs. She underwent thoraco-lumbar vertebral fixation 10 months before admission. A PET/CT revealed multiple bone metastases in the left femur as well as vertebrae, and CEA rose markedly. She received radiotherapy and trastuzumab monotherapy in addition to bisphosphonate. Temporarily, CEA decreased, but because recurrence nests were recognized in the supraclavicle and mediastinum after the eight-month treatment, trastuzumab monotherapy was followed by trastuzumab plus vinorelbine combined therapy. This regimen markedly reduced CEA after three months, but it rose again over the following three months. As S-1-combined therapy was not effective, trastuzumab+gemcitabine (1 g/week and two weeks on/one week off) combined therapy was started. CEA decreased markedly after 4 cycles, and FDG accumulation in the recurrence region was markedly improved. The adverse event during this treatment was minor, and PS was sufficiently maintained. These results suggest that trastuzumab plus gemcitabine combination therapy is effective for HER2-positive metastatic breast cancer. PMID:18408445

  12. Radiation recall dermatitis induced by trastuzumab.

    PubMed

    Moon, Dochang; Koo, Ja Seung; Suh, Chang-Ok; Yoon, Chang Yun; Bae, Jaehyun; Lee, Soohyeon

    2016-01-01

    We report a case of radiation recall dermatitis caused by trastuzumab. A 55-year-old woman with metastatic breast cancer received palliative first-line trastuzumab/paclitaxel and a salvage partial mastectomy with lymph node dissection was subsequently performed. In spite of the palliative setting, the pathology report indicated that no residual carcinoma was present, and then she underwent locoregional radiotherapy to ensure a definitive response. After radiotherapy, she has maintained trastuzumab monotherapy. Nine days after the fifth cycle of trastuzumab monotherapy, dermatitis in previously irradiated skin developed, with fever. Radiation recall dermatitis triggered by trastuzumab is extremely rare. A high fever developed abruptly with a skin rash. This may be the first case of this sort to be reported. PMID:23543400

  13. Resistance to Trastuzumab in Breast Cancer.

    PubMed

    Pohlmann, Paula R; Mayer, Ingrid A; Mernaugh, Ray

    2009-12-15

    HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20 to 25% of invasive breast cancers. It can be therapeutically targeted by trastuzumab, a humanized IgG1 kappa light chain monoclonal antibody. Although trastuzumab is currently considered one of the most effective treatments in oncology, a significant number of patients with HER2-overexpressing breast cancer do not benefit from it. Understanding the mechanisms of action and resistance to trastuzumab is therefore crucial for the development of new therapeutic strategies. This review discusses proposed trastuzumab mode of action as well as proposed mechanisms for resistance. Mechanisms for resistance are grouped into four main categories: (1) obstacles preventing trastuzumab binding to HER2; (2) upregulation of HER2 downstream signaling pathways; (3) signaling through alternate pathways; and (4) failure to trigger an immune-mediated mechanism to destroy tumor cells. These potential mechanisms through which trastuzumab resistance may arise have been used as a guide to develop drugs, presently in clinical trials, to overcome resistance. The mechanisms conferring trastuzumab resistance, when completely understood, will provide insight on how best to treat HER2-overexpressing breast cancer. The understanding of each mechanism of resistance is therefore critical for the educated development of strategies to overcome it, as well as for the development of tools that would allow definitive and efficient patient selection for each therapy. (Clin Cancer Res 2009;15(24):7479-91). PMID:20008848

  14. Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

    PubMed Central

    Palmieri, Carlo; Macpherson, Iain RJ; Yan, Kelvin; Ades, Felipe; Riddle, Pippa; Ahmed, Riz; Owadally, Waheeda; Stanley, Barbara; Shah, Deep; Gojis, Ondrej; Januszewski, Adam; Lewanski, Conrad; Asher, Rebecca; Lythgoe, Daniel; de Azambuja, Evandro; Beresford, Mark; Howell, Sacha J.

    2016-01-01

    Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC. PMID:26334099

  15. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

    PubMed

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul

    2016-08-01

    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies. PMID:27357488

  16. Skin/nail infections with the addition of pertuzumab to trastuzumab-based chemotherapy.

    PubMed

    Mortimer, Joanne; Jung, Jae; Yuan, Yuan; Kruper, Laura; Stewart, Daphne; Chung, Samuel; Yu, Kim Wai; Mendelsohn, Mary; D'Apuzzo, Massimo; Tegtmeier, Bernard; Dadwal, Sanjeet

    2014-12-01

    We report a series of breast cancer patients with invasive skin and nail infections with Staphylococcus species that we attribute to the addition of pertuzumab to trastuzumab-based therapy. With the suspicion of an increased incidence of cutaneous infection in patients treated with pertuzumab and trastuzumab-based chemotherapy, treating medical oncologists identified patients receiving therapy who experienced infection. Between March and October 2014, 18 patients treated with pertuzumab and trastuzumab-based chemotherapy were found to have 21 separate skin/nail infections. Treatment was administered as neoadjuvant therapy in 12 (67%) patients, adjuvant therapy in four (22%) patients, and for metastatic disease in two (11%) patients. Granulocyte growth factors were administered in 11 (61%) patients and no patients were documented to be neutropenic. New skin and nail lesions developed as early as cycle 1 and as late as 8 months from initial therapy. The 21 separate infections documented were folliculitis and "bite-like" lesions (10), abscess (6), paronychia (3), and cellulitis (2). The appearance of these lesions was distinct from typical EGFR-associated skin changes. When cultures were obtained, Staphylococcus species were isolated. Quantitative immunoglobulins were assessed in 14 (78%) patients and were abnormally low in six (43%) of these patients. The skin infections resulted in treatment delay in two (11%) patients and premature discontinuation of therapy in one patient. We believe that the skin/nail infections reported here in patients treated with the combination of pertuzumab and trastuzumab represent a previously unrecognized toxicity of adding pertuzumab to trastuzumab-based therapies. PMID:25385180

  17. Safety and Tolerability of Docetaxel, Cyclophosphamide, and Trastuzumab Compared to Standard Trastuzumab-Based Chemotherapy Regimens for Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

    PubMed Central

    Jitawatanarat, Potjana; O'Connor, Tracey L.; Kossoff, Ellen B.; Levine, Ellis G.; Chittawatanarat, Kaweesak

    2014-01-01

    Purpose We evaluated the tolerability and cardiac safety of docetaxel, cyclophosphamide, and trastuzumab (TCyH) for the treatment of early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared to the standard trastuzumab-based chemotherapy regimens doxorubicin with cyclophosphamide followed by paclitaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCaH). Methods We retrospectively reviewed early-stage, resectable, HER2-positive breast cancer patients treated with trastuzumab-based chemotherapy at a single comprehensive cancer center between 2004 and 2011. Patient characteristics, comorbidities, relative dose intensity (RDI) of each regimen, tolerability, and cardiac toxicity were evaluated. Results One hundred seventy-seven patients were included in the study (AC-TH, n=114; TCaH, n=39; TCyH, n=24). TCyH was solely administered in the adjuvant setting, whereas two-thirds of the AC-TH and TCaH groups were administered postoperatively. Patients treated with TCyH tended to have a more significant underlying cardiac history, higher Charlson comorbidity index, and were of an earlier stage. All patients treated with TCyH received granulocyte colony stimulating factor primary prophylaxis. No febrile neutropenia or grade ≥3 hematologic toxicity was observed in the TCyH group as compared to the AC-TH and TCaH groups. There were no significant differences in the rates of early termination, hospitalization, dose reduction, or RDI between the regimens. The symptomatic congestive heart failure rate between AC-TH, TCaH, and TCyH groups was not significantly different (4.4% vs. 2.6% vs. 8.3%, respectively, p=0.57). There was also no significant difference in the rate of early trastuzumab termination between patients treated with each regimen. Conclusion TCyH is well tolerated and should be investigated as an alternative adjuvant chemotherapy option for patients who are not candidates for standard trastuzumab

  18. Superior antitumor activity of trastuzumab combined with capecitabine plus oxaliplatin in a human epidermal growth factor receptor 2-positive human gastric cancer xenograft model

    PubMed Central

    HARADA, SUGURU; YANAGISAWA, MIEKO; KANEKO, SAORI; YOROZU, KEIGO; YAMAMOTO, KANAME; MORIYA, YOICHIRO; HARADA, NAOKI

    2015-01-01

    In the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction cancer, it has been reported that the combination of trastuzumab with capecitabine plus cisplatin, or with 5-fluorouracil (5-FU) plus cisplatin, significantly increased overall survival compared with chemotherapy alone (ToGA trial). In addition, adjuvant therapy with capecitabine plus oxaliplatin (XELOX) improved the survival of patients who received curative D2 gastrectomy (CLASSIC trial). However, the efficacy of the combination of trastuzumab with XELOX for patients with HER2-positive gastric cancer remains unknown. The aim of this study, was to investigate the efficacy of the combination of trastuzumab with XELOX in a HER2-positive human gastric cancer xenograft model. Combination treatment with these three agents (trastuzumab 20 mg/kg, capecitabine 359 mg/kg and oxaliplatin 10 mg/kg), was found to exhibit a significantly stronger antitumor activity in NCI-N87 xenografts compared with either trastuzumab or XELOX alone. In this model, treatment with trastuzumab alone or trastuzumab plus oxaliplatin enhanced the expression of thymidine phosphorylase (TP), a key enzyme in the generation of 5-FU from capecitabine in tumor tissues. In in vitro experiments, trastuzumab induced TP mRNA expression in NCI-N87 cells. In addition, NCI-N87 cells co-cultured with the natural killer (NK) cell line CD16(158V)/NK-92 exhibited increased expression of TP mRNA. When NCI-N87 cells were cultured with CD16(158V)/NK-92 cells in the presence of trastuzumab, the mRNA expression of cytokines reported to have the ability to induce TP was upregulated in tumor cells. Furthermore, a medium conditioned by CD16(158V)/NK-92 cells also upregulated the expression of TP mRNA in NCI-N87 cells. These results suggest that trastuzumab promotes TP expression, either by acting directly on NCI-N87 cells, or indirectly via a mechanism that includes trastuzumab-mediated interactions

  19. The debate about the funding of Herceptin: a case study of 'countervailing powers'.

    PubMed

    Gabe, Jonathan; Chamberlain, Kerry; Norris, Pauline; Dew, Kevin; Madden, Helen; Hodgetts, Darrin

    2012-12-01

    In December 2008 the newly elected Prime Minister of New Zealand bypassed the agency that negotiates with manufacturers about the cost of medicines and agreed to fund Herceptin for women with early stage breast cancer for a twelve months course of treatment. This paper describes the unfolding of this decision and seeks to explain it in terms of the theory of countervailing powers, which has recently been applied to understand the rapid growth of medicines and the governance of the pharmaceutical industry. We explore the role of various actors in this debate about Herceptin funding, drawing on documentary analysis based on a systematic search of journals, websites and media databases. The case of Herceptin both confirms and questions the propositions of countervailing powers theory. On the one hand the manufacturers of the drug proved to be highly influential in their attempts to get Herceptin funded and were generally supported by consumer groups. On the other hand some scientists and regulators attempted to challenge the power of the manufacturers, with the regulators not showing signs of corporate bias as one might expect. Groups did not, as has been proposed, exert power monolithically, with several groups exhibiting opposing factions. The media, ignored in this literature, are considered as a potential countervailing force in the debate. In the end the government bypassed the recommendation of its regulators, thereby undermining the latter's efforts to act as a countervailing power. PMID:23036988

  20. In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib.

    PubMed

    Chakraborty, Ashok K; Zerillo, Cynthia; DiGiovanna, Michael P

    2015-08-01

    The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile. PMID:26195122

  1. Novel approaches to target HER2-positive breast cancer: trastuzumab emtansine

    PubMed Central

    Recondo, Gonzalo; de la Vega, Maximo; Galanternik, Fernando; Díaz-Cantón, Enrique; Leone, Bernardo Amadeo; Leone, José Pablo

    2016-01-01

    The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer. PMID:27274311

  2. [Adjuvant drug therapies for breast cancer].

    PubMed

    Huovinen, Riikka; Auvinen, Päivi; Mattson, Johanna; Joensuu, Heikki

    2015-01-01

    Most breast cancers are hormone receptor positive and exhibit a slow growth pattern. Based on biological properties, breast cancers are divided into four different biological subtypes. Furthermore, these subtypes are indicative of the risk of recurrence, which is also influenced by the size of the tumor and extension to lymph nodes. Postoperative adjuvant drug therapy is chosen on the basis of the biological type. Chemotherapy can be used in all subtypes. Hormonal therapies are used exclusively for the treatment of hormone receptor positive breast cancer. Trastuzumab antibody belongs to the treatment of the HER2 positive subtype. PMID:26245052

  3. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer.

    PubMed

    O'Shaughnessy, Joyce A; Vukelja, Sasha; Marsland, Thomas; Kimmel, Gary; Ratnam, Suresh; Pippen, John E

    2004-06-01

    We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy. PMID:15245619

  4. Immunoselection of breast and ovarian cancer cells with trastuzumab and natural killer cells: selective escape of CD44high/CD24low/HER2low breast cancer stem cells.

    PubMed

    Reim, Florian; Dombrowski, Yvonne; Ritter, Cathrin; Buttmann, Mathias; Häusler, Sebastian; Ossadnik, Monika; Krockenberger, Mathias; Beier, Dagmar; Beier, Christoph P; Dietl, Johannes; Becker, Jürgen C; Hönig, Arnd; Wischhusen, Jörg

    2009-10-15

    Although trastuzumab (Herceptin) has substantially improved the overall survival of patients with mammary carcinomas, even initially well-responding tumors often become resistant. Because natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) is thought to contribute to the therapeutic effects of trastuzumab, we have established a cell culture system to select for ADCC-resistant SK-OV-3 ovarian cancer and MCF7 mammary carcinoma cells. Ovarian cancer cells down-regulated HER2 expression, resulting in a more resistant phenotype. MCF7 breast cancer cells, however, failed to develop resistance in vitro. Instead, treatment with trastuzumab and polyclonal NK cells resulted in the preferential survival of individual sphere-forming cells that displayed a CD44(high)CD24(low) "cancer stem cell-like" phenotype and expressed significantly less HER2 compared with non-stem cells. Likewise, the CD44(high)CD24(low) population was also found to be more immunoresistant in SK-BR3, MDA-MB231, and BT474 breast cancer cell lines. When immunoselected MCF7 cells were then re-expanded, they mostly lost the observed phenotype to regenerate a tumor cell culture that displayed the initial HER2 surface expression and ADCC-susceptibility, but was enriched in CD44(high)CD24(low) cancer stem cells. This translated into increased clonogenicity in vitro and tumorigenicity in vivo. Thus, we provide evidence that the induction of ADCC by trastuzumab and NK cells may spare the actual tumor-initiating cells, which could explain clinical relapse and progress. Moreover, our observation that the "relapsed" in vitro cultures show practically identical HER2 surface expression and susceptibility toward ADCC suggests that the administration of trastuzumab beyond relapse might be considered, especially when combined with an immune-stimulatory treatment that targets the escape variants. PMID:19826050

  5. The Clinical Efficacy and Cardiotoxicity of Fixed-Dose Monthly Trastuzumab in HER2-Positive Breast Cancer: A Single Institutional Analysis

    PubMed Central

    Tsai, Tsung-Neng; Chen, Jia-Hong; Dai, Ming-Shen; Chang, Ping-Ying; Ho, Ching-Liang; Ye, Ren-Hua; Chung, Tsai-Rong; Chen, Yeu-Chin; Chao, Tsu-Yi

    2016-01-01

    Objective Trastuzumab-containing treatment regimens have been shown to improve survival outcomes in HER2-positive breast cancer (BC). It is much easier to infuse a fixed one-vial dose to every patient on a regular schedule in the general clinical setting. The aims of this study were evaluating the efficacy of a 440 mg fixed-dose of trastuzumab administered on a monthly infusion schedule, and the risk factors for cardiac events. Patients and methods We retrospectively reviewed data from 300 HER2-positive BC patients in our institute: 208 were early-stage BC patients undergoing adjuvant trastuzumab treatment, and 92 were metastatic BC patients treated with trastuzumab infusions until disease progression. There were 181 patients receiving regular trastuzumab infusions every 3 weeks (Q3W; 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks), and the other 119 patients were treated monthly with a fixed 440 mg dose (QM; fixed 440 mg every 4 weeks). Results The medians of progression-free survival (PFS) and overall survival (OS) in the adjuvant setting were not reached in both treatment groups. In the metastatic setting, there was no significant difference between groups in PFS or OS. The median time to significant cardiovascular (CV) dysfunction was 4.54 months. The incidence of congestive heart failure requiring medication in our cohort was 3.4%. Conclusion In our study, we found that fixed-dose monthly trastuzumab was feasible and effective. In addition, the CV risk was not higher with the fixed-dose protocol. This treatment modality could lower the cost and was easier to implement in clinical practice. Larger prospective randomized studies with longer-term follow up are needed to confirm our results. PMID:26953588

  6. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer

    PubMed Central

    Baselga, J.; Manikhas, A.; Cortés, J.; Llombart, A.; Roman, L.; Semiglazov, V. F.; Byakhov, M.; Lokanatha, D.; Forenza, S.; Goldfarb, R. H.; Matera, J.; Azarnia, N.; Hudis, C. A.; Rozencweig, M.

    2014-01-01

    Background Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet®) in combination with trastuzumabHerceptin® (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. Patients and Methods Patients were randomly assigned to NPLD (M, 50 mg/m2 every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m2 weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). Results One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47–0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42–0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. Conclusion(s) The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. Clinical trial number NCT00294996. PMID:24401928

  7. The socio-economical impact of intravenous (IV) versus subcutaneous (SC) administration of trastuzumab: future prospectives.

    PubMed

    Papadmitriou, K; Trinh, X B; Altintas, S; Van Dam, P A; Huizing, M T; Tjalma, W A A

    2015-01-01

    Trastuzumab was the first targeted therapy for HER2 positive breast cancer. It has become the standard of care for HER2 positive metastatic breast cancer since 2000 and in the adjuvant setting since 2006. Adjuvant it is given for a year and in patients with metastatic disease until progression. The standard mode of administration is intravenous. Recently a subcutaneous form has become available. A phase III study showed that there is no difference between the intravenous and subcutaneous form in terms of safety and efficacy. The patient's preference however significantly favoured the subcutaneous form. It is estimated that the use of the SC form could contribute to a cost saving between 758 and 2576 euro per annual course. For Belgium alone this could mean an estimated saving of 1.4 to 4.6 million euros per year. The potential benefit of the SC administration for healthcare facilities could be further increased when applied in a LEAN working day-care chemotherapy unit. After reviewing the existing literature we suggest to further validate the potential financial impact of SC trastuzumab compared to the traditional IV form and to introduce a scientific proposal incorporating the benefits of this formulation in a LEAN working healthcare unit. PMID:26977267

  8. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

    PubMed

    Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

    2013-10-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab. PMID:24009064

  9. Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer

    PubMed Central

    Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Slamon, Dennis; McGowan, Patricia; Duffy, Michael J.

    2013-01-01

    Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab. PMID:24009064

  10. Internalization: acute apoptosis of breast cancer cells using herceptin-immobilized gold nanoparticles

    PubMed Central

    Rathinaraj, Pierson; Al-Jumaily, Ahmed M; Huh, Do Sung

    2015-01-01

    Herceptin, the monoclonal antibody, was successfully immobilized on gold nanoparticles (GNPs) to improve their precise interactions with breast cancer cells (SK-BR3). The mean size of the GNPs (29 nm), as determined by dynamic light scattering, enlarged to 82 nm after herceptin immobilization. The in vitro cell culture experiment indicated that human skin cells (FB) proliferated well in the presence of herceptin-conjugated GNP (GNP–Her), while most of the breast cancer cells (SK-BR3) had died. To elucidate the mechanism of cell death, the interaction of breast cancer cells with GNP–Her was tracked by confocal laser scanning microscopy. Consequently, GNP–Her was found to be bound precisely to the membrane of the breast cancer cell, which became almost saturated after 6 hours incubation. This shows that the progression signal of SK-BR3 cells is retarded completely by the precise binding of antibody to the human epidermal growth factor receptor 2 receptor of the breast cancer cell membrane, causing cell death. PMID:25709498

  11. Trastuzumab for Her2/neu-positive metastatic salivary gland carcinoma: Case report and review of the literature

    PubMed Central

    Firwana, Belal; Atassi, Bassel; Hasan, Rim; Hasan, Nour; Sukari, Ammar

    2012-01-01

    Salivary gland carcinomas metastasize to distant organs in 20% of salivary gland malignancies. Applying immunohistochemistry (IHC) measures, salivary gland tumors showed a wide range of oncogene markers expression, including the human epidermoid receptor 2 (Her2/neu), which could be targeted with monoclonal antibody. Treating salivary gland tumors, which have Her2/neu over-expression, with trastuzumab was reported in a few case reports. We report a 61-year-old Caucasian male, with a history of salivary gland tumor, who presented after 20 years of complete surgical resection with kidney mass. He was treated as primary renal cell carcinoma, unclassified, with nephrectomy and adjuvant clinical trail where he received placebo. Subsequently, he developed multiple hepatic lesions and retroperitoneal mesenteric lymphadenopathy; CT-guided biopsy revealed adenocarcinoma with Her2/neu, 3+ by IHC. The patient was treated successfully with trastuzumab with near-complete response. PMID:23826550

  12. Trastuzumab for Her2/neu-positive metastatic salivary gland carcinoma: Case report and review of the literature.

    PubMed

    Firwana, Belal; Atassi, Bassel; Hasan, Rim; Hasan, Nour; Sukari, Ammar

    2012-07-01

    Salivary gland carcinomas metastasize to distant organs in 20% of salivary gland malignancies. Applying immunohistochemistry (IHC) measures, salivary gland tumors showed a wide range of oncogene markers expression, including the human epidermoid receptor 2 (Her2/neu), which could be targeted with monoclonal antibody. Treating salivary gland tumors, which have Her2/neu over-expression, with trastuzumab was reported in a few case reports. We report a 61-year-old Caucasian male, with a history of salivary gland tumor, who presented after 20 years of complete surgical resection with kidney mass. He was treated as primary renal cell carcinoma, unclassified, with nephrectomy and adjuvant clinical trail where he received placebo. Subsequently, he developed multiple hepatic lesions and retroperitoneal mesenteric lymphadenopathy; CT-guided biopsy revealed adenocarcinoma with Her2/neu, 3+ by IHC. The patient was treated successfully with trastuzumab with near-complete response. PMID:23826550

  13. Native mass spectrometry and ion mobility characterization of trastuzumab emtansine, a lysine-linked antibody drug conjugate.

    PubMed

    Marcoux, Julien; Champion, Thierry; Colas, Olivier; Wagner-Rousset, Elsa; Corvaïa, Nathalie; Van Dorsselaer, Alain; Beck, Alain; Cianférani, Sarah

    2015-08-01

    Antibody-drug conjugates (ADCs) are biochemotherapeutics consisting of a cytotoxic chemical drug linked covalently to a monoclonal antibody. Two main classes of ADCs, namely cysteine and lysine conjugates, are currently available on the market or involved in clinical trials. The complex structure and heterogeneity of ADCs makes their biophysical characterization challenging. For cysteine conjugates, hydrophobic interaction chromatography is the gold standard technique for studying drug distribution, the naked antibody content, and the average drug to antibody ratio (DAR). For lysine ADC conjugates on the other hand, which are not amenable to hydrophobic interaction chromatography because of their higher heterogeneity, denaturing mass spectrometry (MS) and UV/Vis spectroscopy are the most powerful approaches. We report here the use of native MS and ion mobility (IM-MS) for the characterization of trastuzumab emtansine (T-DM1, Kadcyla(®)). This lysine conjugate is currently being considered for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and combines the anti-HER2 antibody trastuzumab (Herceptin(®)), with the cytotoxic microtubule-inhibiting maytansine derivative, DM1. We show that native MS combined with high-resolution measurements and/or charge reduction is beneficial in terms of the accurate values it provides of the average DAR and the drug load profiles. The use of spectral deconvolution is discussed in detail. We report furthermore the use of native IM-MS to directly determine DAR distribution profiles and average DAR values, as well as a molecular modeling investigation of positional isomers in T-DM1. PMID:25694334

  14. Combinatorial approach to increase efficacy of Cetuximab, Panitumumab and Trastuzumab by dianthin conjugation and co-application of SO1861.

    PubMed

    Gilabert-Oriol, Roger; Weng, Alexander; Trautner, Alexandra; Weise, Christoph; Schmid, Daniel; Bhargava, Cheenu; Niesler, Nicole; Wookey, Peter J; Fuchs, Hendrik; Thakur, Mayank

    2015-10-01

    The therapeutic relevance of immunotoxins is based on the conjugation of monoclonal antibodies to toxins. In cancer therapies, the conjugated antibodies not only direct the binding of immunotoxins to cancer-specific receptors and mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. In the present study, the therapeutic antibodies Cetuximab (anti-EGFR, Erbitux(®)), Panitumumab (anti-EGFR, Vectibix(®)) and Trastuzumab (anti-HER2, Herceptin(®)) were chemically conjugated to the toxin dianthin. In the first instance, recombinant dianthin was characterized by mass spectrometry and its stability was analyzed by circular dichroism. Dianthin showed increased cytotoxicity on MCF-7 cells when tested in combination with a glycosylated triterpenoid (SO1861) in a real-time impedance-based cytotoxicity assay. In data obtained by live cell imaging, SO1861 specifically mediated the endo/lysosomal escape of dianthin without disrupting the plasma membrane. The purity of immunotoxins was confirmed by SDS-PAGE and Western blot. Their cytotoxicity was evaluated in the presence of SO1861 and dianthin-Cetuximab presented a GI50 (50% growth inhibition) of 5.3pM, dianthin-Panitumumab of 1.5pM, and dianthin-Trastuzumab of 23pM. Finally, the specificity of these immunotoxins was validated in a fluorescence-based real-time assay, where their binding to target cells was prevented by preincubation with an excess of label-free unconjugated antibody. Based on these data, we propose the use of dianthin and SO1861 as a new platform technology to enhance the efficacy of therapeutic antibodies. PMID:26253687

  15. Native mass spectrometry and ion mobility characterization of trastuzumab emtansine, a lysine-linked antibody drug conjugate

    PubMed Central

    Marcoux, Julien; Champion, Thierry; Colas, Olivier; Wagner-Rousset, Elsa; Corvaïa, Nathalie; Van Dorsselaer, Alain; Beck, Alain; Cianférani, Sarah

    2015-01-01

    Antibody–drug conjugates (ADCs) are biochemotherapeutics consisting of a cytotoxic chemical drug linked covalently to a monoclonal antibody. Two main classes of ADCs, namely cysteine and lysine conjugates, are currently available on the market or involved in clinical trials. The complex structure and heterogeneity of ADCs makes their biophysical characterization challenging. For cysteine conjugates, hydrophobic interaction chromatography is the gold standard technique for studying drug distribution, the naked antibody content, and the average drug to antibody ratio (DAR). For lysine ADC conjugates on the other hand, which are not amenable to hydrophobic interaction chromatography because of their higher heterogeneity, denaturing mass spectrometry (MS) and UV/Vis spectroscopy are the most powerful approaches. We report here the use of native MS and ion mobility (IM-MS) for the characterization of trastuzumab emtansine (T-DM1, Kadcyla®). This lysine conjugate is currently being considered for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and combines the anti-HER2 antibody trastuzumab (Herceptin®), with the cytotoxic microtubule-inhibiting maytansine derivative, DM1. We show that native MS combined with high-resolution measurements and/or charge reduction is beneficial in terms of the accurate values it provides of the average DAR and the drug load profiles. The use of spectral deconvolution is discussed in detail. We report furthermore the use of native IM-MS to directly determine DAR distribution profiles and average DAR values, as well as a molecular modeling investigation of positional isomers in T-DM1. PMID:25694334

  16. Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine

    PubMed Central

    Sadeghi, Saeed; Olevsky, Olga; Hurvitz, Sara A

    2014-01-01

    Purpose This article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent. Background The development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody–drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab. Results Preclinical and phase 1–3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician’s Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac

  17. Adjuvant treatment

    PubMed Central

    Sultana, Asma; Neoptolemos, John

    2006-01-01

    Exocrine pancreatic cancer (pancreatic ductal adenocarcinoma) is one of the leading causes of cancer deaths in the western world, accounting for 5% of all cancer-related deaths. Only a small percentage of patients with pancreatic cancer are able to undergo potentially curative resection, even in specialized centres, and prognosis remains poor after successful surgery. Over the last few years efforts have been directed towards the development of adjuvant therapies in attempts to improve outcome. The main trials of adjuvant chemotherapy, chemoradiotherapy and chemoradiotherapy with follow-on chemotherapy are described in this paper, followed by the results of the ESPAC-1 trial and the status of ESPAC-2 and -3 trials. PMID:18333088

  18. Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer

    PubMed Central

    Advani, Pooja; Cornell, Lauren; Chumsri, Saranya; Moreno-Aspitia, Alvaro

    2015-01-01

    Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%–20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. PMID:26451122

  19. Specific intracellular uptake of herceptin-conjugated CdSe/ZnS quantum dots into breast cancer cells.

    PubMed

    Han, Seung-Jin; Rathinaraj, Pierson; Park, Soo-Young; Kim, Young Kyoo; Lee, Joon Hyung; Kang, Inn-Kyu; Moon, Jong-Sik; Winiarz, Jeffrey G

    2014-01-01

    Herceptin, a typical monoclonal antibody, was immobilized on the surface of CdSe/ZnS core-shell quantum dots (QDs) to enhance their specific interactions with breast cancer cells (SK-BR3). The mean size of the core-shell quantum dots (28 nm), as determined by dynamic light scattering, increased to 86 nm after herceptin immobilization. The in vitro cell culture experiment showed that the keratin forming cancer cells (KB) proliferated well in the presence of herceptin-conjugated QDs (QD-Her, 5 nmol/mL), whereas most of the breast cancer cells (SK-BR3) had died. To clarify the mechanism of cell death, the interaction of SK-BR3 cells with QD-Her was examined by confocal laser scanning microscopy. As a result, the QD-Her bound specifically to the membrane of SK-BR3, which became almost saturated after 6 hours incubation. This suggests that the growth signal of breast cancer cells is inhibited completely by the specific binding of herceptin to the Her-2 receptor of SK-BR3 membrane, resulting in cell death. PMID:24511553

  20. Heparan sulfate mediates trastuzumab effect in breast cancer cells

    PubMed Central

    2013-01-01

    Background Trastuzumab is an antibody widely used in the treatment of breast cancer cases that test positive for the human epidermal growth factor receptor 2 (HER2). Many patients, however, become resistant to this antibody, whose resistance has become a major focus in breast cancer research. But despite this interest, there are still no reliable markers that can be used to identify resistant patients. A possible role of several extracellular matrix (ECM) components—heparan sulfate (HS), Syn-1(Syndecan-1) and heparanase (HPSE1)—in light of the influence of ECM alterations on the action of several compounds on the cells and cancer development, was therefore investigated in breast cancer cell resistance to trastuzumab. Methods The cDNA of the enzyme responsible for cleaving HS chains from proteoglycans, HPSE1, was cloned in the pEGFP-N1 plasmid and transfected into a breast cancer cell lineage. We evaluated cell viability after trastuzumab treatment using different breast cancer cell lines. Trastuzumab and HS interaction was investigated by confocal microscopy and Fluorescence Resonance Energy Transfer (FRET). The profile of sulfated glycosaminoglycans was also investigated by [35S]-sulfate incorporation. Quantitative RT-PCR and immunofluorescence were used to evaluate HPSE1, HER2 and Syn-1 mRNA expression. HPSE1 enzymatic activity was performed using biotinylated heparan sulfate. Results Breast cancer cell lines responsive to trastuzumab present higher amounts of HER2, Syn-1 and HS on the cell surface, but lower levels of secreted HS. Trastuzumab and HS interaction was proven by FRET analysis. The addition of anti-HS to the cells or heparin to the culture medium induced resistance to trastuzumab in breast cancer cells previously sensitive to this monoclonal antibody. Breast cancer cells transfected with HPSE1 became resistant to trastuzumab, showing lower levels of HER2, Syn-1 and HS on the cell surface. In addition, HS shedding was increased significantly in

  1. Societal Costs and Benefits of Treatment with Trastuzumab in Patients with Early HER2neu-Overexpressing Breast Cancer in Singapore

    PubMed Central

    2011-01-01

    Background Trastuzumab has revolutionized the way we treat early Her2Neu-positive breast cancer, as it significantly improves disease-free and overall survival. Little is known about the societal costs and benefits of treatment with trastuzumab in the adjuvant setting in Southeast Asia. Methods Societal costs (benefits) were estimated as the sum of direct and indirect costs minus benefits in the base case. Direct costs were derived from 4 treatment centers in Singapore (2 private and 2 public, comprising 60-70% of all patients with cancer seen in the island-nation); indirect costs were assessed as the loss of productivity caused by the disease or treatment. Benefits to society were based on extra years of productivity, as measured by GNI per capita, resulting from the quality adjusted life-years (QALYs) saved with the use of trastuzumab as determined in the models by Kurian, Liberato and Garrison. Results Incremental costs in Singapore, in 2005 US dollars, were $26,971.05. Average Cost per QALY was $19,174.59 (Median: $18,993.70). Costs (benefits) to society ranged from a cost of $79.42 to a benefit of $9,263.06, depending on the model used (Average benefit: $4,375.89, Median $3,944.03). Sensitivity analysis ranged from a cost of $10,685.00 to a Benefit of US$17,298.79 Conclusions Treatment with adjuvant trastuzumab is likely to generate net societal economic benefits in Singapore. Nevertheless, the lower range of possible outcomes does not refute the possibility that treatment may actually generate costs. These costs however clearly fall within the usual range of acceptable cost-effectiveness. PMID:21586176

  2. First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.

    PubMed

    Blumenthal, Gideon M; Scher, Nancy S; Cortazar, Patricia; Chattopadhyay, Somesh; Tang, Shenghui; Song, Pengfei; Liu, Qi; Ringgold, Kimberly; Pilaro, Anne M; Tilley, Amy; King, Kathryn E; Graham, Laurie; Rellahan, Barbara L; Weinberg, Wendy C; Chi, Bo; Thomas, Colleen; Hughes, Patricia; Ibrahim, Amna; Justice, Robert; Pazdur, Richard

    2013-09-15

    On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues. PMID:23801166

  3. Analysis of Fcγ Receptor IIIa and IIa Polymorphisms: Lack of Correlation with Outcome in Trastuzumab-Treated Breast Cancer Patients

    PubMed Central

    Hurvitz, Sara A.; Betting, David J.; Stern, Howard M.; Quinaux, Emmanuel; Stinson, Jeremy; Seshagiri, Somasekar; Zhao, Ying; Buyse, Marc; Mackey, John; Driga, Adrian; Damaraju, Sambasivarao; Sliwkowski, Mark X.; Robert, Nicholas J.; Valero, Vicente; Crown, John; Falkson, Carla; Brufsky, Adam; Pienkowski, Tadeusz; Eiermann, Wolfgang; Martin, Miguel; Bee, Valerie; Marathe, Omkar; Slamon, Dennis J.; Timmerman, John M.

    2013-01-01

    Purpose The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its anti-tumor effects. Single nucleotide polymorphisms (SNPs) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131 respectively and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high affinity SNPs are associated with disease free survival (DFS) among patients with HER2-positive non-metastatic breast cancer. Experimental Design Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was performed using Sanger sequencing and Sequenom mass spectrometry. Results 1,189 patient samples were successfully genotyped for FCGR3A and 1,218 for FCGR2A. Compared to the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms compared to control arm (HR=0.842, P=0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR=0.74, P=0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs V/F vs F/F, P=0.98; 131H/H vs H/R vs R/R, P=0.76; 158V/V and/or 131H/H vs others, P=0.67). Conclusion This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not demonstrate a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab. PMID:22504044

  4. The effect of trastuzumab-based chemotherapy in small node-negative HER2-positive breast cancer.

    PubMed

    van Ramshorst, Mette S; van der Heiden-van der Loo, Margriet; Dackus, Gwen M H E; Linn, Sabine C; Sonke, Gabe S

    2016-07-01

    The prognosis of patients with stage II-III Human Epidermal growth factor Receptor 2 (HER2)-positive breast cancer has significantly improved since the addition of trastuzumab to (neo-)adjuvant chemotherapy. Several reports have shown that small (≤2 cm), node-negative, HER2-positive tumors have a relatively poor prognosis and these patients increasingly receive trastuzumab-based chemotherapy. We aimed to provide evidence for this approach in a population-based cohort. All T1N0M0 HER2-positive breast cancer patients diagnosed between 2006 and 2012 were identified from the Netherlands Cancer Registry. Patient, tumor, and treatment characteristics were recorded. Kaplan-Meier statistics were used for overall survival (OS) and breast cancer-specific survival (BCSS) estimations overall and in T1a, T1b, and T1c tumors separately. Cox regression analyses were performed to account for imbalances in baseline characteristics between treated and untreated patients. A total of 3512 patients were identified: 385 with T1a, 800 with T1b, and 2327 with T1c tumors. Forty-five percent of patients received chemotherapy and/or trastuzumab: 92 % received both. Chemotherapy and/or trastuzumab significantly improved 8-year OS (95 vs. 84 %; hazard ratio [HR] 0.29; 95 % confidence interval [CI] 0.21-0.41, P < 0.001). The effect remained significant in multivariable analyses (HR 0.35; 95 % CI 0.23-0.52, P < 0.001). BCSS was also improved with systemic treatment in univariable (96 vs. 92 %; HR 0.41; 95 % CI 0.27-0.63, P < 0.001) and multivariable analyses (HR 0.31; 95 % CI 0.19-0.53, P < 0.001). Treatment effect on OS and BCSS was similar in T1a, T1b, and T1c tumors. Chemotherapy and/or trastuzumab improves OS and BCSS and can be considered in all patients with small node-negative HER2-positive breast cancer. PMID:27357813

  5. Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer.

    PubMed

    Bhargava, Rohit; Dabbs, David J; Beriwal, Sushil; Yildiz, Isil A; Badve, Preeti; Soran, Atilla; Johnson, Ronald R; Brufsky, Adam M; Lembersky, Barry C; McGuire, Kandace P; Ahrendt, Gretchen M

    2011-03-01

    Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptor-negative/HER2+ tumors is seen in 27-45% of cases. In contrast, estrogen receptor (ER)+/HER2+ tumors demonstrate pathologic complete response in ∼ 8% of cases and is generally limited to weak-to-moderate ER+/HER2+ tumors. It is speculated that addition of trastuzumab to neoadjuvant chemotherapy regimen will increase the pathologic complete response rates in all HER2+ tumors. A list of HER2+ patients who received neoadjuvant chemotherapy (with trastuzumab) in the years 2007-2010 was obtained from our hospital database. The 104 HER2+ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results as follows: ERBB2 (ER-/PR-[H-score ≤10]/HER2+), Luminal B-HER2 Hybrid (LBHH; weak to moderate ER+ [H-score 11-199]/HER2+), and Luminal A-HER2 Hybrid (LAHH; strong ER+[H-score ≥200]/HER2+). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and in the lymph nodes. Percentage tumor volume reduction was also calculated based on pretherapy size and detailed evaluation of the resection specimen. In all, 52% (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33%; 10 of 30) and LAHH (8%; 2 of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86%), followed by LBHH (74%) and LAHH (64%) tumors. We conclude that addition of trastuzumab to neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2+ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be utilized to counsel patients considered for neoadjuvant chemotherapy and the same principle could be applied in the adjuvant setting. PMID:21102420

  6. Intrathecal Trastuzumab Treatment in Patients with Breast Cancer and Leptomeningeal Carcinomatosis.

    PubMed

    Park, Won-Young; Kim, Han-Jo; Kim, Kyoungha; Bae, Sang-Byung; Lee, Namsu; Lee, Kyu-Taek; Won, Jong-Ho; Park, Hee-Sook; Lee, Sang-Cheol

    2016-04-01

    Leptomeningeal carcinomatosis is a fatal manifestation of metastatic breast cancer. Investigation of intrathecal (IT) trastuzumab for leptomeningeal carcinomatosis is currently underway; however, there has been no consensus. We report on two cases of human epidermal growth factor receptor 2 positive (HER2+) breast cancer following IT trastuzumab for leptomeningeal carcinomatosis. The first patient was treated with weekly IT 15 mg methotrexate plus IT 50 mg trastuzumab for 7 months, followed by IT trastuzumab (50 mg > 25 mg) for 18 months. The other patient received IT trastuzumab with systemic chemotherapy (trastuzumab and/or paclitaxel) for 13 months. Good control of leptomeningeal disease was achieved with IT trastuzumab in both patients, with survival durations of 20 and 29 months, respectively. We suggest that IT trastuzumab is a promising treatment for patients with HER2+ breast cancer and leptomeningeal carcinomatosis. PMID:25761487

  7. Cardiac toxicity of trastuzumab in elderly patients with breast cancer

    PubMed Central

    Denegri, Andrea; Moccetti, Tiziano; Moccetti, Marco; Spallarossa, Paolo; Brunelli, Claudio; Ameri, Pietro

    2016-01-01

    Breast cancer (BC) is diagnosed in ≥ 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unfortunately, administration of trastuzumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure (CHF), possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%–15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in > 60–65 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques (three-dimension, tissue Doppler echocardiography, magnetic resonance imaging) is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart. PMID:27403145

  8. Comparison of three different conjugation strategies in the construction of herceptin-bearing paclitaxel-loaded nanoparticles.

    PubMed

    Yu, Kongtong; Zhou, Yulin; Li, Yuhuan; Sun, Xiangshi; Sun, Fengying; Wang, Xinmei; Mu, Hongyan; Li, Jie; Liu, Xiaoyue; Teng, Lesheng; Li, Youxin

    2016-08-19

    Research on quantitatively controlling the ligand density on the surface of nanocarriers is in the frontier and becomes a technical difficulty for targeted delivery system designing. In this study, we developed an improved pre-conjugation (Imp) strategy, in which herceptin as a ligand was pre-conjugated with DSPE-PEG2000-Mal via chemical cross-linking, followed by conjugation onto the surface of pre-prepared paclitaxel-loaded PLGA/DODMA nanoparticles (PDNs) through hydrophobic interaction and electrostatic attraction for paclitaxel delivery. Compared with the post-conjugation (Pos) strategy, in which the ligand was conjugated onto the nanoparticle surface after the preparation of the nanoparticles, it realized a precise control targeting effect via adjustment of the herceptin density on the surface of the nanoparticles. Within the range of 0-20% of DSPE-PEG2000-herceptin in the blend, it showed a linear relation with the ligand density on the surface of the nanoparticles. The Imp strategy protected the bioactivity of the ligand during the preparation of nanoparticles. At the same time it avoided the waste of an excess amount of herceptin to drive the conjugation reaction in comparison with the post-conjugation (Pos) strategy. The nanoparticles from the Imp strategy showed much better cytotoxicity (p < 0.001), tumor targeting and cellular uptake efficiency (p < 0.001) than that of the other strategies in BT474 cells, in which BT474 cells were HER2 receptor over-expression breast cancer cell lines. A significant reduction in cellular uptake of the nanoparticles from the Imp strategy was observed in the presence of sucrose and cytochalasin D, indicating that clathrin-mediated and caveolae-dependent endocytosis was as a primary mechanism of cellular entry for these antibody-modified nanoparticles. PMID:27367271

  9. Correlation between HER-2/neu(erbB-2) expression level and therapeutic effect of combination treatment with HERCEPTIN and chemotherapeutic agents in gastric cancer cell lines

    PubMed Central

    2014-01-01

    Introduction Although advanced gastric cancer has many limitations and response rate is marginal in chemotherapy. Overexpression of human epidermal growth factor receptor 2(HER-2/neu) gene and its protein are associated with increased cell division and a high rate of tumor growth and have been reported in several malignancies. Especially, approximately 30% of breast cancer patients have overexpression of HER-2/neu protein and the overexpression metastasize faster, induces resistance of the chemotherapy and down-regulate function of estrogen receptor. Recombinant humanized anti-HER2 antibody (Herceptin) inhibits proliferation of HER-2/neu overexpressing tumor cells and the use of that in combination in metastatic breast cancer have increased cytotoxicity of chemotherapeutic agents. Methods We evaluated the expression of HER-2/neu protein in gastric cell lines by FACS and then comparing the cytotoxicity in chemotherapeutics (doxorubicin, cisplatin, paclitaxel, 5-FU) alone and in combination with Herceptin according to the expression of HER-2/neu protein by MTT assay. Results 1. NCI-N87 (88%) gastric cancer cell line and SK-BR-3 (89%) breast cancer cell line with strong positivity of HER-2/neu expression. YBC-2 (55%) and YBC-3 (48%) gastric cancer cell line with intermediated, weak positivity respectively. Negative control U-87 MG (6%) brain cancer cell line were showed low expression of HER-2/neu. 2. Cell growth was dose-dependently inhibited in HER-2/neu positive, control cell line SK-BR-3 by Herceptin treatment but not observed in HER-2/neu negative control cell line U-87 MG. Effective growth inhibition was not observed in gastric cancer cell lines with single treatment of Herceptin, all cell lines observed the dose-dependent growth inhibition to chemotherapeutic agents (doxorubicin, cisplatin, paclitaxel and 5-FU). 3. Combination of Herceptin with doxorubicin observed synergistic effects in all cancer cell lines except YBC-3, combination of Herceptin with

  10. Evaluation of a quantitative RT-PCR assay to detect HER2 mRNA overexpression for diagnosis and selection of trastuzumab therapy in breast cancer tissue samples.

    PubMed

    Wang, Hye-Young; Kim, Sunghyun; Park, Sangjung; Kim, Seungil; Jung, Dongju; Park, Kwang Hwa; Lee, Hyeyoung

    2014-12-01

    Breast cancer patients who have a positive result for HER2 overexpression are commonly treated with Herceptin, a HER2-targeted therapy. In the present study, the BrightGen HER2 RT-qDx (Syantra, Calgary, Canada), which is based on a one-tube nested RT-qPCR method that detects HER2 mRNA overexpression, was clinically evaluated in a total of 237 formalin-fixed paraffin-embedded (FFPE) tissue samples from breast cancer patients. Among the 38 HER2 positive samples, which were determined via IHC/FISH methods, 13 samples out of 16 (81.3%) that were IHC2+/FISH+ and 22 samples out of 22 (100%) that were IHC3+ have been decided positive for HER2 expression via the RT-qPCR method. The true positivity and false positivity results for the RT-qPCR were 92% (35/38) and 2% (1/65), respectively. The concordance between RT-qPCR and IHC results and RT-qPCR and IHC/FISH was 87.2% and 92.1%, respectively. Conclusively, the BrightGen HER2 RT-qDx may be a reliable and convenient method that can supplement traditional IHC and FISH methods for efficient use of trastuzumab. PMID:25236569

  11. HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy

    PubMed Central

    Stocker, Albina; Hilbers, Marie-Luise; Gauthier, Claire; Grogg, Josias; Kullak-Ublick, Gerd A.; Seifert, Burkhardt; Varga, Zsuzsanna

    2016-01-01

    Background Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS). Methods Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007–2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression. Results A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23–89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy

  12. Long-term cardiovascular outcomes and overall survival of early-stage breast cancer patients with early discontinuation of trastuzumab: a population-based study.

    PubMed

    Gong, Inna Y; Verma, Sunil; Yan, Andrew T; Ko, Dennis T; Earle, Craig C; Tomlinson, George A; Trudeau, Maureen E; Krahn, Murray D; Krzyzanowska, Monika K; Brezden-Masley, Christine B; Gavura, Scott; Peacock, Stuart; Chan, Kelvin K W

    2016-06-01

    We critically examined long-term cardiovascular (CV) outcomes and overall survival (OS) of breast cancer (BC) patients who had cardiotoxicity during adjuvant trastuzumab treatment requiring discontinuation in a population-based sample. This was a retrospective cohort of early-stage BC patients diagnosed before 2010 and treated with trastuzumab in Ontario. Patients were stratified based on trastuzumab doses received: 1-8, 9-15, ≥16 (therapy completion). Time-dependent multivariable Cox models were used to analyze primary endpoint OS, and the following composite endpoints: hospitalization/emergency room visit for heart failure (HF) or death; non-HF CV (myocardial infarction, stroke) or death; and clinically significant relapse (palliative systemic therapy initiation >90 days after last trastuzumab dose) or death. Of the 3134 women, 6, 10, and 85 % received 1-8, 9-15, and ≥16 doses, respectively. Over 5-year median follow-up, early trastuzumab discontinuation was associated with more HF/death [1-8 doses hazard ratio (HR) 4.0, 95 % confidence interval (CI) 2.7-6.0; 9-15 doses HR 2.97, 95 % CI 2.1-4.3], non-HF/death (1-8 doses HR 4.3, 95 % CI 3.0-6.1; 9-15 doses HR 3.1, 95 % CI 2.2-4.4), clinically significant relapse/death (1-8 doses HR 3.1, 95 % CI 2.2-4.4; 9-15 doses HR 2.4, 95 % CI 1.8-3.3), and importantly lower OS (77, 80, 93 %; P < 0.001). Early discontinuation (1-8 doses HR 2.41, 95 % CI 1.5-3.8; 9-15 doses HR 2.9, 95 % CI 2.0-4.1) and clinically significant relapse (HR 34.0, 95 % CI 24.9-46.6) were both independent predictors of mortality. Of note, early discontinuation remained a critical independent predictor of OS even after adjusting for incident HF. Early trastuzumab discontinuation is a powerful independent predictor of cardiac events and clinically significant relapse, and both may contribute to poor survival. Both adequate cancer control and optimal CV management are required to improve long-term outcomes. PMID:27271767

  13. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells

    PubMed Central

    2013-01-01

    Background Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. Methods MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs’ antitumor activity. Immunohistochemical analyses were carried out to study the Abs’ inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo. Results MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of

  14. Challenges in the implementation of trastuzumab biosimilars: an expert panel's recommendations.

    PubMed

    Pivot, Xavier; Aulagner, Gilles; Blay, Jean Yves; Fumoleau, Pierre; Kaliski, Alexandre; Sarkozy, François; Limat, Samuel

    2015-11-01

    Trastuzumab has transformed the treatment of HER2-positive breast cancer. Because of impending European patent expiry in 2017, numerous trastuzumab biosimilars are currently undergoing comparability exercises for marketing authorization. Although biosimilar products have been approved in Europe since 2006, many obstacles are expected for trastuzumab, resulting from its nature as a monoclonal antibody, its impact on overall survival, and its extensive biochemical complexities. Unsolved questions need to be addressed for the evaluation of biosimilars' activity in terms of appropriate clinical endpoint definitions for such anticancer drugs, specific assessment pathways and comparative testing of biosimilars, untested ensuing de facto combination of trastuzumab biosimilars with cytotoxics, and immunogenicity monitoring among immunocompromised patients. In such a context of uncertainties, the recent approval by the French parliament of biosimilar substitution, which would allow dispensing trastuzumab biosimilars in place of the originator, should interrogate the oncological community. A think tank of experts was created to delineate specificities and challenges stemming from trastuzumab biosimilars. PMID:26352219

  15. Successful readministration of trastuzumab after severe immune reactions in two breast cancer patients.

    PubMed

    Tanz, R; Meillan, N; Libert, N; Magne, N; Vedrine, L; Chargari, C

    2014-06-01

    Trastuzumab is a standard treatment in breast cancer overexpressing Her2 oncogene. However, its administration carries the risk of severe immune adverse events which often lead to the discontinuation of trastuzumab. There is no clear guideline on how patients experiencing trastuzumab-related reaction should be rechallenged with the monoclonal antibody. Here, we present two case reports of patients who have presented severe anaphylactic reactions during trastuzumab infusion. Both of them have been successfully rechallenged in intensive care units with premedication, lower rate of infusion and vitals monitoring. Thereafter, trastuzumab could be continued without any serious adverse reaction. Given the positive impact of trastuzumab on patients' survival, treatment rechallenge should be carefully considered in patients who presented anaphylactic reactions. PMID:24682736

  16. Constructing narratives of heroism and villainy: case study of Myriad's BRACAnalysis® compared to Genentech's Herceptin®

    PubMed Central

    2013-01-01

    Background The development of Herceptin® is welcomed as a major advance in breast cancer treatment, while Myriad's development of BRACAnalysis® is a widely used diagnostic. However useful and successful this product is, its presence in the public eye is tainted by predominantly negative press about gene patenting and business practices. Discussion While retrospection invites a sharp contrast between Genentech's triumphal narrative of scientific achievement and Myriad's public image as a controversial monopolist, a comparative history of these companies' products reveals two striking consistencies: patents and public discontent. Despite these similarities, time has reduced the narrative to that of hero versus villain: Genentech is lauded - at least for the final outcome of the Herceptin® story - as a corporate good citizen, Myriad as a ruthless mercenary. Since patents undergird both products yet the narratives are so different, the stories raise the question: why have patents taken the fall as the scapegoat in current biotechnology policy debate? Summary A widely publicized lawsuit and accompanying bad press have cast Myriad as a villain in the evolving narrative of biotechnology. While the lawsuit suggests that this villainy is attributable to Myriad's intellectual property, we suggest through a comparative case study that, at least in the Myriad case, it is not simply about the patents but also other business strategies the company chose to pursue. Patents were a necessary but not sufficient cause of controversy. PMID:23369278

  17. Trends in vaccine adjuvants.

    PubMed

    Schijns, Virgil E J C; Lavelle, Ed C

    2011-04-01

    Adjuvants are essential components of most clinically used vaccines. This is because the majority of nonliving vaccines are relatively poor inducers of adaptive immunity unless effective adjuvants are co-administered. Aluminum salts (alum) have been used as adjuvants with great success for almost a century and have been particularly effective at promoting protective humoral immunity. However, alum is not optimally effective for diseases where cell-mediated immunity is required for protection. Furthermore, adjuvants including oil-in-water emulsions have shown improved efficacy for avian influenza protection suggesting that even for diseases where humoral immunity can confer protection, there is scope for developing improved adjuvants. There have been major developments in antigen discovery over the past decade, which has accelerated the vaccine development process for new indications and this demands a new generation of adjuvants that can drive and specifically direct the desired immune responses. A number of systems are under investigation that combine different types of adjuvants into specific formulations with greater activity. Additionally, targeting of vaccines to specific immune cells shows great promise. In the case of cancer and chronic infectious diseases, it may be difficult to develop effective vaccines without blocking immune regulatory pathways, which impede cell-mediated responses. However, increased understanding of immunology and particularly the innate immune system is informing vaccine adjuvant research and consequently driving the development of novel and specifically directed vaccine adjuvant strategies. In this article we address the importance of adjuvants in vaccine development, the known mode of action of specific adjuvants and recent developments in this important field. PMID:21506650

  18. Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation

    SciTech Connect

    Diermeier, Simone; Horvath, Gabor; Knuechel-Clarke, Ruth; Hofstaedter, Ferdinand; Szoellosi, Janos; Brockhoff, Gero . E-mail: Gero.Brockhoff@klinik.uni-regensburg.de

    2005-04-01

    Background: Growth factors and Herceptin specifically and differentially modulate cell proliferation of tumor cells. However, the mechanism of action on erbB-receptor level is incompletely understood. We evaluated Herceptin's capacity to modulate erbB-receptor activation and interaction on the cell surface level and thereby potentially impair cell proliferation of HER2/neu (c-erbB2) overexpressing breast cancer cells, both in the presence and absence of relevant growth factors. Methods: BT474 and SK-BR-3 breast cancer cell lines were treated with Epidermal Growth Factor (EGF), Heregulin, and with Herceptin in different combinations. Kinetics of cell proliferation were evaluated flow cytometrically based on BrdU-labeling. Fluorescence Resonance Energy Transfer, ELISAs and phosphorylation site specific Western Blotting was performed to investigate erbB-receptor interaction and activation. Results: EGF induced EGFR/EGFR and EGFR/c-erbB2 interactions correlate with stimulation of cell proliferation in BT474 cells. Both homo- and heterodimerization are considerably less pronounced in SK-BR-3 cells and heterointeraction is additionally reduced by EGF treatment, causing inhibition of cell proliferation. Heregulin stimulates cell proliferation extensively in both cell lines. Herceptin drives BT474 cells more efficiently into quiescence than it does with SK-BR-3 cells and thereby blocks cell cycle progress. In SK-BR-3 Herceptin treatment causes c-erbB2 phosphorylation of Y877 and Y1248, EGF induces Y877 and Y1112 phosphorylation. The Y1112 phosphorylation site, activated by EGF in SK-BR-3 cell, is bypassed in BT474. In addition the inhibitory capacity of Herceptin on BT474 and SK-BR-3 cell proliferation depends on the presence and absence of growth factors to a various extent. Conclusion: The growth inhibitory effect of Herceptin on c-erbB2 overexpressing breast cancer cells is considerably modulated by EGFR coexpression and consequently EGFR/c-erbB2 homo- and

  19. Anthracycline- and trastuzumab-induced cardiotoxicity: a retrospective study.

    PubMed

    Hamirani, Yasmin; Fanous, Ibrahim; Kramer, Christopher M; Wong, Andrew; Salerno, Michael; Dillon, Patrick

    2016-07-01

    Some chemotherapeutic agents cause cardiotoxic effects including reduction in left ventricular ejection fraction (LVEF) and occasionally congestive heart failure. Anthracyclines and HER2 monoclonal antibodies are common offenders, but clinical practice data on LVEF changes, risk factors and acute recovery is lacking. We retrospectively examined the electronic medical record at an academic medical center for receipt of anthracyclines and/or trastuzumab from 2000 to 2013 in cancer patients. Patient characteristics and serial LVEF assessments were collected. Patients with and without LVEF decline were analyzed by univariate and multivariate analysis. A total of 549 patients were identified with anthracycline/trastuzumab use and 216 had multiple LVEF assessments. Only 27 of the 216 patients who had multiple LVEF assessments at multiple occasions suffered a clinically significant LVEF fall (12.5 %), and symptomatic CHF was rare (0.5 %). Compared to unaffected patients, those with a fall in LVEF were more likely to have hypertension, hyperlipidemia or coronary artery disease (CAD). Concomitant trastuzumab and anthracycline use was a risk factor (36 vs 9.5 % for anthracycline alone, p < 0.001). The median time from start of chemotherapy to reduced LVEF was 202 days (5-3008). On multivariate analysis, hypertension and use of trastuzumab remained independent predictors of LVEF fall. Acute recovery in LVEF was observed in 44 % of patients. LVEF changes from cancer therapies are frequent and hard to predict. Hypertension, hyperlipidemia and CAD are associated with LVEF decline. Acute recovery of LVEF is observed in those experiencing treatment-related cardiotoxicity. Attention to timely interruption of cardiotoxic chemo is recommended. PMID:27334792

  20. Trastuzumab-binding peptide display by Tobacco mosaic virus

    SciTech Connect

    Frolova, Olga Y.; Petrunia, Igor V.; Komarova, Tatiana V.; Kosorukov, Vyacheslav S.; Sheval, Eugene V.; Gleba, Yuri Y.; Dorokhov, Yuri L.

    2010-11-10

    Human epidermal growth factor receptor-2 (HER2/neu) is a target for the humanized monoclonal antibody trastuzumab. Recently, trastuzumab-binding peptides (TBP) of HER2/neu that inhibit proliferation of breast cancer cells were identified. We have now studied conditions of efficient assembly in vivo of Tobacco mosaic virus (TMV)-based particles displaying TBP on its surface. The system is based on an Agrobacterium-mediated co-delivery of binary vectors encoding TMV RNA and coat protein (CP) with TBP in its C-terminal extension into plant leaves. We show how the fusion of amino acid substituted TBP (sTBP) to CP via a flexible peptide linker can improve the manufacturability of recombinant TMV (rTMV). We also reveal that rTMV particles with exposed sTBP retained trastuzumab-binding capacity but lost an anti-HER2/neu immunogenic scaffold function. Mouse antibodies against rTMV did not recognize HER2/neu on surface of human SK-BR-3 cells.

  1. [Influenza vaccine and adjuvant].

    PubMed

    Nakayama, Tetsuo

    2011-01-01

    Adjuvant is originated from the Latin word "adjuvare" which means "help" in English to enhance the immunological responses when given together with antigens. The beginning of adjuvant was mineral oil which enhanced the immune response when it was given with inactivated Salmonella typhimurium. Aluminium salt was used to precipitate diphtheria toxoid and increased level of antibody response was demonstrated when administered with alum-precipitated antigens. Since 1930, aluminium salt has been used as DTaP (diphtheria-tetanus-acellular pertussis vaccine) adjuvant. Many candidates were tested for adjuvant activity but only aluminum salt is allowed to use for human vaccines. New adjuvant MF59, oil-in-water emulsion type, was developed for influenza vaccine for elderly (Fluad) and series of AS adjuvant are used for hepatitis B, pandemic flue, and human papiloma virus vaccines. Oil-adjuvanted influenza pandemic vaccines induced higher antibody response than alum-adjuvanted vaccine with higher incidence of adverse events, especially for local reactions. Alum-adjuvanted whole virion inactivated H5N1 vaccine was developed in Japan, and it induced relatively well immune responses in adults. When it applied for children, febrile reaction was noted in approximately 60% of the subjects, with higher antibodies. Recent investigation on innate immunity demonstrates that adjuvant activity is initiated from the stimulation on innate immunity and/or inflammasome, resulting in cytokine induction and antigen uptake by monocytes and macrophages. The probable reason for high incidence of febrile reaction should be investigated to develop a safe and effective influenza vaccine. PMID:22129866

  2. Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine

    DOE PAGESBeta

    Fitzsimmons, Jonathan; Nayak, Tapan; Cutler, Cathy; Atcher, Robert

    2015-12-30

    Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab wasmore » concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. In conclusion, the results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.« less

  3. [Hepatic Resection of Multiple Liver Metastases from Gastric Cancer after Molecular Targeted Chemotherapy(S-1 plus Cisplatin plus Trastuzumab)].

    PubMed

    Kim, Yongkook; Hosoda, Yohei; Nishino, Masaya; Okano, Miho; Kawada, Junji; Yamasaki, Masaru; Nagai, Ken-ichi; Yasui, Masayosi; Okuyama, Masaki; Tsujinaka, Toshimasa

    2015-11-01

    A 62-year-old man was diagnosed with gastric cancer and underwent distal gastrectomy, and D1+b lymph node dissection. He was diagnosed postoperatively with T1b (sm2) N0M0, StageⅠA gastric adenocarcinoma and did not receive any adjuvant chemotherapy after surgery. One year and 6 months after gastrectomy, blood analysis indicated high levels of carcinoembryonic antigen (CEA 262.1 ng/mL) while abdominal computed tomography (CT) revealed multiple liver tumors (S7: 15 mm, S7/8: 20 mm). The patient was diagnosed with metachronous multiple liver metastases from gastric cancer. Chemotherapy, combined with molecular targeted therapy (S-1 plus cisplatin [CDDP] plus trastuzumab), was administered because of overexpression of the human epidermal growth factor receptor 2 (HER2) protein in the primary tumor as assessed by immunohistochemistry, the CEA levels decreased immediately after 2 cycles of the chemotherapy, and the liver metastases shrank markedly with no evidence of new lesions on abdominal CT. However, after treatment, Grade 3 neutropenia and diarrhea were observed. Chemotherapy was suspended and hepatic resection was performed. After hepatic resection, the liver tumors were histologically evaluated as Grade 2 metastatic gastric adenocarcinoma, and the HER2 expression of remnant carcinoma cells was established. The patient has been in good health and remained free of recurrences in the 2 years and 3 months after the liver resection. Surgery with preoperative chemotherapy (S-1 plus CDDP plus trastuzumab) can be an effective treatment for liver metastasis from HER2-positive gastric cancer. PMID:26805121

  4. Multifunctional poly(D,L-lactide-co-glycolide)/montmorillonite (PLGA/MMT) nanoparticles decorated by Trastuzumab for targeted chemotherapy of breast cancer.

    PubMed

    Sun, Bingfeng; Ranganathan, Balu; Feng, Si-Shen

    2008-02-01

    This paper continued our earlier work on the poly(D,L-lactide-co-glycolide)/montmorillonite nanoparticles (PLGA/MMT NPs), which were further decorated by human epidermal growth factor receptor-2 (HER2) antibody Trastuzumab for targeted breast cancer chemotherapy with paclitaxel as a model anticancer drug. Such a NP system is multifunctional, which formulates anticancer drugs with no harmful adjuvant, reduces the side effects of the formulated anticancer drug, promotes synergistic therapeutic effects, and achieves targeted delivery of the therapy. The paclitaxel-loaded PLGA/MMT NPs were prepared by a modified solvent extraction/evaporation technique, which were then decorated with Trastuzumab. The effects of the surface decoration on particle size and size distribution, surface morphology, drug encapsulation efficiency, as well as the drug release kinetics, were investigated. The NP formulation exhibited a biphasic drug release with a moderate initial burst followed by a sustained release profile. The surface decoration speeded the drug release. Surface chemistry analysis was conducted by X-ray photoelectron spectroscopy (XPS), which confirmed the presence of Trastuzumab on the NP surface. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed the stability of the antibody in the NP preparation process. Internalization of the coumarin-6-loaded PLGA/MMT NPs with or without the antibody decoration by both of Caco-2 colon adeno carcinoma cells and SK-BR-3 breast cancer cells was visualized by confocal laser scanning microscopy and quantitatively analyzed, which shows that the antibody decoration achieved significantly higher cellular uptake of the NPs. The results of in vitro cytotoxicity experiment on SK-BR-3 cells further proved the targeting effects of the antibody decoration. Judged by IC50 after 24h culture, the therapeutic effects of the drug formulated in the NPs with surface decoration could be 12.74 times higher than that of the

  5. Therapeutic Efficacy of Astatine-211-Labeled Trastuzumab on Radioresistant SKOV-3 Tumors in Nude Mice

    SciTech Connect

    Palm, Stig Baeck, Tom; Claesson, Ingela; Danielsson, Anna; Elgqvist, Joergen; Frost, Sofia; Hultborn, Ragnar; Jensen, Holger; Lindegren, Sture; Jacobsson, Lars

    2007-10-01

    Purpose: To investigate the potential use of astatine-211 ({sup 211}At)-labeled trastuzumab for the treatment of HER-2-positive, radioresistant ovarian carcinoma. Methods and Materials: Four-week-old nude mice were inoculated intraperitoneally with 5 . 10{sup 6} SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and {sup 211}At-labeled antibody was evaluated. Results: Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between {sup 211}At activity (0-400 kBq on Day 7) and therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq {sup 211}At-trastuzumab, and different groups received 5, 50, or 500 {mu}g trastuzumab on Day 7. The increase from 5 to 50 {mu}g trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 {mu}g trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq {sup 211}At-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24% less tumor weight than the corresponding controls. Conclusion: The combination of 500 {mu}g trastuzumab and 400 kBq {sup 211}At-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model.

  6. Mechanisms of Action of Adjuvants

    PubMed Central

    Awate, Sunita; Babiuk, Lorne A.; Mutwiri, George

    2013-01-01

    Adjuvants are used in many vaccines, but their mechanisms of action are not fully understood. Studies from the past decade on adjuvant mechanisms are slowly revealing the secrets of adjuvant activity. In this review, we have summarized the recent progress in our understanding of the mechanisms of action of adjuvants. Adjuvants may act by a combination of various mechanisms including formation of depot, induction of cytokines and chemokines, recruitment of immune cells, enhancement of antigen uptake and presentation, and promoting antigen transport to draining lymph nodes. It appears that adjuvants activate innate immune responses to create a local immuno-competent environment at the injection site. Depending on the type of innate responses activated, adjuvants can alter the quality and quantity of adaptive immune responses. Understanding the mechanisms of action of adjuvants will provide critical information on how innate immunity influences the development of adaptive immunity, help in rational design of vaccines against various diseases, and can inform on adjuvant safety. PMID:23720661

  7. Inhibition of ErbB2 by herceptin reduces viability and survival, induces apoptosis and oxidative stress in Calu-3 cell line.

    PubMed

    Dogan, Irem; Cumaoglu, Ahmet; Aricioglu, Aysel; Ekmekci, Abdullah

    2011-01-01

    Human epidermal growth factor receptor 2 (ErbB2) amplification and overexpression has been seen in many cancer types including non-small cell lung cancer (NSCLC). Thus, ErbB2 is an important target for cancer therapies. Increased ErbB2 expression has been associated with drug resistance in cancer cells. Herceptin is a humanized monoclonal antibody that targets the extracellular domain of ErbB2. In this study, we aimed to block ErbB2 signaling with Herceptin and assess cytotoxicity and effects on apoptosis, oxidative stress, nuclear factor kappa-B (NF-kB), and Survivin expression in Calu-3 cell line. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay were used to assess cell viability as a marker of proliferation. Acridine orange/ethidium bromide (AO/EB) staining and caspase 3/7 activity were measured as the markers of apoptosis. The relative expressions of NF-kB-p50 and Survivin mRNAs were evaluated. Activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), and the levels of glutathione (GSH) and reactive oxygen species (ROS) were determined in a time- and dose-dependent manner. Our results show that Herceptin treatment inhibits cell proliferation and activates apoptosis but without effects on Survivin and NF-kB expression in Calu-3 cell line. Intracellular glutathione levels and SOD and CAT activities were decreased in a time- and dose-dependent manner associated with oxidative stress. Also, ROS were increased at 24 h. These results provide evidence that Herceptin can be used as a cytotoxic and apoptotic agent in NSCLC. PMID:20936496

  8. Astatinated trastuzumab, a putative agent for radionuclide immunotherapy of ErbB2-expressing tumours.

    PubMed

    Persson, M I; Gedda, L; Jensen, H J; Lundqvist, H; Malmström, P-U; Tolmachev, V

    2006-03-01

    The anti-ErbB2 antibody trastuzumab is used for the treatment of patients with advanced breast cancer, resulting in a response rate of 40-60%. Coupling with a cytotoxic nuclide, e.g. alpha-emitting 211At, may further increase tumour response. The tumour-targeting properties of trastuzumab, astatinated using N-succinimidyl-para-(tri-n-methylstannyl)-benzoate, were evaluated and compared with those of radioiodinated trastuzumab in this study. We found that astatinated trastuzumab retains high specificity towards ErbB2. While the immunoreactive fraction of radioiodinated trastuzumab was higher than that of astatinated trastuzumab (76+/-9% versus 54+/-28%), both radioconjugates showed high affinity (KD 0.75+/-0.16 nM versus 1.8+/-0.3 nM). A growth inhibition study indicated a dose-dependent cell deactivation, in which approximately 74 cell-associated astatine decays per cell gave a survival fraction of 4.5+/-0.8x10(-4). Results of a comparative animal study on normal mice gave no indication that astatination would have any adverse effects on the biodistribution of the antibody. In conclusion, the results of the study suggest that astatinated trastuzumab is a promising candidate for treating ErbB2-expressing tumours. PMID:16465429

  9. A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells

    PubMed Central

    Papadakis, Emmanouil; Robson, Natalia; Yeomans, Alison; Bailey, Sarah; Laversin, Stephanie; Beers, Stephen; Sayan, A. Emre; Ashton-Key, Margaret; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Packham, Graham; Cutress, Ramsey

    2016-01-01

    Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial. PMID:26958811

  10. Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission

    PubMed Central

    Haq, R.; Gulasingam, P.

    2016-01-01

    Background Outcomes in metastatic breast cancer (mbc) positive for her2 (human epidermal growth factor receptor 2) are generally unfavourable. Trastuzumab has revolutionized the prognosis of her2-positive mbc. Some her2-positive mbc patients go into prolonged remission, and a few patients remain in remission even after discontinuation of trastuzumab, suggesting the possibility of a cure. In our practice, 4 her2-positive mbc patients treated with chemotherapy and trastuzumab have remained in remission on maintenance therapy for 5 years or more. Of those 4 patients, 2 have continued in remission after discontinuation of trastuzumab for more than 1 year. The objective of the present paper was therefore to address the duration of trastuzumab therapy in her2-positive mbc patients in prolonged remission. Methods We conducted a literature review of the duration of trastuzumab in her2-positive mbc patients in remission. We also conducted an online survey of oncologists in Ontario to determine their treatment practices in her2-positive mbc patients. Results The literature search found no specific evidence about the optimal duration of trastuzumab maintenance therapy in her2-positive mbc in prolonged remission. However, retrospective studies suggest predictive markers of good prognosis in patients in complete remission taking maintenance trastuzumab. Identifying those markers could lead to more personalized treatment. Our survey of oncologists about their treatment practices in her2-positive mbc patients revealed that 82.93% of respondents (n = 34) follow the currently available guidelines. Conclusions With the emergence of patients in prolonged remission, duration of trastuzumab in her2-positive mbc has become an important and relevant clinical question worldwide. Collaborative efforts are needed for the further study of this topic. PMID:27122973

  11. Physicochemical and biological characterization of a biosimilar trastuzumab.

    PubMed

    López-Morales, Carlos A; Miranda-Hernández, Mariana P; Juárez-Bayardo, L Carmina; Ramírez-Ibáñez, Nancy D; Romero-Díaz, Alexis J; Piña-Lara, Nelly; Campos-García, Víctor R; Pérez, Néstor O; Flores-Ortiz, Luis F; Medina-Rivero, Emilio

    2015-01-01

    According to the World Health Organization, the incidence of malignant neoplasms and endocrine, blood, and immune disorders will increase in the upcoming decades along with the demand of affordable treatments. In response to this need, the development of biosimilar drugs is increasing worldwide. The approval of biosimilars relies on the compliance with international guidelines, starting with the demonstration of similarity in their physicochemical and functional properties against the reference product. Subsequent clinical studies are performed to demonstrate similar pharmacological behavior and to diminish the uncertainty related to their safety and efficacy. Herein we present a comparability exercise between a biosimilar trastuzumab and its reference product, by using a hierarchical strategy with an orthogonal approach, to assess the physicochemical and biological attributes with potential impact on its pharmacokinetics, pharmacodynamics, and immunogenicity. Our results showed that the high degree of similarity in the physicochemical attributes of the biosimilar trastuzumab with respect to the reference product resulted in comparable biological activity, demonstrating that a controlled process is able to provide consistently the expected product. These results also constitute the basis for the design of subsequent delimited pharmacological studies, as they diminish the uncertainty of exhibiting different profiles. PMID:26075238

  12. Physicochemical and Biological Characterization of a Biosimilar Trastuzumab

    PubMed Central

    López-Morales, Carlos A.; Miranda-Hernández, Mariana P.; Juárez-Bayardo, L. Carmina; Ramírez-Ibáñez, Nancy D.; Romero-Díaz, Alexis J.; Piña-Lara, Nelly; Campos-García, Víctor R.; Pérez, Néstor O.; Flores-Ortiz, Luis F.

    2015-01-01

    According to the World Health Organization, the incidence of malignant neoplasms and endocrine, blood, and immune disorders will increase in the upcoming decades along with the demand of affordable treatments. In response to this need, the development of biosimilar drugs is increasing worldwide. The approval of biosimilars relies on the compliance with international guidelines, starting with the demonstration of similarity in their physicochemical and functional properties against the reference product. Subsequent clinical studies are performed to demonstrate similar pharmacological behavior and to diminish the uncertainty related to their safety and efficacy. Herein we present a comparability exercise between a biosimilar trastuzumab and its reference product, by using a hierarchical strategy with an orthogonal approach, to assess the physicochemical and biological attributes with potential impact on its pharmacokinetics, pharmacodynamics, and immunogenicity. Our results showed that the high degree of similarity in the physicochemical attributes of the biosimilar trastuzumab with respect to the reference product resulted in comparable biological activity, demonstrating that a controlled process is able to provide consistently the expected product. These results also constitute the basis for the design of subsequent delimited pharmacological studies, as they diminish the uncertainty of exhibiting different profiles. PMID:26075238

  13. Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy

    PubMed Central

    Baselga, José; Gelmon, Karen A.; Verma, Shailendra; Wardley, Andrew; Conte, PierFranco; Miles, David; Bianchi, Giulia; Cortes, Javier; McNally, Virginia A.; Ross, Graham A.; Fumoleau, Pierre; Gianni, Luca

    2010-01-01

    Purpose Pertuzumab, a human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibody, potently inhibits HER2 dimerization and HER-mediated signaling pathways. Pertuzumab and the approved HER2-targeted monoclonal antibody trastuzumab have complementary mechanisms of action and result in enhanced antitumor activity when combined. This phase II trial assessed the efficacy and safety profile of the combination in patients with HER2-positive breast cancer whose disease had progressed during prior trastuzumab-based therapy. Patients and Methods This was a multicenter, open-label, single-arm, Simon two-stage study. Patients with advanced HER2-positive breast cancer in whom disease progression had occurred during prior trastuzumab-based therapy received trastuzumab weekly (4 mg/kg loading dose, then 2 mg/kg every week) or every 3 weeks (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) and pertuzumab every 3 weeks (840 mg loading dose, then 420 mg every 3 weeks). Treatment continued until disease progression or excessive toxicity. Results All 66 patients were assessable for efficacy and safety. The objective response rate was 24.2%, and the clinical benefit rate was 50%. Five patients (7.6%) experienced a complete response, 11 patients (16.7%) experienced a partial response, and 17 patients (25.8%) experienced stable disease of ≥ 6 months. Median progression-free survival was 5.5 months. Overall, the combination of pertuzumab and trastuzumab was well tolerated, and adverse events were mild to moderate. Cardiac dysfunction was minimal, and no patients withdrew as a result of cardiac-related adverse events. Conclusion The combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy. PMID:20124182

  14. Novel adjuvant systems.

    PubMed

    McCluskie, M J; Weeratna, R D

    2001-11-01

    Vaccination remains the single most valuable tool in the prevention of infectious disease. Nevertheless, there exists a need to improve the performance of existing vaccines such that fewer boosts are needed or to develop novel vaccines. For the development of effective vaccines for humans, a great need exists for safe and effective adjuvants. A number of novel adjuvants have been reported in recent years including: i) bacterial toxins such as cholera toxin, CT, and the Escherichia coli heat-labile enterotoxin, LT; ii) less toxic derivatives of CT and LT; iii) endogenous human immunomodulators, such as IL-2, IL-12, GM-CSF; iv) hormones; v) lipopeptides; vi) saponins, such as QS-21; vii) synthetic oligonucleotides containing CpG motifs (CpG ODN); viii) lipid 'A derivatives, such as monophosphoryl lipid A, MPL, and ix) muramyl dipeptide (MDP) derivatives. Herein, we will review recent findings using these novel adjuvant systems. PMID:12455400

  15. Adjuvant Therapy for Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad A.

    2012-01-01

    Estimates from the U.S. Surveillance, Epidemiology, and End Results (SEER) registry suggest that melanoma incidence will reach 70,230 in 2011, of which 8,790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society. High-dose interferon-α2b is the only agent approved for adjuvant therapy of melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However toxicity affects compliance and current research is focusing upon biomarkers that may allow selection of patients with greater likelihood of response, and exploring new agents either singly or in combination that may improve upon the benefit of IFN. In this article, we review the data for the adjuvant therapy of malignant melanoma - focusing on the results obtained with various regimens testing the several formulations of interferon-α2, and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, and raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway. PMID:22453021

  16. Laser vaccine adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C

    2014-01-01

    Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines. The development of new adjuvants with the potential to be both efficacious and safe constitutes a significant need in modern vaccine practice. The use of non-damaging laser light represents a markedly different approach to enhancing immune responses to a vaccine antigen, particularly with intradermal vaccination. This approach, which was initially explored in Russia and further developed in the US, appears to significantly improve responses to both prophylactic and therapeutic vaccines administered to the laser-exposed tissue, particularly the skin. Although different types of lasers have been used for this purpose and the precise molecular mechanism(s) of action remain unknown, several approaches appear to modulate dendritic cell trafficking and/or activation at the irradiation site via the release of specific signaling molecules from epithelial cells. The most recent study, performed by the authors of this review, utilized a continuous wave near-infrared laser that may open the path for the development of a safe, effective, low-cost, simple-to-use laser vaccine adjuvant that could be used in lieu of conventional adjuvants, particularly with intradermal vaccines. In this review, we summarize the initial Russian studies that have given rise to this approach and comment upon recent advances in the use of non-tissue damaging lasers as novel physical adjuvants for vaccines. PMID:25424797

  17. Trastuzumab Alters the Expression of Genes Essential for Cardiac Function and Induces Ultrastructural Changes of Cardiomyocytes in Mice

    PubMed Central

    ElZarrad, M. Khair; Mukhopadhyay, Partha; Mohan, Nishant; Hao, Enkui; Dokmanovic, Milos; Hirsch, Dianne S.; Shen, Yi; Pacher, Pal; Wu, Wen Jin

    2013-01-01

    Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity. PMID:24255707

  18. Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer

    PubMed Central

    Arienti, Chiara; Zanoni, Michele; Pignatta, Sara; Del Rio, Alberto; Carloni, Silvia; Tebaldi, Michela; Tedaldi, Gianluca; Tesei, Anna

    2016-01-01

    HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2-signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones. PMID:26919099

  19. Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel.

    PubMed

    Cortés, Javier; Swain, Sandra M; Kudaba, Iveta; Hauschild, Maik; Patel, Taral; Grincuka, Elza; Masuda, Norikazu; McNally, Virginia; Ross, Graham; Brewster, Mike; Marier, Jean-François; Trinh, My My; Garg, Amit; Nijem, Ihsan; Visich, Jennifer; Lum, Bert L; Baselga, José

    2013-11-01

    Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer. PMID:23969513

  20. ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3

    PubMed Central

    Ebbing, Eva A.; Medema, Jan Paul; Damhofer, Helene; Meijer, Sybren L.; Krishnadath, Kausilia K.; van Berge Henegouwen, Mark I.

    2016-01-01

    Receptor tyrosine kinases of the HER-family are involved in the development and progression of multiple epithelial tumors, and have consequently become widely used targets for new anti-cancer therapies. Trastuzumab, an antibody against HER2, has shown potent growth inhibitory effects on HER2 overexpressing tumors, including gastro-esophageal cancer, however, resistance to this therapy is inevitable. Unfortunately, a paucity of data on the cellular mechanisms of resistance to targeted therapeutic agents exists in esophageal adenocarcinoma. Using primary established HER2-overexpressing cultures and patient-derived xenograft models, we now reveal a novel resistance mechanism to trastuzumab in esophageal cancer: In response to trastuzumab, both HER3 and the metalloprotease ADAM10 are simultaneously upregulated. The proteolytic activity of the latter then releases the HER3 ligand heregulin from the cell surface to activate HER3 and confer resistance to trastuzumab by inducing compensatory growth factor receptor signaling. Blocking either HER3 or ADAM10 effectively reverts the acquired resistance to trastuzumab. Our data thus provide strategies to inhibit this signaling and circumvent resistance to trastuzumab. PMID:26863569

  1. Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer.

    PubMed

    Arienti, Chiara; Zanoni, Michele; Pignatta, Sara; Del Rio, Alberto; Carloni, Silvia; Tebaldi, Michela; Tedaldi, Gianluca; Tesei, Anna

    2016-04-01

    HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2-signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones. PMID:26919099

  2. New-onset heart failure in association with severe hypertension during trastuzumab therapy.

    PubMed

    Herrmann, Joerg; Herrmann, Sandra M; Haddad, Tufia C

    2014-12-01

    Heart failure is a dreaded complication of trastuzumab therapy in women with breast cancer overexpressing the human epidermal growth factor receptor (HER)-2. Experimental studies have pointed out that the HER-2 signaling pathway is important in the adaptation to high afterload conditions and its inactivation leads to cardiac decompensation. Herein, we report on 2 patients with breast cancer who were receiving trastuzumab monotherapy and required hospital admission for new-onset heart failure. This occurred at a time of unprecedented blood pressure elevations, in one case due to cessation of antihypertensive medications and in the other case due to a scleroderma crisis. Although trastuzumab may not have been the precipitating factor for blood pressure dyscontrol in these patients, severe, uncontrolled hypertension may have been the precipitating factor for trastuzumab-related acute heart failure. These 2 cases add to previous reports recognizing systemic hypertension as a risk factor for the development of trastuzumab cardiotoxicity and translate experimental observations of the significance of the HER-2 signaling pathway to the bedside. Pending further confirmation, the present observations may raise awareness of the need for appropriate monitoring and control of systemic hypertension in patients receiving trastuzumab, or potentially any other HER-2-targeted therapy. PMID:25441402

  3. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?

    PubMed

    Arnould, L; Gelly, M; Penault-Llorca, F; Benoit, L; Bonnetain, F; Migeon, C; Cabaret, V; Fermeaux, V; Bertheau, P; Garnier, J; Jeannin, J-F; Coudert, B

    2006-01-30

    This study evaluated by immunohistochemistry (IHC) immune cell response during neoadjuvant primary systemic therapy (PST) with trastuzumab in patients with HER2-positive primary breast cancer. In all, 23 patients with IHC 3+ primary breast cancer were treated with trastuzumab plus docetaxel. Pathological complete and partial responses were documented for nine (39%) and 14 (61%) patients, respectively. Case-matched controls comprised patients treated with docetaxel-based PST without trastuzumab (D; n=23) or PST without docetaxel or trastuzumab (non-taxane, non-trastuzumab, NT-NT; n=23). All surgical specimens were blind-analysed by two independent pathologists, with immunohistochemical evaluation of B and T lymphocytes, macrophages, dendritic cells and natural killer (NK) cells. Potential cytolytic cells were stained for Granzyme B and TiA1. HER2 expression was also evaluated in residual tumour cells. Trastuzumab treatment was associated with significantly increased numbers of tumour-associated NK cells and increased lymphocyte expression of Granzyme B and TiA1 compared with controls. This study supports an in vivo role for immune (particularly NK cell) responses in the mechanism of trastuzumab action in breast cancer. These results suggest that trastuzumab plus taxanes lead to enhanced NK cell activity, which may partially account for the synergistic activity of trastuzumab and docetaxel in breast cancer. PMID:16404427

  4. HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

    PubMed Central

    2013-01-01

    combination of immunohistochemistry (IHC) and in situ hybridization as the current gold standard [9,10]. As an additional approach determination of HER2 mRNA expression is technically feasible in formalin-fixed paraffin-embedded (FFPE) tissue [11-13]. Crosstalk between the estrogen receptor (ER) and the HER2 pathway has been suggested based on cell culture and animal models [14]. Consequently, the 2011 St Gallen panel has pointed out that HER2-positive tumors should be divided into two groups based on expression of the ER [15]. A retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study has suggested that mRNA levels of HER2 and ESR1 might be relevant for the degree of benefit from adjuvant trastuzumab. By subpopulation treatment effect pattern plot (STEPP) analysis in ER-positive tumors, benefit from trastuzumab was shown to be restricted to those with higher levels of HER2 mRNA (S Paik, personal communication, results summarized in [15]). In our study we evaluated this hypothesis in the neoadjuvant setting in a cohort of 217 patients from the neoadjuvant GeparQuattro trial [5]. All patients had been HER2- positive by local pathology assessment and had received 24 to 36 weeks of neoadjuvant trastuzumab plus an anthracycline/taxane-based chemotherapy. For central evaluation we used three different methods, HER2 IHC, and HER2 silver in situ hybridization (SISH), as well as measurement of HER2 mRNA by quantitative real-time (qRT)-PCR [11]. The primary objective of this analysis was to investigate if pathological complete response (pCR) rate in HER2-positive breast cancer would depend on the level of HER2 mRNA expression, with a separate analysis for HR-positive and -negative tumors. Central evaluation of the HER2 status showed that 27% of the tumors with HER2 overexpression by local pathology were HER2-negative. This enabled us to compare response rates in patients with HER2-positive and -negative tumors as a secondary objective. PMID

  5. Trastuzumab use during pregnancy: long-term survival after locally advanced breast cancer and long-term infant follow-up.

    PubMed

    Andrade, Jurandyr M de; Brito, Luiz G O; Moises, Elaine C D; Amorim, Andréa C; Rapatoni, Liane; Carrara, Hélio H A; Tiezzi, Daniel G

    2016-04-01

    Here, we describe the case of a patient diagnosed with locally advanced breast cancer 8 years ago. Her treatment course was neoadjuvant chemotherapy, followed by mastectomy and then adjuvant radiotherapy and trastuzumab (TTZ). During the use of adjuvant targeted therapy, an incidental pregnancy was diagnosed. Four years later, she developed bone and cerebral metastases, and since then, she has received courses of TTZ, capecitabine, lapatinib, and radiotherapy with intermittent control of the disease. Her 7-year-old son presents a normal physical and long-term neurological developmental curve according to specialized evaluation. This case is unique for several reasons: the patient received the highest dose of TTZ yet described during pregnancy (4400 mg); there has been a long period of disease-free survival after treatment for locally advanced breast cancer and long overall survival despite successive disease progressions during the metastatic phase of the disease (97 months), and there was a monitored pediatric follow-up period (7 years). PMID:26825868

  6. Inhibition of autophagy induced by PTEN loss promotes intrinsic breast cancer resistance to trastuzumab therapy.

    PubMed

    Ning, Liao; Guo-Chun, Zhang; Sheng-Li, An; Xue-Rui, Li; Kun, Wang; Jian, Zu; Chong-Yang, Ren; Ling-Zhu, Wen; Hai-Tong, Lv

    2016-04-01

    This study aims to explore the effects of the phosphatase and tension homolog (PTEN) expression level on autophagic status and on the resistance of breast cancer to trastuzumab treatment. PTEN and LC3I/II were knocked down with shRNA expression vectors, which were transfected into estrogen receptor (ER)-positive breast cancer cell lines. After trastuzumab treatment, the changes in the autophagy signal transduction pathways and autophagic proteins (LC3I/II, p62, LAMP, and cathepsin B) in these stably transfected cells were detected using western blot. The cells were also orthotopically implanted into nude mice to explore the influence of PTEN knockdown on tumor size, cell viability, and autophagic proteins after trastuzumab treatment. Similar determinations were performed using the LC3I/II overexpressed shPTEN breast cancer cells (LC3I/II-shPTEN). Downregulation of PTEN and autophagic proteins LC3-I and LC3-II was observed in resistant human breast cancer samples. Knockdown of PTEN and PTEN+ LC3I/II with shRNA in breast cancer cells resulted in increased resistance to trastuzumab. Consistently, trastuzumab treatment could not effectively reduce tumor size. Significant decreases in the levels of autophagic proteins LC3I/II, LAMP, p62, cathepsin B, and PI3K-Akt-mTOR and the signaling pathway protein Akt were found in PTEN knockdown cells, compared to the PTEN normal group, after trastuzumab administration, both in vitro and in vivo. However, these findings were reversed with the LC3I/II-shPTEN treatment. Therefore, the loss of PTEN may promote the development of primary resistance to trastuzumab in breast cancer via autophagy defects. PMID:26563373

  7. In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

    PubMed Central

    El-Sahwi, K; Bellone, S; Cocco, E; Cargnelutti, M; Casagrande, F; Bellone, M; Abu-Khalaf, M; Buza, N; Tavassoli, F A; Hui, P; Silasi, D-A; Azodi, M; Schwartz, P E; Rutherford, T J; Pecorelli, S; Santin, A D

    2009-01-01

    Background: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. Methods: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. Results: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. Conclusion: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic

  8. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers

    PubMed Central

    Ghosh, Ritwik; Narasanna, Archana; Wang, Shizhen Emily; Liu, Shuying; Chakrabarty, Anindita; Balko, Justin M.; González-Angulo, Ana María; Mills, Gordon B.; Penuel, Elicia; Winslow, John; Sperinde, Jeff; Dua, Rajiv; Pidaparthi, Sailaja; Mukherjee, Ali; Leitzel, Kim; Kostler, Wolfgang J.; Lipton, Allan; Bates, Michael; Arteaga, Carlos L.

    2011-01-01

    In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2+ breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated non-transformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. As expected, trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of HER2-overexpressing patients. Together, our findings corroborate the hypothesis that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers reflects an inability to activate the PI3K/AKT pathway. One of the most important clinical implications of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID:21324925

  9. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers.

    PubMed

    Ghosh, Ritwik; Narasanna, Archana; Wang, Shizhen Emily; Liu, Shuying; Chakrabarty, Anindita; Balko, Justin M; González-Angulo, Ana María; Mills, Gordon B; Penuel, Elicia; Winslow, John; Sperinde, Jeff; Dua, Rajiv; Pidaparthi, Sailaja; Mukherjee, Ali; Leitzel, Kim; Kostler, Wolfgang J; Lipton, Allan; Bates, Michael; Arteaga, Carlos L

    2011-03-01

    In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers, and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2(+) breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. Trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, the HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with HER2-overexpressing breast cancer. Together, our findings confirm the notion that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway. A clinical implication of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID:21324925

  10. Trastuzumab Administration in Patients with Metastatic Breast Cancer – Experience of a Large University Breast Center

    PubMed Central

    Hartkopf, A. D.; Brendel, M. H.; Wallwiener, M.; Taran, F.-A.; Brucker, S.; Grischke, E.-M.

    2014-01-01

    Background: Administered either alone or in combination with various cytostatic, endocrine or targeted therapies, trastuzumab significantly improves the prognosis of patients with HER2-positive breast cancer. As trastuzumab is effective across multiple lines of therapy in the metastatic setting (treatment beyond progression: TBP), it is often administered over a long period of time. The aim of this study was to evaluate the tolerability and clinical practice of long-term trastuzumab administration (> 1 year) in metastatic breast cancer patients treated in a large university breast center. Methods: Metastatic breast cancer patients who received at least 18 cycles of trastuzumab administered every three weeks at the University Gynecological Hospital of Tuebingen between 1999 and 2012 were included in this retrospective study. Typical combination drugs, side effects, and the impact of administration on left ventricular ejection fraction (LVEF) were investigated. Results: 72 patients were eligible for inclusion in the study. The mean number of administrations was 50.14 (SD: 27.51). In 53 patients the principle of TBP was followed across an average of 2.4 therapy lines. Classic cardiac risk factors were present at the beginning of trastuzumab treatment in 34 patients (47 %). Seven patients (10 %) experienced a decrease in LVEF during treatment, 9 patients (13 %) had hypersensitivity reactions. Treatment was discontinued in two patients due to side effects (1 × progressive LVEF decrease, 1 × intolerance). Summary: The administration of trastuzumab across multiple lines of therapy was generally tolerated well. Cardiac risk factors were not a limiting factor. If regular cardiac monitoring is done, trastuzumab appears not only to improve survival but also helps preserve the quality of life of patients with HER2-positive metastatic breast cancer. PMID:24976638

  11. Lipid-conjugated telomerase template antagonists sensitize resistant HER2-positive breast cancer cells to trastuzumab.

    PubMed

    Goldblatt, Erin M; Erickson, Priscilla A; Gentry, Erin R; Gryaznov, Sergei M; Herbert, Brittney-Shea

    2009-11-01

    HER2 amplification in breast cancer is associated with a more aggressive disease, greater likelihood of recurrence, and decreased survival compared to women with HER2-negative breast cancer. Trastuzumab is a monoclonal antibody that inhibits HER2 activity, making this compound an important therapeutic option for patients with HER2-positive breast cancer. However, resistance to trastuzumab develops rapidly in a large number of breast cancer patients. The objective of this study was to determine whether GRN163L, a telomerase template antagonist currently in clinical trials for cancer treatment, can augment the effects of trastuzumab in breast cancer cells with HER2 amplification. GRN163L was effective in inhibiting telomerase activity and shortening telomeres in HER2-positive breast cancer cells. We show that GRN163L acts synergistically with trastuzumab in inhibiting HER2-positive breast cancer cell growth. More importantly, we show that GRN163L can restore the sensitivity of therapeutic-resistant breast cancer cells to trastuzumab. These findings implicate that telomerase template antagonists have potential use in the treatment of cancers that have developed resistance to traditional cancer therapy. PMID:18853252

  12. Trastuzumab-mediated selective delivery for platinum drug to HER2-positive breast cancer cells.

    PubMed

    Huang, Rong; Sun, Yu; Gao, Qihe; Wang, Qiucui; Sun, Baiwang

    2015-10-01

    Oxaliplatin is used widely as an anticancer drug for clinical treatment. However, its applications are limited because of its poor selectivity. In this work, we described the design, synthesis, and characterization of conjugates combining trastuzumab with a platinum (IV) analog of oxaliplatin, in which the trastuzumab acted as an active targeting agent for HER2-positive cancer cells. Indirect enzyme-linked immunosorbent assay and immunofluorescence study indicated the platinum (IV)-trastuzumab conjugates retained specific binding activity to HER2 overexpressed SK-BR-3 cells. In the presence of ascorbic acid, platinum (IV)-trastuzumab conjugates were reduced to platinum (II) analogs, which could bind to and unwind PUC19 DNA in a manner similar to oxaliplatin. The cytotoxic study was tested on three breast cell lines: SK-BR-3, MCF-7, and MDA-MB-231. Platinum (IV)-trastuzumab conjugates showed promising antiproliferative activity against SK-BR-3 cells, but significantly decreased the inhibition to MDA-MB-231 and MCF-7 cells. The flow cytometric analysis showed that the conjugates arrested the cell cycle mainly at the G2/M phase and killed the cells through an apoptotic pathway. PMID:26186063

  13. Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance.

    PubMed

    Pedersen, Mikkel W; Jacobsen, Helle J; Koefoed, Klaus; Dahlman, Anna; Kjær, Ida; Poulsen, Thomas T; Meijer, Per-Johan; Nielsen, Lars S; Horak, Ivan D; Lantto, Johan; Kragh, Michael

    2015-03-01

    HER2 plays an important role in the development and maintenance of the malignant phenotype of several human cancers. As such, it is a frequently pursued therapeutic target and two antibodies targeting HER2 have been clinically approved, trastuzumab and pertuzumab. It has been suggested that optimal inhibition of HER2 is achieved when utilizing two or more antibodies targeting nonoverlapping epitopes. Superior clinical activity of the trastuzumab plus pertuzumab combination in metastatic breast cancer supports this hypothesis. Because trastuzumab and pertuzumab were not codeveloped, there may be potential for further optimizing HER2 targeting. The study herein evaluated functional activity of anti-HER2 antibody combinations identifying optimal epitope combinations that provide efficacious HER2 inhibition. High-affinity antibodies to all four extracellular domains on HER2 were identified and tested for ability to inhibit growth of different HER2-dependent tumor cell lines. An antibody mixture targeting three HER2 subdomains proved to be superior to trastuzumab, pertuzumab, or a combination in vitro and to trastuzumab in two in vivo models. Specifically, the tripartite antibody mixture induced efficient HER2 internalization and degradation demonstrating increased sensitivity in cell lines with HER2 amplification and high EGFR levels. When compared with individual and clinically approved mAbs, the synergistic tripartite antibody targeting HER2 subdomains I, II, and IV demonstrates superior anticancer activity. PMID:25612619

  14. Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma

    PubMed Central

    Peiró, G; Ortiz-Martínez, F; Gallardo, A; Pérez-Balaguer, A; Sánchez-Payá, J; Ponce, J J; Tibau, A; López-Vilaro, L; Escuin, D; Adrover, E; Barnadas, A; Lerma, E

    2014-01-01

    Background: Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas. Methods: We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome. Results: Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab. Conclusions: Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients. PMID:24937674

  15. Adjuvant Therapy Trials.

    PubMed

    Ursem, Carling; Van Loon, Katherine; Venook, Alan

    2016-01-01

    In 2015, ramucirumab and TAS-102 became the 10th and 11th drugs approved by the Food and Drug administration for the treatment of patients with colorectal cancer, not counting leucovorin, and yet only 3 agents, 5-fluorouracil, capecitabine, and oxaliplatin, have proven benefit in adjuvant treatment. In fact, there have been no additions (and 1 subtraction levamisole) to our arsenal of therapies for patients with stages II and III colon cancer for more than a decade. How did we get here? Are we stuck? And how do we move forward? PMID:27341598

  16. Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine

    SciTech Connect

    Fitzsimmons, Jonathan; Nayak, Tapan; Cutler, Cathy; Atcher, Robert

    2015-12-30

    Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. In conclusion, the results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.

  17. Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

    PubMed

    Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

    2016-01-10

    Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. PMID:26367328

  18. Carbohydrate-based immune adjuvants

    PubMed Central

    Petrovsky, Nikolai; Cooper, Peter D

    2011-01-01

    The role for adjuvants in human vaccines has been a matter of vigorous scientific debate, with the field hindered by the fact that for over 80 years, aluminum salts were the only adjuvants approved for human use. To this day, alum-based adjuvants, alone or combined with additional immune activators, remain the only adjuvants approved for use in the USA. This situation has not been helped by the fact that the mechanism of action of most adjuvants has been poorly understood. A relative lack of resources and funding for adjuvant development has only helped to maintain alum’s relative monopoly. To seriously challenge alum’s supremacy a new adjuvant has many major hurdles to overcome, not least being alum’s simplicity, tolerability, safety record and minimal cost. Carbohydrate structures play critical roles in immune system function and carbohydrates also have the virtue of a strong safety and tolerability record. A number of carbohydrate compounds from plant, bacterial, yeast and synthetic sources have emerged as promising vaccine adjuvant candidates. Carbohydrates are readily biodegradable and therefore unlikely to cause problems of long-term tissue deposits seen with alum adjuvants. Above all, the Holy Grail of human adjuvant development is to identify a compound that combines potent vaccine enhancement with maximum tolerability and safety. This has proved to be a tough challenge for many adjuvant contenders. Nevertheless, carbohydrate-based compounds have many favorable properties that could place them in a unique position to challenge alum’s monopoly over human vaccine usage. PMID:21506649

  19. A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01)1

    PubMed Central

    Yin, Donghua; Barker, Kerry B; Li, Ruifeng; Meng, Xu; Reich, Steven D; Ricart, Alejandro D; Rudin, Dan; Taylor, Carrie T; Zacharchuk, Charles M; Hansson, Arne G

    2014-01-01

    Aims The pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed. Methods In this phase 1, double-blind trial (NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg−1 intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration–time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab-EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria. Results Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax, and AUC(0,∞) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term ‘pyrexia’ was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA). Conclusions This study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab. PMID:25041377

  20. Adjuvant Therapy: Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad; Kirkwood, John M.

    2011-01-01

    With an incidence that is increasing at 2–5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway. PMID:22220281

  1. Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells.

    PubMed

    Carson, W E; Parihar, R; Lindemann, M J; Personeni, N; Dierksheide, J; Meropol, N J; Baselga, J; Caligiuri, M A

    2001-10-01

    The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2/neu+ (MCF-7Her2/neu) and Her2/neu- (MDA-468) breast cancer cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5-coated MCF-7Her2/neu and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respectively (p < 0.05). Lysis was less than 5% when targets were treated with either the non-humanized mu4D5 mAb or control huIgG. Lysis of rhu4D5-coated MCF-7Her2/neu cells was inhibited by 80 % when NK cells were pre-treated with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. Enhanced ADCC of MCF-7Her2/neu target cells was seen when the effector cells consisted of mononuclear cells obtained from a patient demonstrating significant expansion of NK cells secondary to therapy with low-dose IL-2. Serum from patients receiving infusions of rhu4D5 mAb could substitute for exogenous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumor cells in the presence of IL-2 also produced large amounts of IFN-gamma with concomitant up-regulation of cell-surface activation markers CD25 and CD69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2 therapy in patients with cancers that express the Her2/neu oncogene. PMID:11592078

  2. Efficacy of Trastuzumab in Routine Clinical Practice and After Progression for Metastatic Breast Cancer Patients: The Observational Hermine Study

    PubMed Central

    Antoine, Eric C.; Vincent-Salomon, Anne; Delozier, Thierry; Kerbrat, Pierre; Bethune-Volters, Anne; Guastalla, Jean-Paul; Spielmann, Marc; Mauriac, Louis; Misset, Jean-Louis; Serin, Daniel; Campone, Mario; Hebert, Christophe; Remblier, Céline; Bergougnoux, Loïc; Campana, Frank; Namer, Moïse

    2010-01-01

    Background. The Hermine study observed the use of trastuzumab for metastatic breast cancer (MBC) in routine practice, including patients who received trastuzumab treatment beyond progression (TBP). Patients and Methods. The study observed 623 patients for ≥2 years. Treatment was given according to oncologists' normal clinical practices. Endpoints included duration of treatment, efficacy, and cardiac safety. The TBP subanalysis compared overall survival (OS) in 177 patients who received first-line trastuzumab and either continued trastuzumab for ≥30 days following progression or stopped at or before progression. Results. The median treatment duration was 13.3 months. In the first-, second-, and third-line or beyond treatment groups, the median time to progression (TTP) were 10.3 months, 9.0 months, and 6.3 months, and the median OS times were 30.3 months, 27.1 months, and 23.2 months, respectively. Heart failure was observed in 2.6% of patients, although no cardiac-associated deaths occurred. In the TBP subanalysis, the median OS duration from treatment initiation and time of disease progression were longer in patients who continued receiving trastuzumab TBP (>27.8 months and 21.3 months, respectively) than in those who stopped (16.8 months and 4.6 months, respectively). However, the groups were not completely comparable, because patients who continued trastuzumab TBP had better prognoses at treatment initiation. The median TTP was longer in patients who continued trastuzumab TBP (10.2 months) than in those who stopped (7.1 months). Conclusion. The Hermine findings confirm that the pivotal trials of first-line trastuzumab treatment in MBC patients are applicable in clinical practice. The subanalysis suggests that trastuzumab TBP offers a survival benefit to MBC patients treated with first-line trastuzumab. PMID:20671105

  3. Pertuzumab, trastuzumab and docetaxel reduced the recurrence of brain metastasis from breast cancer: a case report.

    PubMed

    Senda, Noriko; Yamaguchi, Ayane; Nishimura, Hideaki; Shiozaki, Toshiki; Tsuyuki, Shigeru

    2016-03-01

    The CLEOPATRA trial reported the survival benefit of pertuzumab with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients. However, there are a few case reports concerning the effects of a pertuzumab-containing regimen on brain metastases. A 55-year-old woman, who underwent curative surgery for breast cancer after neoadjuvant chemotherapy 5 years previously, developed repeated solitary brain metastasis in her right occipital lobe. Whole brain radiation therapy, stereotactic radiosurgery and 3 times of surgical resection were performed. Lapatinib and capecitabine plus tamoxifen were administered. The metastasis recurred in the stump of the previous surgery. Pertuzumab with trastuzumab plus docetaxel was initiated as second-line chemotherapy. A complete response of the brain metastasis was achieved, which persisted for 5 months. Pertuzumab with trastuzumab plus docetaxel was effective in reducing the brain metastases from breast cancer. Further studies are warranted to confirm the effect of this regimen on brain metastases. PMID:26116144

  4. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine.

    PubMed

    Podda, A

    2001-03-21

    Elderly people and subjects with underlying chronic diseases are at increased risk for influenza and related complications. Conventional influenza vaccines provide only limited protection in the elderly population. In order to enhance the immune response to influenza vaccines, several adjuvants have been evaluated. Among these, an oil in water adjuvant emulsion containing squalene, MF59, has been combined with subunit influenza antigens and tested in clinical trials in comparison with non-adjuvanted conventional vaccines. Data from a clinical database of over 10000 elderly subjects immunised with this adjuvanted vaccine (Fluad, Chiron Vaccines, Siena, Italy) demonstrate that, although common postimmunisation reactions are more frequent in recipients of the adjuvanted vaccine, this vaccine is well tolerated, also after re-immunisation in subsequent influenza seasons. Immunogenicity analyses demonstrate a consistently higher immune response with statistically significant increases of postimmunisation geometric mean titres, and of seroconversion and seroprotection rates compared to non-adjuvanted subunit and split influenza vaccines, particularly for the A/H3N2 and the B strains. The higher immunogenicity profile of the MF59-adjuvanted vaccine is maintained also after subsequent immunisations. An even higher adjuvant effect was shown in subjects with low pre-immunisation titre and in those affected by chronic underlying diseases. In conclusion, the addition of MF59 to subunit influenza vaccines enhances significantly the immune response in elderly subjects without causing clinically important changes in the safety profile of the influenza vaccine. PMID:11257408

  5. Cardiac toxicity of trastuzumab in metastatic breast cancer patients previously treated with high-dose chemotherapy: a retrospective study

    PubMed Central

    Bengala, C; Zamagni, C; Pedrazzoli, P; Matteucci, P; Ballestrero, A; Da Prada, G; Martino, M; Rosti, G; Danova, M; Bregni, M; Jovic, G; Guarneri, V; Maur, M; Conte, P F

    2006-01-01

    HER-2 overexpression is associated to a poor prognosis in high-risk and metastatic breast cancer (MBC) patients treated with high-dose chemotherapy (HDC). HER-2 status is also a predictive factor and when trastuzumab is administered in combination with or sequentially to chemotherapy, a significant disease-free and/or overall survival improvement has been observed in HER-2+ early and MBC. Unfortunately, in both settings, trastuzumab is associated with an increased risk of cardiac dysfunction (CD). We have reviewed the clinical charts of HER-2-overexpressing MBC patients treated with trastuzumab after HDC. Age, baseline left ventricular ejection fraction (LVEF), radiation therapy on cardiac area, exposure to anthracycline, single or multiple transplant, high-dose agents, trastuzumab treatment duration were recorded as potential risk factors. In total, 53 patients have been included in the analysis. Median LVEF at baseline was 60.5%; at the end of trastuzumab (data available for 28 patients only), it was 55% (P=0.01). Five out of the 28 (17.9%) patients experienced CD. Two out of 53 (3.8%) patients developed a congestive heart failure. Age ⩾50 years and multiple transplant procedure were potential risk factors for CD. The overall incidence of CD observed in this population of HER-2+ MBC patients treated with trastuzumab after HDC is not superior to that reported with concomitant trastuzumab and anthracyclines. However, patients with age ⩾50 years or receiving multiple course of HDC should be considered at risk for CD. PMID:16570045

  6. Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance

    PubMed Central

    Bailey, Tameka A.; Luan, Haitao; Clubb, Robert J.; Naramura, Mayumi; Band, Vimla; Raja, Srikumar M.; Band, Hamid

    2011-01-01

    The Human Epidermal Growth Factor Receptor 2 (Her2, ErbB2 or Neu) is overexpressed in about 20 – 25% of breast cancers and is causally linked to oncogenesis, providing opportunities for targeted therapy. Trastuzumab (Herceptin™, Genentech Inc, San Francisco, CA), a humanized monoclonal antibody against ErbB2, is a successful example of this concept and has vastly improved the response to treatment and overall survival in a majority of ErbB2+ breast cancer patients. However, lack of response in some patients as well as relapse during the course of therapy in others, continue to challenge researchers and clinicians alike towards a better understanding of the fundamental mechanisms of Trastuzumab action and resistance to treatment. The exact in vivo mechanism of action of Trastuzumab remains enigmatic, given its direct effects on the ErbB2 signaling pathway as well as indirect contributions from the immune system, by virtue of the ability of Trastuzumab to elicit Antibody-Dependent Cellular Cytotoxicity. Consequently, multiple mechanisms of resistance have been proposed. We present here a comprehensive review of our current understanding of the mechanisms, both of Trastuzumab action and clinical resistance to Trastuzumab-based therapies. We also review newer strategies (based on ErbB2 receptor biology) that are being explored to overcome resistance to Trastuzumab therapy. PMID:22190870

  7. A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer.

    PubMed

    Nam, Seungyoon; Chang, Hae Ryung; Jung, Hae Rim; Gim, Youme; Kim, Nam Youl; Grailhe, Regis; Seo, Haeng Ran; Park, Hee Seo; Balch, Curt; Lee, Jinhyuk; Park, Inhae; Jung, So Youn; Jeong, Kyung-Chae; Powis, Garth; Liang, Han; Lee, Eun Sook; Ro, Jungsil; Kim, Yon Hui

    2015-01-28

    Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance. PMID:25449779

  8. Experimental α-particle radioimmunotherapy of breast cancer using 227Th-labeled p-benzyl-DOTA-trastuzumab

    PubMed Central

    2011-01-01

    Background The aim of the present study was to explore the biodistribution, normal tissue toxicity, and therapeutic efficacy of the internalizing low-dose rate alpha-particle-emitting radioimmunoconjugate 227Th-trastuzumab in mice with HER2-expressing breast cancer xenografts. Methods Biodistribution of 227Th-trastuzumab and 227Th-rituximab in nude mice bearing SKBR-3 xenografts were determined at different time points after injection. Tumor growth was measured after administration of 227Th-trastuzumab, 227Th-rituximab, cold trastuzumab, and saline. The toxicity of 227Th-trastuzumab was evaluated by measurements of body weight, blood cell, and clinical chemistry parameters, as well as histological examination of tissue specimens. Results The tumor uptake reached peak levels of 34% ID/g (4.6 kBq/g) 3 days after injection of 400 kBq/kg of 227Th-trastuzumab. The absorbed radiation dose to tumor was 2.9 Gy, while it was 2.4 Gy to femur due to uptake of the daughter nuclide 223Ra in bone; the latter already explored in clinical phases I and II trials without serious toxicity. A significant dose-dependent antitumor effect was observed for dosages of 200, 400, and 600 kBq/kg of 227Th-trastuzumab but no effect of 400 and 600 kBq/kg 227Th-rituximab (non-tumor binding). No serious delayed bone marrow or normal organ toxicity was observed, but there was a statistical significant reduction in blood cell parameters for the highest-dose group of 227Th-trastuzumab treatment. Conclusion Internalizing 227Th-trastuzumab therapy was well tolerated and resulted in a dose-dependent inhibition of breast cancer xenograft growth. These results warrant further preclinical studies aiming at a clinical trial in breast cancer patients with metastases to bone. PMID:22214432

  9. Bench to Bedside: Stability Studies of GMP Produced Trastuzumab-TCMC in Support of a Clinical Trial

    PubMed Central

    Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2015-01-01

    The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with 212Pb-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (212Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate that after five dose-levels of intraperitoneally administered 212Pb-TCMC-trastuzumab, patients with carcinomatosis experienced minimal agent-related toxicity. This report presents the data accumulated to date on the stability of the clinical grade, produced according to current good manufacturing practices (cGMP), TCMC-trastuzumab conducted in support of that clinical trial. Of the eleven tests performed with the cGMP TCMC-trastuzumab all but one remained within specifications throughout the 5 year testing period. The protein concentration varied by 0.01 mg/mL at 48 months. Two other assays, ion-exchange high performance liquid chromatography (IEX-HPLC) and a competitive radioimmunoassay (RIA) indicated that the cGMP TCMC-trastuzumab integrity may be changing, although the change thus far is within specifications. Subsequent stability testing will confirm if a trend has truly developed. The cGMP TCMC-trastuzumab was also evaluated for tolerance to higher temperatures and the potential of storage at −80 °C. The immunoconjugate proved stable when subjected to the lower temperatures and to multiple freeze-thaw cycles. The size exclusion (SE) HPLC analysis of the 203Pb-TCMC-trastuzumab was the only indicator that cGMP TCMC-trastuzumab may be sensitive to storage at 37 °C for 3 months. PMID:26230702

  10. Bench to Bedside: Stability Studies of GMP Produced Trastuzumab-TCMC in Support of a Clinical Trial.

    PubMed

    Milenic, Diane E; Baidoo, Kwamena E; Brechbiel, Martin W

    2015-01-01

    The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with 212Pb-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (212Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate that after five dose-levels of intraperitoneally administered 212Pb-TCMC-trastuzumab, patients with carcinomatosis experienced minimal agent-related toxicity. This report presents the data accumulated to date on the stability of the clinical grade, produced according to current good manufacturing practices (cGMP), TCMC-trastuzumab conducted in support of that clinical trial. Of the eleven tests performed with the cGMP TCMC-trastuzumab all but one remained within specifications throughout the 5 year testing period. The protein concentration varied by 0.01 mg/mL at 48 months. Two other assays, ion-exchange high performance liquid chromatography (IEX-HPLC) and a competitive radioimmunoassay (RIA) indicated that the cGMP TCMC-trastuzumab integrity may be changing, although the change thus far is within specifications. Subsequent stability testing will confirm if a trend has truly developed. The cGMP TCMC-trastuzumab was also evaluated for tolerance to higher temperatures and the potential of storage at -80 °C. The immunoconjugate proved stable when subjected to the lower temperatures and to multiple freeze-thaw cycles. The size exclusion (SE) HPLC analysis of the 203Pb-TCMC-trastuzumab was the only indicator that cGMP TCMC-trastuzumab may be sensitive to storage at 37 °C for 3 months. PMID:26230702

  11. Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.

    PubMed

    Kawajiri, Hidemi; Takashima, Tsutomu; Kashiwagi, Shinichiro; Noda, Satoru; Onoda, Naoyoshi; Hirakawa, Kosei

    2015-01-01

    Overexpression of HER2 - found in approximately 15-20% of all breast cancers - is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer. PMID:25494663

  12. Trastuzumab-based chemotherapy modulates systemic redox homeostasis in women with HER2-positive breast cancer.

    PubMed

    Lemos, L G T; Victorino, V J; Herrera, A C S A; Aranome, A M F; Cecchini, A L; Simão, A N C; Panis, C; Cecchini, R

    2015-07-01

    Trastuzumab is an immunotargeting therapeutic against breast tumors with amplification of the human epithelial growth factor receptor 2 (HER2). HER2 patients naturally exhibit disruption in the pro-oxidant inflammatory profiling; however, the impact of trastuzumab-based chemotherapy in modulating this process is still unknown. Here we determined the systemic pro-inflammatory profile of women diagnosed with HER2-amplified tumors, undergoing trastuzumab-based chemotherapy (TZ), and compared the results with that of healthy controls (CTR) and untreated patients with HER2-amplified breast cancer (CA). The plasmatic inflammatory profile was assessed by evaluating pro-oxidant parameters such as lipid peroxidation, total antioxidant capacity (TRAP), levels of advanced oxidation protein products (AOPPs), nitric oxide (NO), C-reactive protein (CRP), and total thiol content. Markers of cardiac damage were also assessed. Our findings showed increased NO levels in TZ than that in either CA or CTR groups. Furthermore, TZ augmented TRAP and reduced total thiol than that of the CA group. Our data also revealed that AOPP levels were significantly higher in the TZ than the CA group. AOPP and the MB fraction of creatine-kinase (CKMB) levels were positively correlated in TZ patients. These findings suggest that trastuzumab-associated chemotherapy can modulate the pro-inflammatory markers of HER2-positive breast cancer patients to the levels found in healthy controls. PMID:25937481

  13. Examination of the clinical efficacy of eribulin and trastuzumab in HER2-positive recurrent breast cancer

    PubMed Central

    KIBA, TAKAYOSHI; MORII, NAO; TAKAHASHI, HIROTOSHI; OZAKI, SHINJI; ATSUMI, MISAO; MASUMOTO, FUMI; SHITAKUBO, YOSHIMI; YAMASHIRO, HIROYASU

    2016-01-01

    There are limited studies reported that describe the efficacy of eribulin and trastuzumab in the treatment of recurrent breast cancer. The present study examined the therapeutic efficacy of eribulin and trastuzumab in the treatment of recurrent breast cancer. Between October 2011 and August 2013, 5 recurrent breast cancer patients who were treated with eribulin and trastuzumab were included in the study. The cancer stages in the 5 women who received this regimen were stage IIIB in 1 (20%) and stage IV in 4 (80%). The sites of recurrence were the lung in 3 patients, liver in 2, bone in 1, brain in 1, supraclavicular lymph nodes in 1, infraclavicular lymph nodes in 1 and mediastinal lymph nodes in 1. The median number of prior treatment regimens was 5 (range, 5–11). Complete response was achieved in 0 patients, 1 achieved partial response, 3 had stable disease, and 1 had progressive disease. The overall response rate was 20%, and the clinical benefit rate was 80%. Patients also reported grade 3/4 neutropenia (80.0%). However, hematological toxicity was reversible and manageable. The most common grade 3/4 nonhematological toxicities were fatigue (20.0%), peripheral neuropathy (20.0%) and appetite loss (20.0%). No patients withdrew from treatment, and favorable compliance was achieved in the study. The results indicated that eribulin and trastuzumab have the potential to be one of the drugs for treatment of recurrent breast cancer. PMID:26870356

  14. [Two cases of breast cancer responding to primary systemic chemotherapy containing trastuzumab without surgery].

    PubMed

    Konishi, Kazuya; Hasegawa, Naoto; Kaneko, Hiroyuki; Iimura, Yasuaki; Shoji, Yasuhito; Kawabata, Makoto

    2010-01-01

    The first case was a 40-year-old woman who was referred to our hospital with a complaint of left breast tumor. She was diagnosed as invasive ductal carcinoma (T2N0M0, Stage IIA). The tumor was ER-negative, PR-negative and HER2-positive. After primary systemic chemotherapy with 6 courses of 5-fluorouracil+epirubicin+cyclophosphamide(FEC)and 3 courses of weekly paclitaxel (PTX)+trastuzumab, the efficacy of chemotherapy was judged as a complete response (CR). After chemotherapy, radiotherapy for her left breast was performed without surgery. At 21 months after CR, local efficacy was judged as CR, but liver and bone metastases appeared, and were treated by capecitabine and trastuzumab. The efficacy of chemotherapy was judged as a partial response (PR). The second case was a 26-year-old woman referred to our hospital with a complaint of right breast tumor. She was diagnosed as invasive lobular carcinoma (T2N0M0, Stage IIA). The tumor was ER-positive, PR-negative and HER2-positive. After primary systemic chemotherapy with 4 courses of FEC and 6 courses of docetaxel+trastuzumab, the efficacy of chemotherapy was judged as CR. Then, 4 courses of weekly PTX+trastuzumab were performed. After chemotherapy, radiotherapy for her right breast was performed without surgery. The efficacy of treatment was judged as CR for 15 months. PMID:20087043

  15. Trastuzumab triggers phagocytic killing of high HER2 cancer cells in vitro and in vivo by interaction with Fcγ receptors on macrophages.

    PubMed

    Shi, Yun; Fan, Xuejun; Deng, Hui; Brezski, Randall J; Rycyzyn, Michael; Jordan, Robert E; Strohl, William R; Zou, Quanming; Zhang, Ningyan; An, Zhiqiang

    2015-05-01

    Trastuzumab has been used for the treatment of HER2-overexpressing breast cancer for more than a decade, but the mechanisms of action for the therapy are still being actively investigated. Ab-dependent cell-mediated cytotoxicity mediated by NK cells is well recognized as one of the key mechanisms of action for trastuzumab, but trastuzumab-mediated Ab-dependent cellular phagocytosis (ADCP) has not been established. In this study, we demonstrate that macrophages, by way of phagocytic engulfment, can mediate ADCP and cancer cell killing in the presence of trastuzumab. Increased infiltration of macrophages in the tumor tissue was associated with enhanced efficacy of trastuzumab whereas depletion of macrophages resulted in reduced antitumor efficacy in mouse xenograft tumor models. Among the four mouse FcγRs, FcγRIV exhibits the strongest binding affinity to trastuzumab. Knockdown of FcγRIV in mouse macrophages reduced cancer cell killing and ADCP activity triggered by trastuzumab. Consistently, an upregulation of FcγRIV expression by IFN-γ triggered an increased ADCP activity by trastuzumab. In an analogous fashion, IFN-γ priming of human macrophages increased the expression of FcγRIII, the ortholog of murine FcγRIV, and increased trastuzumab-mediated cancer cell killing. Thus, in two independent systems, the results indicated that activation of macrophages in combination with trastuzumab can serve as a therapeutic strategy for treating high HER2 breast cancer by boosting ADCP killing of cancer cells. PMID:25795760

  16. Innate immunity and adjuvants.

    PubMed

    Akira, Shizuo

    2011-10-12

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  17. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  18. Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study

    PubMed Central

    Zhang, Ningyan; Liu, Liming; Dumitru, Calin Dan; Cummings, Nga Rewa Houston; Cukan, Michael; Jiang, Youwei; Li, Yuan; Li, Fang; Mitchell, Teresa; Mallem, Muralidhar R; Ou, Yangsi; Patel, Rohan N; Vo, Kim; Wang, Hui; Burnina, Irina; Choi, Byung-Kwon; Huber, Hans; Stadheim, Terrance A

    2011-01-01

    Mammalian cell culture systems are used predominantly for the production of therapeutic monoclonal antibody (mAb) products. A number of alternative platforms, such as Pichia engineered with a humanized N-linked glycosylation pathway, have recently been developed for the production of mAbs. The glycosylation profiles of mAbs produced in glycoengineered Pichia are similar to those of mAbs produced in mammalian systems. This report presents for the first time the comprehensive characterization of an anti-human epidermal growth factor receptor 2 (HER2) mAb produced in glycoengineered Pichia, and a study comparing the anti-HER2 from Pichia, which had an amino acid sequence identical to trastuzumab, with trastuzumab. The comparative study covered a full spectrum of preclinical evaluation, including bioanalytical characterization, in vitro biological functions, in vivo anti-tumor efficacy and pharmacokinetics in both mice and non-human primates. Cell signaling and proliferation assays showed that anti-HER2 from Pichia had antagonist activities comparable to trastuzumab. However, Pichia-produced material showed a 5-fold increase in binding affinity to FcγIIIA and significantly enhanced antibody dependent cell-mediated cytotoxicity (ADCC) activity, presumably due to the lack of fucose on N-glycans. In a breast cancer xenograft mouse model, anti-HER2 was comparable to trastuzumab in tumor growth inhibition. Furthermore, comparable pharmacokinetic profiles were observed for anti-HER2 and trastuzumab in both mice and cynomolgus monkeys. We conclude that glycoengineered Pichia provides an alternative production platform for therapeutic mAbs and may be of particular interest for production of antibodies for which ADCC is part of the clinical mechanism of action. PMID:21487242

  19. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial

    PubMed Central

    Buzdar, Aman U; Suman, Vera J; Meric-Bernstam, Funda; Leitch, A Marilyn; Ellis, Matthew J; Boughey, Judy C; Unzeitig, Gary; Royce, Melanie; McCall, Linda M; Ewer, Michael S; Hunt, Kelly K

    2014-01-01

    Summary Background Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30–65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy. Methods This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292. Findings From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56.5%, 95% CI 47.8–64.9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54.2%, 95% CI 45.7–62.6) who received concurrent

  20. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

    PubMed Central

    Gulati, Geeta; Heck, Siri Lagethon; Ree, Anne Hansen; Hoffmann, Pavel; Schulz-Menger, Jeanette; Fagerland, Morten W.; Gravdehaug, Berit; von Knobelsdorff-Brenkenhoff, Florian; Bratland, Åse; Storås, Tryggve H.; Hagve, Tor-Arne; Røsjø, Helge; Steine, Kjetil; Geisler, Jürgen; Omland, Torbjørn

    2016-01-01

    Aims Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. Methods and results In a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed. Conclusion In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function. PMID:26903532

  1. Evaluation of a trastuzumab-containing treatment regimen for patients with unresectable advanced or recurrent gastric cancer

    PubMed Central

    NAMIKAWA, TSUTOMU; MUNEKAGE, ERI; MUNEKAGE, MASAYA; MAEDA, HIROMICHI; YATABE, TOMOAKI; KITAGAWA, HIROYUKI; SAKAMOTO, KOUICHI; OBATAKE, MASAYUKI; KOBAYASHI, MICHIYA; HANAZAKI, KAZUHIRO

    2016-01-01

    The present study aimed to evaluate the efficacy and safety of trastuzumab plus chemotherapy for patients with unresectable advanced or recurrent gastric cancer. A retrospective analysis of 213 patients with unresectable advanced or recurrent gastric cancer who received systemic chemotherapy, including 15 patients who were also administered trastuzumab, at Kochi Medical School between 2007 and 2013 was performed. The overall survival was compared between patients who received trastuzumab plus chemotherapy and patients who received chemotherapy alone, and the safety and efficacy of the trastuzumab-containing regimen was evaluated. Human epidermal growth factor receptor (HER)2 status was examined in 86 patients, of whom 15 (17.4%) exhibited strong positive HER2 expression. The rate of strong positive HER2 expression was significantly higher for intestinal type tumors compared with diffuse type tumors [23.6 (13/55) vs. 6.5% (2/31); P=0.044]. The median overall survival of the patients treated with trastuzumab was significantly longer compared with that for patients who were not treated with trastuzumab (22.9 vs. 11.6 months; P=0.014). The objective response rate and disease control rate for trastuzumab plus chemotherapy were 46.7 and 86.7%, respectively. Frequently encountered grade 3–4 toxicities included neutropenia (26.7%; 4/15), anemia (13.3%; 2/15) and fatigue (13.3%; 2/15). Trastuzumab plus chemotherapy is effective for patients with HER2-positive advanced or recurrent gastric cancer, and the frequencies of hematological and non-hematological toxicities experienced by patients in the present study indicated that it can be safely administered clinically. PMID:27330770

  2. TARGETING THE MUC1-C ONCOPROTEIN DOWNREGULATES HER2 ACTIVATION AND ABROGATES TRASTUZUMAB RESISTANCE IN BREAST CANCER CELLS

    PubMed Central

    Raina, Deepak; Uchida, Yasumitsu; Kharbanda, Akriti; Rajabi, Hasan; Panchamoorthy, Govind; Jin, Caining; Kharbanda, Surender; Scaltriti, Maurizio; Baselga, Jose; Kufe, Donald

    2014-01-01

    Patients with HER2 positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane MUC1-C oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1-C in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (~20-fold) as compared to that in sensitive cells. Additionally, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance. PMID:23912457

  3. Classification of Laser Vaccine Adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Poznansky, Mark C

    2016-01-01

    An immunologic adjuvant, which enhances the magnitude and quality of immune responses to vaccine antigens, has become an essential part of modern vaccine practice. Chemicals and biologicals have been typically used for this purpose, but there are an increasing number of studies that are being conducted on the vaccine adjuvant effect of laser light on the skin. Currently, four different types or classes of laser devices have been shown to systemically enhance immune responses to intradermal vaccination: ultra-short pulsed lasers, non-pulsed lasers, non-ablative fractional lasers and ablative fractional lasers. Aside from involving the application of laser light to the skin in a manner that minimizes discomfort and damage, each type of laser vaccine adjuvant involves emission parameters, modes of action and immunologic adjuvant effects that are quite distinct from each other. This review provides a summary of the four major classes of “laser vaccine adjuvant” and clarifies and resolves their characteristics as immunologic adjuvants. These aspects of each adjuvant’s properties will ultimately help define which laser would be most efficacious in delivering a specific clinical benefit with a specific vaccine. PMID:27104047

  4. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer.

    PubMed

    Kohrt, Holbrook E; Houot, Roch; Weiskopf, Kipp; Goldstein, Matthew J; Scheeren, Ferenc; Czerwinski, Debra; Colevas, A Dimitrios; Weng, Wen-Kai; Clarke, Michael F; Carlson, Robert W; Stockdale, Frank E; Mollick, Joseph A; Chen, Lieping; Levy, Ronald

    2012-03-01

    Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the FcγRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors. PMID:22326955

  5. H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy

    PubMed Central

    Price, Eric W.; Zeglis, Brian M.; Cawthray, Jacqueline F.; Ramogida, Caterina F.; Ramos, Nicholas

    2013-01-01

    A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCNBn- H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator DOTA. The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94–95%) than those based on DOTA-trastuzumab (60 min, 37 °C ~50–88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapatrastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93–0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. PMID:23901833

  6. Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: A review in the era of trastuzumab.

    PubMed

    Kordbacheh, T; Law, W Y; Smith, I E

    2016-04-01

    The development of trastuzumab and other targeted systemic therapies has transformed the management of HER-2 positive breast cancers. However, as patients live longer and systemic therapies may not cross the blood brain barrier a rising number of patients are developing leptomeningeal metastases and brain metastases as a sanctuary site of disease. Intrathecal trastuzumab has been reported to treat these. We describe a breast cancer patient with HER-2 positive leptomeningeal disease in the spinal cord successfully treated with intrathecal trastuzumab and methotrexate, alongside systemic anti-HER-2 therapy and radiotherapy. We also review the literature to date on the efficacy and safety of intrathecal trastuzumab, and recent evidence suggesting that intrathecal trastuzumab passes via the blood brain barrier into the serum to achieve intravenous concentrations similar to that seen with systemic therapy alone. Overall, intrathecal trastuzumab appears to be a safe and often effective treatment for leptomeningeal metastases in HER-2 positive breast cancer. Ongoing phase I and II studies are required to determine optimum dosing schedules, validate CSF and CSF-to-serum pharmacokinetics, determine efficacy, and to assess the added benefits or disadvantages of prior radiotherapy and concomitant systemic therapy. PMID:27017242

  7. Adjuvant treatment for pancreatic cancer.

    PubMed

    Daoud, Vladimir; Saif, Muhammad Wasif; Goodman, Martin

    2014-07-01

    Pancreatic cancer is the fourth leading cause of cancer deaths in both men and women. Surgical resection has been shown to be the only curable treatment available. Unfortunately only 20% of all patients diagnosed with pancreatic cancer are surgical candidates due to the aggressive biology of this disease. There is no clear consensus on what type of adjuvant therapy should be used for patients with pancreatic cancer. Chemoradiation is the favored treatment modality by many in the United States while gemcitabine based chemotherapy is favored in Europe. Both of these approaches have been shown by large prospective, randomized trials to improve disease free intervals and in some studies overall survival. The survival of these patients, even status post resection and adjuvant therapy, remains poor and therefore the need for alternative adjuvant therapies is needed. We will therefore discuss Abstracts #4124, #TPS4162, #4120 and #E15191 in this paper which are relevant to the issues described above. PMID:25076340

  8. Adjuvant chemotherapy of pT1a and pT1b breast carcinoma: results from the NEMESI study

    PubMed Central

    2012-01-01

    Background The prognosis of pT1a-pT1b breast cancer (BC) used to be considered very good, with a 10-y RFS of 90%. However, some retrospective studies reported a 10-y RFS of 81%–86% and suggested benefit from adjuvant systemic therapy. Methods To evaluate the variables that determined the choice of adjuvant chemotherapy and the type of chemotherapy delivered in pT1a-pT1b BC, we analysed the small tumours enrolled in the NEMESI study. Results Out of 1,894 patients with pathological stage I-II BC enrolled in NEMESI, 402 (21.2%) were pT1a-pT1b. Adjuvant chemotherapy was delivered in 127/402 (31.59%). Younger age, grading G3, high proliferative index, ER-negative and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy. An anthracycline without taxane regimen was administered in 59.1% of patients, anthracycline with taxane in 24.4%, a CMF-like regimen in 14.2% and taxane in 2.4%. Adjuvant chemotherapy was administered in 88.4% triple-negative and 73.46% HER2-positive pT1a-pT1b BC. Adjuvant trastuzumab was delivered in 30/49 HER2-positive BC (61.2%). Conclusions Adjuvant chemotherapy was delivered in 31.59% T1a-pT1b BC treated at 63 Italian oncological centres from January 2008 to June 2008. The choice to deliver chemotherapy was based on biological prognostic factors. Anthracycline-based chemotherapy was administered in 83.5% patients. PMID:22545982

  9. Chemokines as Cancer Vaccine Adjuvants

    PubMed Central

    Bobanga, Iuliana D.; Petrosiute, Agne; Huang, Alex Y.

    2013-01-01

    We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs) and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants. PMID:24967094

  10. Aiming at the target: improved adjuvant medical therapy.

    PubMed

    Bedard, Philippe L; Dinh, Phuong; Sotiriou, Christos; Piccart-Gebhart, Martine J

    2009-10-01

    The 2007 St. Gallen Expert Panel recognized the existence of molecular tools for risk stratification, but recommended the use of high-quality standard pathological testing alone for risk allocation and treatment selection. Over the last two years, much has been learned about these novel molecular tools: they demonstrate similar prognostic power; their performance appears to be driven by improved quantification of cellular proliferation; tumour burden remains an important determinant of long-term outcome; and their prediction of responsiveness to systemic therapy is suboptimal. In the meantime, great effort has continued to be invested in evaluating individual predictive markers to guide treatment selection. A number of putative targets that showed early promise--such as HER-2 and TOP2A gene amplification for anthracyclines, Myc amplification for trastuzumab, and Tau expression for taxanes--have yielded disappointing results when subjected to subsequent validation. These failings underscore the difficulty of accurate, reproducible target measurement and the inherent complexity of early breast cancer which is unlikely to be captured by a single gene or protein alteration. Future progress in adjuvant treatment tailoring will require a fundamental shift towards multi-dimensional thinking--with the development of multi-parameter assays that integrate tumour biology, disease burden, and host-related factors. The traditional model of post hoc predictive marker validation appears unlikely to produce tangible gains in the era of targeted systemic therapy. It is hoped that coupling prospective biomarker discovery with new drug development in earlier stages of disease will yield additional targets that can be used to guide clinical decision-making in the future. PMID:19914538

  11. [Case report of advanced breast cancer responding to capecitabine and trastuzumab combination therapy].

    PubMed

    Yoshidome, Katsuhide; Imabun, Shigeru; Nakahara, Masaaki; Hiraoka, Kazuya; Yamagami, Yuko; Tsujimoto, Masahiko; Nakao, Kazuyasu

    2006-10-01

    We conducted a concomitant administration of capecitabine (2,400 mg/day for 21 days followed by a 7-day interval) and trastuzumab (2 mg/kg weekly) to a 73-year-old female patient with impaired lower limb function diagnosed with bilateral breast cancer. The patient had a complete response (CR) to pulmonary metastases, and carcinoembryonic antigen (CEA) level had normalized from 46.4 ng/ml to 0.6 ng/ml. Left mastectomy was performed in order to control bleeding from tumors. No adverse events attributable to medication were observed. The concomitant administration of capecitabine and trastuzumab is a promising therapy with the potential to greatly improve patient quality of life (QOL). PMID:17033236

  12. Rapid and multi-level characterization of trastuzumab using sheathless capillary electrophoresis-tandem mass spectrometry

    PubMed Central

    Gahoual, Rabah; Burr, Alicia; Busnel, Jean-Marc; Kuhn, Lauriane; Hammann, Phillipe; Beck, Alain; François, Yannis-Nicolas; Leize-Wagner, Emmanuelle

    2013-01-01

    Monoclonal antibodies (mAbs) are highly complex proteins that display a wide range of microheterogeneity that requires multiple analytical methods for full structure assessment and quality control. As a consequence, the characterization of mAbs on different levels is particularly product - and time - consuming. This work presents the characterization of trastuzumab sequence using sheathless capillary electrophoresis (referred as CESI) – tandem mass spectrometry (CESI-MS/MS). Using this bottom-up proteomic-like approach, CESI-MS/MS provided 100% sequence coverage for both heavy and light chain via peptide fragment fingerprinting (PFF) identification. The result was accomplished in a single shot, corresponding to the analysis of 100 fmoles of digest. The same analysis also enabled precise characterization of the post-translational hot spots of trastuzumab, used as a representative widely marketed therapeutic mAb, including the structural confirmation of the five major N-glycoforms. PMID:23563524

  13. Coexistence of Gastric Adenocarcinoma and Choriocarcinoma: Complete Response to Trastuzumab and Chemotherapy

    PubMed Central

    Gunduz, Seyda; Elpek, Gulsum Ozlem; Uysal, Mukremin; Goksu, Sema Sezgin; Tatli, Murat; Arslan, Deniz; Coskun, Hasan Senol; Bozcuk, Hakan; Savas, Burhan; Ozdogan, Mustafa

    2012-01-01

    Gastric choriocarcinoma is a rare neoplasm and usually accompanies gastric adenocarcinoma. The prognosis is poor due to the aggressive course of the disease. A 57-year-old female patient with weight loss and abdominal pain was examined. The patient was operated following the examination, and pathological analysis revealed the presence of a gastric adenocarcinoma associated with choriocarcinoma. Immunohistochemical analysis showed a positive reaction with antibodies to beta-human chorionic gonadotropin and overexpression of the cErbB2 proto-oncogene. Staging revealed multiple metastases in the liver. A complete response was obtained with a combination of trastuzumab and chemotherapy. The diagnosis of gastric choriocarcinomas without pathological examination is difficult due to their rare occurrence. A complete response can be obtained with trastuzumab in the treatment of cases with overexpression of the cErbB2 protein. PMID:23525369

  14. Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity.

    PubMed

    Yan, Haoheng; Endo, Yukinori; Shen, Yi; Rotstein, David; Dokmanovic, Milos; Mohan, Nishant; Mukhopadhyay, Partha; Gao, Bin; Pacher, Pal; Wu, Wen Jin

    2016-03-01

    Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFα in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFα enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. PMID:26712117

  15. Dose Escalation and Dosimetry of First in Human Alpha Radioimmunotherapy with 212Pb-TCMC-trastuzumab

    PubMed Central

    Meredith, Ruby; Torgue, Julien; Shen, Sui; Fisher, Darrell R.; Banaga, Eileen; Bunch, Patty; Morgan, Desiree; Fan, Jinda; Straughn, J. Michael

    2015-01-01

    Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity and tumor response of intraperitoneal (IP) 212Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyantobenzl)-1, 4, 7, 10-tetraaza-1, 4, 7, 10=tetra (2-carbamoylmethl) cyclododecane) in patients with HER-2 expressing malignancy. Methods In a standard 3+3 Phase 1 design for dose escalation, 212Pb-TCMC-trastuzumab was delivered IP less than 4 hours after giving 4mg/kg IV trastuzumab to patients with peritoneal carcinomatosis who had failed standard therapies. Results Five dosage levels (7.4, 9.6, 12.6, 16.3, 21.1 MBq/m2) showed minimal toxicity at >1 year for the first group and >4 months for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow = 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n=3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion and no specific uptake in major organs was observed in 24 hours. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24h (decay corrected to injection time) and 500 Bq/mL (decay corrected to collection time). Non-decay corrected cumulative urinary excretion was ≤6% in 24h (2.3 half lives). Dose rate measurements performed at 1m from the patient registered less than 5μSv/hr (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Anti-drug antibody assays performed on serum from the first 4 cohorts were all negative. Conclusions Five dose levels of IP 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent related toxicity, consistent with the dosimetry calculations. PMID:25157044

  16. Pharmacokinetics and Imaging of 212Pb-TCMC-Trastuzumab After Intraperitoneal Administration in Ovarian Cancer Patients

    PubMed Central

    Torgue, Julien; Azure, Michael T.; Shen, Sui; Saddekni, Souheil; Banaga, Eileen; Carlise, Ronda; Bunch, Patty; Yoder, Daniel; Alvarez, Ronald

    2014-01-01

    Abstract Purpose: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy. Experimental Design: IP 212Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters. Results: Imaging studies after 0.2 mCi/m2 (7.4 MBq/m2) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity. Conclusions: Pharmacokinetics and imaging after 0.2 mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance. PMID:24229395

  17. Her2/neu extracellular domain shedding in uterine serous carcinoma: implications for immunotherapy with trastuzumab

    PubMed Central

    Todeschini, P; Cocco, E; Bellone, S; Varughese, J; Lin, K; Carrara, L; Guzzo, F; Buza, N; Hui, P; Silasi, D-A; Ratner, E; Azodi, M; Schwartz, P E; Rutherford, T J; Pecorelli, S; Santin, A D

    2011-01-01

    Background: We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro. Methods: Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays. Results: Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01). Conclusion: FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo. PMID:21915118

  18. Production and Quality Control of [67Ga]-DOTA-trastuzumab for Radioimmunoscintigraphy

    PubMed Central

    Alirezapour, Behrooz; R. Jalilian, Amir; Bolourinovin, Fatemeh; Moradkhani, Sedigheh

    2013-01-01

    Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. In this study, trastuzumab was successively labeled with [67Ga] GaCl3 after conjugation with DOTA-NHS-ester. The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA-Trastuzumab was labeled with 67Ga. Radiochemical purity, integrity of protein after radiolabeling and stability of 67Ga-DOTA-Trastuzumab were determined followed by biodistribution studies in wild-type rats (30 ± 5.5 μCi, 2, 4 and 24 h p.i.). The radioimmunoconjugate was prepared with a radiochemical purity of higher than 95% (RTLC). The average chelate to antibody ratio (c/a) for the conjugate used in this study was 5.8:1. The final compound was stable in presence of PBS at 37ºC and room temperature. The sample was showed to have similar patterns of migration in the gel electrophoresis similar to the native protein. The accumulation of the radiolabeled antibody in liver, spleen, kidney, heart and other tissues demonstrates. 67Ga-DOTA-Trastuzumab was prepared as a surrogate for important clinically applicable radionuclides used in SPECT and PET including In-111 and Cu-64 as a model of radiolabeling. It is also a potential compound for molecular imaging of SPECT for diagnosis and treatment studies and follow-up of HER2 expression in oncology. PMID:24250610

  19. Trastuzumab-deBouganin Conjugate Overcomes Multiple Mechanisms of T-DM1 Drug Resistance.

    PubMed

    Dillon, Rachelle L; Chooniedass, Shilpa; Premsukh, Arjune; Adams, Gregory P; Entwistle, Joycelyn; MacDonald, Glen C; Cizeau, Jeannick

    2016-04-01

    The development of antibody drug conjugates has provided enhanced potency to tumor-targeting antibodies by the addition of highly potent payloads. In the case of trastuzumab-DM1 (T-DM1), approved for the treatment of metastatic breast cancer, the addition of mertansine (DM1) to trastuzumab substantially increased progression-free survival. Despite these improvements, most patients eventually relapse due to complex mechanisms of resistance often associated with small molecule chemotherapeutics. Therefore, identifying payloads with different mechanisms of action (MOA) is critical for increasing the efficacy of targeted therapeutics and ultimately improving patient outcomes. To evaluate payloads with different MOA, deBouganin, a deimmunized plant toxin that inhibits protein synthesis, was conjugated to trastuzumab and compared with T-DM1 both in vitro and in vivo. The trastuzumab-deBouganin conjugate (T-deB) demonstrated greater potency in vitro against most cells lines with high levels of Her2 expression. In addition, T-deB, unlike T-DM1, was unaffected by inhibitors of multidrug resistance, Bcl-2-mediated resistance, or Her2-Her3 dimerization. Contrary to T-DM1 that showed only minimal cytotoxicity, T-deB was highly potent in vitro against tumor cells with cancer stem cell properties. Overall, the results demonstrate the potency and efficacy of deBouganin and emphasize the importance of using payloads with different MOAs. The data suggest that deBouganin could be a highly effective against tumor cell phenotypes not being addressed by current antibody drug conjugate formats and thereby provide prolonged clinical benefit. PMID:26938945

  20. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Five new drift control adjuvants were sele...

  1. Spray drift mitigation with spray mix adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Four new drift control adjuvants were sele...

  2. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Four new drift control adjuvants were sele...

  3. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  4. Trastuzumab-targeted gene delivery to Her2-overexpressing breast cancer cells.

    PubMed

    Mann, K; Kullberg, M

    2016-07-01

    We describe a novel gene delivery system that specifically targets human epidermal growth factor receptor 2 (Her2)-overexpressing breast cancer cells. The targeting complexes consist of a PEGylated polylysine core that is bound to DNA molecules coding for either green fluorescent protein or shrimp luciferase. The complex is disulfide linked to the monoclonal antibody trastuzumab and to a pore-forming protein, Listeriolysin O (LLO). Trastuzumab is responsible for specific targeting of Her2 receptors and uptake of the gene delivery complex into endosomes of recipient cells, whereas LLO ensures that the DNA molecules are capable of transit from the endosomes into the cytoplasm. Omission of either trastuzumab or LLO from the nanocomplexes results in minimal gene product in targeted cells. Treatment of isogeneic MCF7 and MCF7/Her18 cell lines, differing only in number of Her2 receptors, with the complete gene delivery system results in a 30-fold greater expression of luciferase activity in the Her2-overexpressing MCF7/Her18 cells. Our nanocomplexes are small (150-250 nm), stable to storage, nontoxic and generic in make-up such that any plasmid DNA or antibody specific for cell-surface receptors can be coupled to the PEGylated polylysine core. PMID:27199219

  5. Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer.

    PubMed

    Roy, Vivek; Perez, Edith A

    2009-11-01

    HER-2 is a transmembrane, tyrosine kinase (TK) receptor whose overexpression is associated with adverse prognosis in breast cancer. The biological effects of HER-2 are mediated by kinase activity causing phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor molecule, leading to activation of downstream growth-promoting pathways. Antibody-mediated inhibition by trastuzumab as well as TK inhibition are clinically effective anti-HER-2 strategies. Kinase inhibitors offer some potential therapeutic advantages over antibody-based therapies. Being small molecules, TK inhibitors (TKIs) have oral bioavailability and ability to cross the blood-brain barrier. Because of their different mode of action, TKIs may be able to overcome some of the mechanisms of trastuzumab resistance. Preclinical, and limited clinical data also suggest that TKIs and trastuzumab have synergistic activity. Lapatinib is the only TKI available for clinical use at present, but several molecules with anti-HER-2 activity have been identified and are undergoing evaluation. These differ in the spectrum of kinases that they inhibit, potency of HER-2 inhibition, pharmacokinetic properties, and toxicity profiles, and are at various stages of clinical development. In this article we summarize selected HER-2 TKIs approved for clinical use or in development for which clinical data are available. PMID:19887469

  6. Trastuzumab-targeted gene delivery to Her2-overexpressing breast cancer cells

    PubMed Central

    Mann, K; Kullberg, M

    2016-01-01

    We describe a novel gene delivery system that specifically targets human epidermal growth factor receptor 2 (Her2)-overexpressing breast cancer cells. The targeting complexes consist of a PEGylated polylysine core that is bound to DNA molecules coding for either green fluorescent protein or shrimp luciferase. The complex is disulfide linked to the monoclonal antibody trastuzumab and to a pore-forming protein, Listeriolysin O (LLO). Trastuzumab is responsible for specific targeting of Her2 receptors and uptake of the gene delivery complex into endosomes of recipient cells, whereas LLO ensures that the DNA molecules are capable of transit from the endosomes into the cytoplasm. Omission of either trastuzumab or LLO from the nanocomplexes results in minimal gene product in targeted cells. Treatment of isogeneic MCF7 and MCF7/Her18 cell lines, differing only in number of Her2 receptors, with the complete gene delivery system results in a 30-fold greater expression of luciferase activity in the Her2-overexpressing MCF7/Her18 cells. Our nanocomplexes are small (150–250 nm), stable to storage, nontoxic and generic in make-up such that any plasmid DNA or antibody specific for cell-surface receptors can be coupled to the PEGylated polylysine core. PMID:27199219

  7. Gene expression profiling upon (212) Pb-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model.

    PubMed

    Yong, Kwon J; Milenic, Diane E; Baidoo, Kwamena E; Kim, Young-Seung; Brechbiel, Martin W

    2013-10-01

    Recent studies have demonstrated that therapy with (212) Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of (212) Pb-TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to (212) Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to (212) Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45α, GADD45γ, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45α, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by (212) Pb-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by (212) Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by (212) Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using α-particle emitters. PMID:24403230

  8. Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.

    PubMed

    Stemmler, H J; Schmitt, M; Harbeck, N; Willems, A; Bernhard, H; Lässig, D; Schoenberg, S; Heinemann, V

    2006-05-01

    Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-year-old female presenting with HER2-overexpressing MBC and suffering from meningeal carcinomatosis was treated with the humanized antibody trastuzumab directed to HER2 by intrathecal administration. The patient was diagnosed with HER2-overexpressing stage III breast cancer in December 2003. In August 2004, the patient developed a singular intracerebral metastasis which was resected by neurosurgery followed by whole-brain radiotherapy. Since MRI and cerebrospinal fluid (CSF) analyses indicated meningeal carcinomatosis, the patient was commenced on trastuzumab (6 mg/kg q3w) and capecitabine (2.500 mg/m2 d1-14, q3w). Prompted by clinical deterioration, 5 repeated doses of intrathecal methotrexate (15 mg/dose) were administered, yet without clinical improvement. There is initial evidence that trastuzumab does not reach an adequate concentration in CSF after intravenous application. Nevertheless, infiltration of trastuzumab into CSF is facilitated under conditions of an impaired blood-brain barrier, as it is known for meningeal carcinomatosis. For patients with leptomeningeal disease, intrathecal application of trastuzumab may provide an interesting therapeutical approach for patients with HER2 overexpressing metastatic breast cancer. Therefore, an Ommaya reservoir for intrathecal treatment with trastuzumab was placed surgically and intrathecal therapy was begun with escalating doses of trastuzumab (5-20 mg), which proved to be effective and well tolerated by the patient. Within 2 weeks after treatment, the patients' condition improved significantly and cell counts in CSF obtained from the Ommaya reservoir remained low for 11 months after first diagnosis of meningeal carcinomatosis when clinical symptoms and MRI indicated progression of meningeal and cerebral disease. PMID:16596213

  9. Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors.

    PubMed

    Chakrabarty, Anindita; Bhola, Neil E; Sutton, Cammie; Ghosh, Ritwik; Kuba, María Gabriela; Dave, Bhuvanesh; Chang, Jenny C; Arteaga, Carlos L

    2013-02-01

    The antibody trastuzumab is approved for treatment of patients with HER2 (ERBB2)-overexpressing breast cancer. A significant fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective. The development of resistance has been attributed to failure of the antibody to inhibit phosphoinositide 3-kinase (PI3K), which is activated by the HER2 network. Herein, we examined the effects of PI3K blockade in trastuzumab-resistant breast cancer cell lines. Treatment with the pan-PI3K inhibitor XL147 and trastuzumab reduced proliferation and pAKT levels, triggering apoptosis of trastuzumab-resistant cells. Compared with XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts. Furthermore, treatment with XL147 and trastuzumab reduced the cancer stem-cell (CSC) fraction within trastuzumab-resistant cells both in vitro and in vivo. These effects were associated with FoxO-mediated inhibition of transcription of the antiapoptosis gene survivin (BIRC5) and the CSC-associated cytokine interleukin-8. RNA interference-mediated or pharmacologic inhibition of survivin restored sensitivity to trastuzumab in resistant cells. In a cohort of patients with HER2-overexpressing breast cancer treated with trastuzumab, higher pretreatment tumor levels of survivin RNA correlated with poor response to therapy. Together, our results suggest that survivin blockade is required for therapeutic responses to trastuzumab and that by combining trastuzumab and PI3K inhibitors, CSCs can be reduced within HER2(+) tumors, potentially preventing acquired resistance to anti-HER2 therapy. PMID:23204226

  10. Vaccine adjuvants as potential cancer immunotherapeutics.

    PubMed

    Temizoz, Burcu; Kuroda, Etsushi; Ishii, Ken J

    2016-07-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  11. Improving vaccine delivery using novel adjuvant systems.

    PubMed

    Pichichero, Michael E

    2008-01-01

    Adjuvants have been common additions to vaccines to help facilitate vaccine delivery. With advancements in vaccine technology, several adjuvants which activate immune specific responses have emerged. Available data show these adjuvants elicit important immune responses in both healthy and immunocompromised populations, as well as the elderly. Guidelines for the use and licensure of vaccine adjuvants remain under discussion. However, there is a greater understanding of the innate and adaptive immune response, and the realization of the need for immune specific adjuvants appears to be growing. This is a focused review of four adjuvants currently in clinical trial development: ASO4, ASO2A, CPG 7907, and GM-CSF. The vaccines including these adjuvants are highly relevant today, and are expected to reduce the disease burden of cervical cancer, hepatitis B and malaria. PMID:18398303

  12. Vaccine adjuvants as potential cancer immunotherapeutics

    PubMed Central

    Temizoz, Burcu; Kuroda, Etsushi

    2016-01-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund’s adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  13. Gene expression profiling upon 212Pb-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model

    PubMed Central

    Yong, Kwon J; Milenic, Diane E; Baidoo, Kwamena E; Kim, Young-Seung; Brechbiel, Martin W

    2013-01-01

    Recent studies have demonstrated that therapy with 212Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of 212Pb-TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to 212Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to 212Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45α, GADD45γ, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45α, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by 212Pb-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by 212Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by 212Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using α-particle emitters. The apoptotic response and associated gene modulations have not been clearly defined following exposure of cells to α-particle radioimmunotherapy (RIT). Gene expression profiling was performed with LS-174T i.p. (intraperitoneal) xenografts after exposure to 212Pb-TCMC-trastuzumab

  14. Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

    PubMed Central

    Lion, Maëva; Harlé, Alexandre; Salleron, Julia; Ramacci, Carole; Campone, Mario; Merlin, Jean-Louis

    2016-01-01

    Human epidermal growth factor 2 (HER2) is overexpressed in 15–20% of breast carcinomas. The overexpression of HER2 was previously associated with a poor prognosis until the development of the first anti-HER2 therapy, trastuzumab, which drastically improves the prognosis of HER2-overexpressing breast cancers. However, its mechanism of action remains not fully understood. Several studies have proposed that the behavior and mechanism of action of trastuzumab may be drastically altered in vitro and in vivo. The present study assesses the ability of trastuzumab to inhibit the phosphorylation of the key-proteins of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin and Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways in vitro, in breast cancer cell lines and in tumor biopsies obtained from patients treated with trastuzumab preoperative monotherapy as part of the Unicancer GEP04 RADHER phase II clinical trial. HER2-positive SKBR3 and HER2-negative MCF-7 cell lines were exposed to trastuzumab for 72 h. In total, 41 patients received trastuzumab alone for 6 weeks of preoperative treatment. Biopsies were collected at the baseline and at surgery. A total of 19 pairs of associated baseline and surgery tumor specimens were eligible for protein extraction and comparative phosphoprotein expression analysis, prior to and subsequent to treatment. The expression of phosphoproteins was quantitatively assessed using a multiplex immunoassay. In the SKBR3 cell line, a statistically significant decrease of the expression level of phosphorylated (p-)AKT, p-ribosomal protein S6 kinase B1, p-extracellular signal regulated kinase 1/2 and p-mitogen-activated protein kinase kinase 1 was observed after exposure to trastuzumab. In contrast, no statistically significant variations for levels expression of these phosphoproteins were observed in patients following treatment. The lack of downregulation of PI3K and MAPK pathways could probably

  15. Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition.

    PubMed

    Di Modica, Martina; Sfondrini, Lucia; Regondi, Viola; Varchetta, Stefania; Oliviero, Barbara; Mariani, Gabriella; Bianchi, Giulia Valeria; Generali, Daniele; Balsari, Andrea; Triulzi, Tiziana; Tagliabue, Elda

    2016-01-01

    Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated HER2-positive breast cancer (BC) patients. In HER2+ BC experimental models and patients, we investigated whether this synergy depends on the ability of drug-induced stress to improve NK cell effectiveness and thus trastuzumab-mediated ADCC. HER2+ BC cell lines BT474 and MDAMB361 treated with docetaxel showed up-modulation of NK activator ligands both in vitro and in vivo, accompanied by a 15-40% increase in in vitro trastuzumab-mediated ADCC; antibodies blocking the NKG2D receptor significantly reduced this enhancement. NKG2D receptor expression was increased by docetaxel treatment in circulating and splenic NK cells from mice xenografted with tumor cells, an increase related to expansion of the CD11b+Ly6G+ cell population. Accordingly, NK cells derived from HER2+ BC patients after treatment with taxane-containing therapy expressed higher levels of NKG2D receptor than before treatment. Moreover, plasma obtained from these patients recapitulated the modulation of NKG2D on healthy donors' NK cells, improving their trastuzumab-mediated activity in vitro. This enhancement occurred mainly using plasma from patients with low NKG2D basal expression. Our results indicate that taxanes increase tumor susceptibility to ADCC by acting on tumor and NK cells, and suggest that taxanes concomitantly administered with trastuzumab could maximize the antibody effect, especially in patients with low basal immune effector cytotoxic activity. PMID:26595802

  16. Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition

    PubMed Central

    Regondi, Viola; Varchetta, Stefania; Oliviero, Barbara; Mariani, Gabriella; Bianchi, Giulia Valeria; Generali, Daniele; Balsari, Andrea

    2016-01-01

    Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated HER2-positive breast cancer (BC) patients. In HER2+ BC experimental models and patients, we investigated whether this synergy depends on the ability of drug-induced stress to improve NK cell effectiveness and thus trastuzumab-mediated ADCC. HER2+ BC cell lines BT474 and MDAMB361 treated with docetaxel showed up-modulation of NK activator ligands both in vitro and in vivo, accompanied by a 15–40% increase in in vitro trastuzumab-mediated ADCC; antibodies blocking the NKG2D receptor significantly reduced this enhancement. NKG2D receptor expression was increased by docetaxel treatment in circulating and splenic NK cells from mice xenografted with tumor cells, an increase related to expansion of the CD11b+Ly6G+ cell population. Accordingly, NK cells derived from HER2+ BC patients after treatment with taxane-containing therapy expressed higher levels of NKG2D receptor than before treatment. Moreover, plasma obtained from these patients recapitulated the modulation of NKG2D on healthy donors' NK cells, improving their trastuzumab-mediated activity in vitro. This enhancement occurred mainly using plasma from patients with low NKG2D basal expression. Our results indicate that taxanes increase tumor susceptibility to ADCC by acting on tumor and NK cells, and suggest that taxanes concomitantly administered with trastuzumab could maximize the antibody effect, especially in patients with low basal immune effector cytotoxic activity. PMID:26595802

  17. The Efficacy of Trastuzumab in Animal Models of Breast Cancer: A Systematic Review and Meta-Analysis

    PubMed Central

    Chen, Jiarong; Yang, Canhong; Guo, Bin; Sena, Emily S.; Macleod, Malcolm R.; Yuan, Yawei; Hirst, Theodore C.

    2016-01-01

    Background Breast cancer is the most frequent cancers and is the second leading cause of cancer death among women. Trastuzumab is an effective treatment, the first monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). To inform the development of other effective treatments we report summary estimates of efficacy of trastuzumab on survival and tumour volume in animal models of breast cancer. Methods We searched PubMed and EMBASE systematically to identify publications testing trastuzumab in animal models of breast cancer. Data describing tumour volume, median survival and animal features were extracted and we assessed quality using a 12-item checklist. We analysed the impact of study design and quality and evidence for publication bias. Results We included data from 83 studies reporting 169 experiments using 2076 mice. Trastuzumab treatment caused a substantial reduction in tumour growth, with tumours in treated animals growing to 32.6% of the volume of tumours in control animals (95%CI 27.8%-38.2%). Median survival was prolonged by a factor of 1.45 (1.30–1.62). Many study design and quality features accounted for between-study heterogeneity and we found evidence suggesting publication bias. Conclusion We have found trastuzumab to be effective in animal breast cancer models across a range of experimental circumstances. However the presence of publication bias and a low prevalence of measures to reduce bias provide a focus for future improvements in preclinical breast cancer research. PMID:27463246

  18. Biosafe Nanoscale Pharmaceutical Adjuvant Materials

    PubMed Central

    Jin, Shubin; Li, Shengliang; Wang, Chongxi; Liu, Juan; Yang, Xiaolong; Wang, Paul C.; Zhang, Xin; Liang, Xing-Jie

    2014-01-01

    Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes. PMID:25429253

  19. Adjuvant therapy for endometrial cancer

    PubMed Central

    DeLeon, Maria C.; Ammakkanavar, Natraj R.

    2014-01-01

    Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. PMID:24761218

  20. Polysaccharides: Candidates of promising vaccine adjuvants.

    PubMed

    Li, Pingli; Wang, Fengshan

    2015-04-01

    Aluminium-based adjuvants remain the only adjuvants approved for human use in the USA for over 80 years because of alum's simplicity, tolerability, safety and cost-efficiency. Recent development of vaccines, especially the increasing applications of recombinant subunit and synthetic vaccines, makes aluminium adjuvants cannot stimulate enough immunity to the antigens, since aluminium adjuvants can only induce Th2 type immune responses. So, novel adjuvants are urgent to make up the disadvantages of aluminium adjuvants. However, some major hurdles need to be overcome, not only the scientific knowledge of adjuvants but also unacceptable side-effects and toxicity. A number of carbohydrate-based polysaccharides from plant, bacterial, yeast and synthetic sources can act as pathogen-associated molecular patterns (PAMPs) and recognize pattern recognition receptors (PRRs) on immune cells, followed by triggering innate immunity and regulating adaptive immunity. What is more, polysaccharides are safe and biodegradable without tissue deposits as observed in aluminium adjuvants. Therefore, polysaccharide-based compounds and formulations are potential vaccine adjuvant candidates. Here, we mainly review polysaccharide-based adjuvants investigated in recent years. PMID:25994059

  1. Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes.

    PubMed

    Mohan, Nishant; Shen, Yi; Endo, Yukinori; ElZarrad, M Khair; Wu, Wen Jin

    2016-06-01

    Dysregulation of autophagy has been implicated in various cardiovascular diseases. Trastuzumab, a humanized monoclonal antibody, binds to HER2 domain IV and is approved for the treatment of HER2-positive breast cancer. Trastuzumab therapy is associated with considerable cardiotoxicity, the mechanism of which remains unclear. HER2 signaling plays a pivotal role in cardiomyocyte development and survival and is essential for the prevention of cardiomyopathy. However, a direct link has not been confirmed between trastuzumab-induced cardiomyopathy and impaired HER2 signaling. Our data reveal a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in upregulation of mTOR signaling pathway and subsequently inhibition of autophagy in primary cardiomyocytes and C57BL/6 mice. Trastuzumab-induced downregulation of autophagy is further supported by the fact that trastuzumab treatment reduces protein levels of autophagosome-associated signaling molecules such as Atg 5-12, Atg 7, Atg 14, and Beclin 1. We further demonstrated that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab, another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to inhibit autophagy and to increase ROS production in cardiomyocytes. This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which may assist in formulating novel approaches for clinical management of trastuzumab-induced cardiomyopathy. Mol Cancer Ther; 15(6); 1321-31. ©2016 AACR. PMID:27197303

  2. Mechanisms Behind the Resistance to Trastuzumab in HER2-Amplified Breast Cancer and Strategies to Overcome It

    PubMed Central

    Luque-Cabal, María; García-Teijido, Paula; Fernández-Pérez, Yolanda; Sánchez-Lorenzo, Luisa; Palacio-Vázquez, Isabel

    2016-01-01

    The introduction of trastuzumab therapy markedly improved the poor prognosis associated with HER2-amplified breast cancers. Despite this, the presence of primary and acquired resistance to trastuzumab treatment remains a significant common challenge. The identification of resistance mechanisms and the incorporation of new drugs that achieve a better blockade of HER family receptors signaling have resulted in improved outcomes. The phosphatidylinositol 3′-kinase/protein kinase B/mammalian target of rapamycin pathway, cross-talk with estrogen receptors, immune response, cell cycle control mechanisms, and other tyrosine kinase receptors such as insulin-like growth factor I receptor are potential pathways involved in trastuzumab resistance. Different therapeutic interventions targeting these pathways are currently under evaluation. PMID:27042153

  3. Adjuvant progestagens for endometrial cancer

    PubMed Central

    Martin-Hirsch, Pierre PL; Bryant, Andrew; Keep, Sarah L; Kitchener, Henry C; Lilford, Richard

    2014-01-01

    Background Endometrial cancer is the most common genital tract carcinoma among women in developed countries, with most women presenting with stage 1 disease. Adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of recurrence of disease. Objectives To evaluate the effectiveness and safety of adjuvant progestagen therapy for the treatment of endometrial cancer. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Specilaised Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. MEDLINE and EMBASE up to April 2009. Selection criteria Randomised controlled trials (RCTs) of progestagen therapy in women who have had surgery for endometrial cancer. Data collection and analysis Two review authors independently abstracted data and assessed risk of bias. Risk ratios (RRs) comparing survival in women who did and did not receive progestagen were pooled in random effects meta-analyses.. Main results Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). Authors’ conclusions There

  4. Subcutaneous Trastuzumab for HER2-positive Breast Cancer – Evidence and Practical Experience in 7 German Centers

    PubMed Central

    Jackisch, C.; Müller, V.; Dall, P.; Neumeister, R.; Park-Simon, T.-W.; Ruf-Dördelmann, A.; Seiler, S.; Tesch, H.; Ataseven, B.

    2015-01-01

    A subcutaneous formulation of trastuzumab to treat patients with HER2-positive breast cancer is available since August 2013. The subcutaneous formulation is administered as a fixed dose of 600 mg over a period of up to 5 minutes. The HannaH trial compared subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy and tolerability for both administration forms of trastuzumab in the neoadjuvant setting. The randomized crossover study PrefHer reported a clear preference from the patientʼs point of view for subcutaneous over intravenous administration of trastuzumab. The accompanying time-and-motion study reported a reduction concerning the total time spent for the institution as well as for the patient receiving trastuzumab s. c.. The experience of 7 German centers largely corresponded with the results of these studies. Patients expressed a clear preference for subcutaneous trastuzumab administration, with the time saved by the subcutaneous administration route cited as the greatest benefit. Although the existing reimbursement terms mean that centers will receive a lower remuneration, the centersʼ overall evaluation of the subcutaneous administration route for trastuzumab was overwhelmingly positive. The greatest benefit cited by the centers was the flexibility in scheduling patient appointments. This increased flexibility improved conditions in some centers which were experiencing pressures due to a shortage of staff, particularly at peak times. The general consensus, however, was that the remuneration systems for oncological treatments urgently need to be amended to ensure that the real costs of treatment are covered, even if the administration route has changed. PMID:26166837

  5. Monitoring Afatinib Treatment in HER2-Positive Gastric Cancer with 18F-FDG and 89Zr-Trastuzumab PET

    PubMed Central

    Janjigian, Yelena Y.; Viola-Villegas, Nerissa; Holland, Jason P.; Divilov, Vadim; Carlin, Sean D.; Gomes-DaGama, Erica M.; Chiosis, Gabriela; Carbonetti, Gregory; de Stanchina, Elisa; Lewis, Jason S.

    2016-01-01

    We evaluated the ability of the PET imaging agent 89Zr-trastuzumab to delineate HER2-positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor afatinib. Methods Using 89Zr-trastuzumab, 18F-FDG, or 3′-deoxy-3′-18F-fluorothymidine (18F-FLT PET), we imaged HER2-positive NCI-N87 and HER2-negative MKN74 gastric cancer xenografts in mice. Next, we examined the pharmacodynamic effects of afatinib in NCI-N87 xenografts using 89Zr-trastuzumab and 18F-FDG PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies. Results Although 18F-FDG uptake in NCI-N87 tumors did not change, a decrease in 89Zr-trastuzumab uptake was observed in the afatinib-treated versus control groups (3.0 ± 0.0 percentage injected dose per gram (%ID/g) vs. 21.0 ± 3.4%ID/g, respectively; P < 0.05). 89Zr-trastuzumab PET results corresponded with tumor reduction, apoptosis, and downregulation of HER2 observed on treatment with afatinib. Downregulation of total HER2, phosphorylated (p)-HER2, and p-EGFR occurred within 24 h of the first dose of afatinib, with a sustained effect over 21 d of treatment. Conclusion Afatinib demonstrated antitumor activity in HER2-positive gastric cancer in vivo. 89Zr-trastuzumab PET specifically delineated HER2-positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib. PMID:23578997

  6. Continuation of trastuzumab beyond disease progression in HER2-positive metastatic gastric cancer: the MD Anderson experience

    PubMed Central

    Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Rogers, Jane E.; Mares, Jeannette Elizabeth; Blum, Mariela A.; Estrella, Jeannelyn; Matamoros, Aurelio; Sagebiel, Tara; Devine, Catherine E.; Badgwell, Brian D.; Lin, Quan D.; Das, Prajnan; Ajani, Jaffer A.

    2016-01-01

    Background Despite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity. Methods HER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression. Results Forty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01–5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5–53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population. Conclusions In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in

  7. [A Case of Unresectable Local Recurrence of Gastric Cancer Successfully Resected after Pre-Operative Chemotherapy with Trastuzumab].

    PubMed

    Okubo, Satoshi; Takahashi, Tsuyoshi; Miyazaki, Yasuhiro; Makino, Tomoki; Kurokawa, Yukinori; Yamazaki, Makoto; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro

    2015-11-01

    A 69-year-old man was diagnosed with advanced gastric cancer and underwent total gastrectomy (tubular adenocarcinoma, tub2, pT3N0M0, stageⅡA). Eight months after the surgery, recurrence on the anastomosis was observed. Tumor invasion of the aortic artery was suspected, and the patient was considered inoperable. He was treated with S-1/CDDP plus trastuzumab therapy as a neoadjuvant chemotherapy regimen. After 4 courses of the chemotherapy, significant tumor reduction was observed, and the patient underwent anastomosis resection. Chemotherapy with trastuzumab appears to be an effective NAC treatment for HER2-positive, advanced gastric cancer. PMID:26805275

  8. [A Case of HER2-Positive Esophagogastric Junction Cancer with Perforation Curatively Resected after Neoadjuvant Chemotherapy plus Trastuzumab].

    PubMed

    Toshima, Hirokazu; Hisamatsu, Atsushi; Shimada, Ken; Saito, Mitsuo; Suzuki, Michitaka; Matsukawa, Masaaki; Inoue, Haruhiro

    2016-06-01

    A 60-year-old man was diagnosed with adenocarcinoma of the esophagogastric junction with lymph node metastasis along the left gastric artery. The clinical stage was determined to be T4b, N1, M0, Stage IIIB, and a neoadjuvant chemotherapy (NAC)regimen of capecitabine/CDDP plus trastuzumab was selected for treatment. Before 3 courses of chemotherapy, the patient developed perforated gastric cancer. With conservative therapy, we were able to obtain closure of the perforation without affecting the curability of the cancer. We changed the chemotherapy regimen to S-1/CDDP plus trastuzumab, and the patient underwent curative resection. PMID:27306816

  9. Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials

    PubMed Central

    Kotoula, Vassiliki; Chatzopoulos, Kyriakos; Lakis, Sotiris; Alexopoulou, Zoi; Timotheadou, Eleni; Zagouri, Flora; Pentheroudakis, George; Gogas, Helen; Galani, Eleni; Efstratiou, Ioannis; Zaramboukas, Thomas; Koutras, Angelos; Aravantinos, Gerasimos; Samantas, Epaminontas; Psyrri, Amanda; Kourea, Helen; Bobos, Mattheos; Papakostas, Pavlos; Kosmidis, Paris; Pectasides, Dimitrios; Fountzilas, George

    2016-01-01

    Background Tumor infiltrating lymphocytes (TILs) are considered in the prognosis of breast cancer (BC) patients. Here, we investigated the prognostic/predictive effect of TILs in patients treated in the frame of four prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab era. Methods TILs density was histologically assessed as percentage of stromal area on whole routine sections of 2613 BC (1563 Luminal A/B; 477 Luminal HER2; 246 HER2-enriched; 327 triple negative [TNBC]) and were evaluated as high/low at three cut-offs (c/o; 50% [lymphocytic predominance, LP], 35% and 25%), in separate training and validation sets. Results High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively. TILs status did not interact with BC subtypes or trastuzumab treatment. LPBC patient outcome was not affected by nodal status, while high TILs were favorable in TNBC with unfavorable nodal status. When adjusted for standard clinicopathological parameters and treatment, high TILs independently predicted for favorable outcome, e.g., disease-free survival with the 35% c/o in the entire cohort (HR = 0.44, 95% CI 0.28-0.69, p < 0.001) and in specific subtypes. Conclusions High TILs tumors, especially LPBC seem worthy validating as a separate entity of favorable prognosis in breast cancer. PMID:26506242

  10. Synergistic antitumor efficacy against the EGFRvIII+HER2+ breast cancers by combining trastuzumab with anti-EGFRvIII antibody CH12

    PubMed Central

    Zhang, Jiqin; Kong, Juan; Jiang, Hua; Tian, Mi; Li, Kesang; Wang, Biao; Chen, Cheng; Song, Fei; Pan, Xiaorong; Shi, Bizhi; Kong, Xianming; Gu, Jianren; Cai, Xiumei; Li, Zonghai

    2015-01-01

    Although Trastuzumab, an anti-HER2 antibody, benefits certain patients with HER2-overexpressing breast cancer, de novo or acquired trastuzumab resistance remains a haunting issue. EGFRvIII, co-expressing with HER2 in some breast tumors, indicates a poor clinical prognosis. However, the role of EGFRvIII in the function of trastuzumab is not clear. Here, we demonstrated that EGFRvIII overexpression contributed to de novo trastuzumab resistance and the feedback activation of STAT3 caused by trastuzumab also resulted in acquired resistance in EGFRvIII+HER2+ breast cancers. CH12, a highly effective anti-EGFRvIII monoclonal antibody that preferentially binds to EGFRvIII, significantly suppressed the growth of EGFRvIII+HER2+ breast cancer cells in vitro and in vivo. Importantly, CH12 in combination with trastuzumab had a synergistic inhibitory effect on EGFRvIII+HER2+ breast cancers in vitro and in vivo via attenuating the phosphorylation of EGFR and HER2 and their downstream signal pathways more effectively and reversing STAT3 feedback activation. Moreover, the combination therapy suppressed angiogenesis and induced cell apoptosis significantly. Together, these results suggested a synergistic efficacy of the combination of trastuzumab with CH12 against EGFRvIII+HER2+ breast cancers, which might be a potential clinical application in the future. PMID:26474285

  11. Treatment of HER2-Expressing Breast Cancer and Ovarian Cancer Cells With Alpha Particle-Emitting {sup 227}Th-Trastuzumab

    SciTech Connect

    Heyerdahl, Helen; Krogh, Cecilie; Borrebaek, Jorgen; Larsen, Asmund; Dahle, Jostein

    2011-02-01

    Purpose: To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate {sup 227}Th-p-isothiocyanato-benzyl-DOTA-trastuzumab ({sup 227}Th-trastuzumab [where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]) internalized by breast and ovarian cancer cell lines in order to assess the potential of {sup 227}Th-trastuzumab as a therapeutic agent against metastatic cancers that overexpress the HER2 oncogene. Methods and Materials: Clonogenic survival and cell growth rates of breast cancer cells treated with {sup 227}Th-trastuzumab were compared with rates of cells treated with nonbinding {sup 227}Th-rituximab, cold trastuzumab, and X-radiation. Cell growth experiments were also performed with ovarian cancer cells. Cell-associated radioactivity was measured at several time points, and the mean radiation dose to cells was calculated. Results: SKBR-3 cells got 50% of the mean absorbed radiation dose from internalized activity and 50% from cell surface-bound activity, while BT-474 and SKOV-3 cells got 75% radiation dose from internalized activity and 25% from cell surface-bound activity. Incubation of breast cancer cells with 2.5 kBq/ml {sup 227}Th-trastuzumab for 1 h at 4{sup o}C, followed by washing, resulted in mean absorbed radiation doses of 2 to 2.5 Gy. A dose-dependent inhibition of cell growth and an increase in apoptosis were induced in all cell lines. Conclusions: Clinically relevant activity concentrations of {sup 227}Th-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of {sup 227}Th-trastuzumab was higher than that of single-dose X-radiation (relative biological effectiveness = 1.2). These results warrant further studies of treatment of breast cancer and ovarian cancer with {sup 227}Th-trastuzumab.

  12. NK-cell and T-cell functions in patients with breast cancer: effects of surgery and adjuvant chemo- and radiotherapy.

    PubMed

    Mozaffari, F; Lindemalm, C; Choudhury, A; Granstam-Björneklett, H; Helander, I; Lekander, M; Mikaelsson, E; Nilsson, B; Ojutkangas, M-L; Osterborg, A; Bergkvist, L; Mellstedt, H

    2007-07-01

    Breast cancer is globally the most common malignancy in women. Her2-targeted monoclonal antibodies are established treatment modalities, and vaccines are in late-stage clinical testing in patients with breast cancer and known to promote tumour-killing through mechanisms like antibody-dependent cellular cytotoxicity. It is therefore increasingly important to study immunological consequences of conventional treatment strategies. In this study, functional tests and four-colour flow cytometry were used to detect natural killer (NK)-cell functions and receptors as well as T-cell signal transduction molecules and intracellular cytokines in preoperative breast cancer patients, and patients who had received adjuvant radiotherapy or adjuvant combined chemo-radiotherapy as well as in age-matched healthy controls. The absolute number of NK cells, the density of NK receptors as well as in vitro quantitation of functional NK cytotoxicity were significantly higher in preoperative patients than the post-treatments group and controls. A similar pattern was seen with regard to T-cell signalling molecules, and preoperative patients produced significantly higher amounts of cytokines in NK and T cells compared to other groups. The results indicate that functions of NK and T cells are well preserved before surgery but decrease following adjuvant therapy, which may speak in favour of early rather than late use of immunotherapeutic agents such as trastuzumab that may depend on intact immune effector functions. PMID:17551492

  13. Pharmacokinetic Comparability of a Biosimilar Trastuzumab Anticipated from Its Physicochemical and Biological Characterization.

    PubMed

    Miranda-Hernández, Mariana P; López-Morales, Carlos A; Piña-Lara, Nelly; Perdomo-Abúndez, Francisco C; Pérez, Néstor O; Revilla-Beltri, Jorge; Molina-Pérez, Aarón; Estrada-Marín, Larisa; Flores-Ortiz, Luis F; Ruiz-Argüelles, Alejandro; Medina-Rivero, Emilio

    2015-01-01

    Comparability between a biosimilar and its reference product requires the evaluation of critical quality attributes that may impact on its pharmacological response. Herein we present a physicochemical characterization of a biosimilar trastuzumab focused on the attributes related to the pharmacokinetic response. Capillary isoelectrofocusing (cIEF) and cation exchange chromatography (CEX) were used to evaluate charge heterogeneity; glycosylation profiles were assessed through hydrophilic interaction liquid chromatography (HILIC); aggregates content was evaluated through size exclusion chromatography (SEC) while binding affinity to FcRn was evaluated using isothermal titration calorimetry (ITC). The biosimilar trastuzumab and its reference product exhibited a high degree of similarity for the evaluated attributes. In regard to the pharmacokinetic parameters, randomized, double blind, and two-arm parallel and prospective study was employed after the administration of a single intravenous dose in healthy volunteers. No significant differences were found between the pharmacokinetic profiles of both products. Our results confirm that similarity of the critical quality attributes between a biosimilar product, obtained from a different manufacturing process, and the reference product resulted in comparable pharmacokinetic profiles, diminishing the uncertainty related to the biosimilar's safety and efficacy. PMID:26682224

  14. Combined Treatment of Herbal Mixture Extract H9 with Trastuzumab Enhances Anti-tumor Growth Effect.

    PubMed

    Lee, Sunyi; Han, Sora; Jeong, Ae Lee; Park, Jeong Su; Jung, Seung Hyun; Choi, Kang-Duk; Yang, Young

    2015-07-01

    Extracts from Asian medicinal herbs are known to be successful therapeutic agents against cancer. In this study, the effects of three types of herbal extracts on anti-tumor growth were examined. Among the three types of herbal extracts, H9 showed stronger anti-tumor growth effects than H5 and H11 in vivo. To find the molecular mechanism by which H9 inhibited the proliferation of breast cancer cell lines, the levels of apoptotic markers were examined. Proapoptotic markers, including cleaved PARP and cleaved caspases 3 and 9, were increased, whereas the anti-apoptotic marker Bcl-2 was decreased by H9 treatment. Next, the combined effect of H9 with the chemotherapeutic drugs doxorubicin/cyclophosphamide (AC) on tumor growth was examined using 4T1-tumor-bearing mice. The combined treatment of H9 with AC did not show additive or synergetic anti-tumor growth effects. However, when tumor-bearing mice were co-treated with H9 and the targeted anti-tumor drug trastuzumab, a delay in tumor growth was observed. The combined treatment of H9 and trastuzumab caused an increase of natural killer (NK) cells and a decrease of myeloid-derived suppressor cells (MDSC). Taken together, H9 induces the apoptotic death of tumor cells while increasing anti-tumor immune activity through the enhancement of NK activity and diminishment of MDSC. PMID:25791851

  15. Non-covalent carriage of anticancer agents by humanized antibody trastuzumab.

    PubMed

    Yadav, Arpita; Sharma, Sweta; Yadav, Veejendra Kumar

    2016-05-01

    This article explores the internalization and non-covalent carriage of small molecule anticancer agents like vinca alkaloids by humanized monoclonal antibody trastuzumab. Such carriage is marked by significant reduction in side effects and increased therapeutic value of these anticancer agents. This study is coherent with few clinical observations of enhanced efficiency of these anticancer agents when co-administered with therapeutic antibodies. This study will also serve as the foundation for screening a database of anticancer agents for possible compounds that may be co-delivered alongwith the antibody. Based on this study vincristine conformation inside antibody and its charge environment may be used as descriptors for screening purposes. Graphical Abstract This article describes the use of immunotherapeutic agents for enhancing the bioavailability and efficacy of small molecule anticancer agents. The internalization and non-covalent carriage of vinca alkaloids by humanized antibody trastuzumab has been investigated utilizing flexible ligand molecular docking and molecular dynamics simulation studies coupled with MMGBSA binding energy calculations. The study concludes efficient non-covalent carriage without probability of premature expulsion. It is recommended that vincristine conformation and charge distribution may be used for screening library of compounds for possible mAb cargo. PMID:27109707

  16. Pharmacokinetic Comparability of a Biosimilar Trastuzumab Anticipated from Its Physicochemical and Biological Characterization

    PubMed Central

    Miranda-Hernández, Mariana P.; López-Morales, Carlos A.; Piña-Lara, Nelly; Perdomo-Abúndez, Francisco C.; Pérez, Néstor O.; Revilla-Beltri, Jorge; Molina-Pérez, Aarón; Estrada-Marín, Larisa; Flores-Ortiz, Luis F.; Ruiz-Argüelles, Alejandro; Medina-Rivero, Emilio

    2015-01-01

    Comparability between a biosimilar and its reference product requires the evaluation of critical quality attributes that may impact on its pharmacological response. Herein we present a physicochemical characterization of a biosimilar trastuzumab focused on the attributes related to the pharmacokinetic response. Capillary isoelectrofocusing (cIEF) and cation exchange chromatography (CEX) were used to evaluate charge heterogeneity; glycosylation profiles were assessed through hydrophilic interaction liquid chromatography (HILIC); aggregates content was evaluated through size exclusion chromatography (SEC) while binding affinity to FcRn was evaluated using isothermal titration calorimetry (ITC). The biosimilar trastuzumab and its reference product exhibited a high degree of similarity for the evaluated attributes. In regard to the pharmacokinetic parameters, randomized, double blind, and two-arm parallel and prospective study was employed after the administration of a single intravenous dose in healthy volunteers. No significant differences were found between the pharmacokinetic profiles of both products. Our results confirm that similarity of the critical quality attributes between a biosimilar product, obtained from a different manufacturing process, and the reference product resulted in comparable pharmacokinetic profiles, diminishing the uncertainty related to the biosimilar's safety and efficacy. PMID:26682224

  17. [Complete Response in a Patient with HER2-Positive Gastric Cancer and Multiple Lung Metastases with Trastuzumab-Containing Chemotherapy].

    PubMed

    Nakata, Wachiko; Tokuyama, Nobuyuki; Yagioka, Hiroshi; Suyama, Yuki; Ogura, Keiji

    2016-05-01

    We report the case ofa 79-year-old Japanese woman diagnosed with human epidermal growth factor receptor 2(HER2)- positive gastric cancer ofthe cardia with multiple lung metastases that showed complete response to trastuzumab-containing chemotherapy. First, we administered tegafur/gimeracil/oteraci(l S-1)and cisplatin(CDDP)concurrently to the patient. Next, we switched to trastuzumab in combination with capecitabine and CDDP because gastric cancer tissue indicated HER2-positivity. Considering the patient's age and renal function, the dose of CDDP was decreased to 50% after starting the medication. Before the 2nd course of trastuzumab-containing chemotherapy, oral mucositis(Grade 3)and hand-foot syndrome (Grade 1)were observed. Therefore, a one-step dose reduction ofcapecitabine was necessary. After the 4th course, the primary gastric tumor was no longer visible endoscopically. After the 7th course, computed tomography(CT)showed the disappearance ofall lung metastases. Accordingly, the patient was considered to be completely responsive to the medication. After the 12th course, recurrence of the tumor was not identified and at the request of the patient, the trastuzumab-containing chemotherapy was discontinued. Regular follow-up showed no evidence ofrecurrence 8 months after discontinuing treatment and the patient was in good condition 21 months after her initial diagnosis. PMID:27210096

  18. The anti-HER3 antibody in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive gastric cancer.

    PubMed

    Wang, Qiwei; Zhang, Xiaotian; Shen, Enyun; Gao, Jing; Cao, Fengqi; Wang, Xiaojuan; Li, Yilin; Tian, Tiantian; Wang, Jingyuan; Chen, Zuhua; Wang, Jiayuan; Shen, Lin

    2016-09-28

    The anti-HER2 monoclonal antibody trastuzumab is central to the treatment of HER2-positive gastric cancer (GC); however, its responses are limited. HER3 seems to be the preferred dimerization partner with HER2 and is emerging as a key target for complete blockade of downstream pathways and better clinical response. In this study, we report that novel anti-HER3 antibodies (1A5-3D4) that can neutralize multiple modes of HER3 activation, combined with trastuzumab, exhibited synergistic inhibitory effect on the cell proliferation in HER2-positive GC cell lines. Follow-up studies revealed that the combination treatment significantly inhibited phosphorylation of HER3 as well as AKT and ERK signals. In vivo experiments further showed that the anti-tumor effect of trastuzumab was enhanced by its combination with 1A5-3D4 in NCI-N87 xenograft and patient derived xenografts (PDX). Particularly in an HER2-negative whereas neuregulin1 (a ligand of HER3) positive PDX, the combination was also superior to monotherapy. 1A5-3D4 in combination with trastuzumab exhibits a synergistic inhibitory effect on tumor activity, suggesting that targeting both HER2 and HER3 resulted in an improved treatment effects on HER2-positive GC. PMID:27317872

  19. A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab.

    PubMed

    Mani, Aruna; Roda, Julie; Young, Donn; Caligiuri, Michael A; Fleming, Gini F; Kaufman, Peter; Brufsky, Adam; Ottman, Susan; Carson, William E; Shapiro, Charles L

    2009-09-01

    Trastuzumab mediates the lysis of HER2-expressing breast cancer cell lines by interleukin-2 (IL-2) primed natural killer (NK) cells. We hypothesized that IL-2 would augment the anti-tumor effects of trastuzumab in MBC in patients who had progressed on or within 12 months of receiving a trastuzumab-containing regimen. Secondary objectives were to measure antibody-directed cellular cytotoxicity (ADCC) against HER2 over-expressing target cells, and to measure serum cytokines. Patients received trastuzumab (4 mg/kg intravenously (IV)) every 2 weeks in combination with daily low-dose IL-2 (1 million IU/m(2) subcutaneously (SC)) and pulsed intermediate-dose IL-2 (12 million IU/m(2) SC). Samples were analyzed for NK cell expansion and ADCC against a HER2-positive breast cancer cell line. In addition, interferon-gamma (IFN-gamma), mRNA expression in peripheral blood mononuclear cells (PBMC) and the following serum cytokines were measured: IFN-gamma, monokine-induced by IFN-gamma (MIG), and interferon-inducible protein ten (IP-10). The median number of treatment cycles was four (range 1-23) and the treatment was well tolerated. There were no objective responses. NK cells were not expanded and ADCC was not enhanced. Eight (62%) patients had a twofold or higher increase in mRNA transcript for IFN-gamma, two (15%) patients had elevated serum levels of IFN-gamma and 12 (92%) had increases angiogenic MIG and IP-10. In trastuzumab-refractory patients adding IL-2 did not produce responses and did not result in NK cell expansion. However, these patients had the ability to respond to IL-2 as evidenced by increases in IFN-gamma transcripts and chemokines. The lack of NK cell expansion may explain the absence of clinical benefit. PMID:19051009

  20. A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab

    PubMed Central

    Mani, Aruna; Roda, Julie; Young, Donn; Caligiuri, Michael A.; Fleming, Gini F.; Kaufman, Peter; Brufsky, Adam; Ottman, Susan; Carson, William E.

    2010-01-01

    Trastuzumab mediates the lysis of HER2-expressing breast cancer cell lines by interleukin-2 (IL-2) primed natural killer (NK) cells. We hypothesized that IL-2 would augment the anti-tumor effects of trastuzumab in MBC in patients who had progressed on or within 12 months of receiving a trastuzumab-containing regimen. Secondary objectives were to measure antibody-directed cellular cytotoxicity (ADCC) against HER2 over-expressing target cells, and to measure serum cytokines. Patients received trastuzumab (4 mg/kg intravenously (IV)) every 2 weeks in combination with daily low-dose IL-2 (1 million IU/m2 subcutaneously (SC)) and pulsed intermediate-dose IL-2 (12 million IU/m2 SC). Samples were analyzed for NK cell expansion and ADCC against a HER2-positive breast cancer cell line. In addition, interferon-gamma (IFN-γ), mRNA expression in peripheral blood mononuclear cells (PBMC) and the following serum cytokines were measured: IFN-γ, monokine-induced by IFN-γ (MIG), and interferon-inducible protein ten (IP-10). The median number of treatment cycles was four (range 1–23) and the treatment was well tolerated. There were no objective responses. NK cells were not expanded and ADCC was not enhanced. Eight (62%) patients had a twofold or higher increase in mRNA transcript for IFN-γ, two (15%) patients had elevated serum levels of IFN-γ and 12 (92%) had increases angiogenic MIG and IP-10. In trastuzumab-refractory patients adding IL-2 did not produce responses and did not result in NK cell expansion. However, these patients had the ability to respond to IL-2 as evidenced by increases in IFN-γ transcripts and chemokines. The lack of NK cell expansion may explain the absence of clinical benefit. PMID:19051009

  1. Adjuvants: Classification, Modus Operandi, and Licensing

    PubMed Central

    Apostólico, Juliana de Souza

    2016-01-01

    Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations. PMID:27274998

  2. Targeted delivery of doxorubicin-utilizing chitosan nanoparticles surface-functionalized with anti-Her2 trastuzumab

    PubMed Central

    Yousefpour, Parisa; Atyabi, Fatemeh; Vasheghani-Farahani, Ebrahim; Movahedi, Ali-Akbar Mousavi; Dinarvand, Rassoul

    2011-01-01

    Background Targeting drugs to their sites of action to overcome the systemic side effects associated with most antineoplastic agents is still a major challenge in pharmaceutical research. In this study, the monoclonal antibody, trastuzumab, was used as a targeting agent in nanoparticles carrying the antitumor drug, doxorubicin, specifically to its site of action. Methods Chitosan-doxorubicin conjugation was carried out using succinic anhydride as a crosslinker. Trastuzumab was conjugated to self-assembled chitosan-doxorubin conjugate (CS-DOX) nanoparticles (particle size, 200 nm) via thiolation of lysine residues and subsequent linking of the resulted thiols to chitosan. Conjugation was confirmed by gel permeation chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance spectroscopy studies. Dynamic light scattering, transmission electron microscopy, and zeta potential determination were used to characterize the nanoparticles. Results CS-DOX conjugated nanoparticles had a spherical shape and smooth surface with a narrow size distribution and core-shell structure. Increasing the ratio of doxorubicin to chitosan in the conjugation reaction gave rise to a higher doxorubicin content but lower conjugation efficiency. Trastuzumab-decorated nanoparticles (CS-DOX-mAb) contained 47 μg/mg doxorubicin and 33.5 μg/mg trastuzumab. Binding of trastuzumab to the nanoparticles was further probed thermodynamically by isothermal titration calorimetry. Fluorescence microscopy demonstrated enhanced and selective uptake of CS-DOX-mAb by Her2+ cancer cells compared with nontargeted CS-DOX nanoparticles and free drug. Conclusion Antibody-conjugated nanoparticles were shown to discriminate between Her2+ and Her2− cells, and thus have the potential to be used in active targeted drug delivery, with reduction of drug side effects in Her2+ breast and ovarian cancers. PMID:21976974

  3. Preliminary Results of Whole Brain Radiotherapy With Concurrent Trastuzumab for Treatment of Brain Metastases in Breast Cancer Patients

    SciTech Connect

    Chargari, Cyrus; Idrissi, Hind Riahi; Pierga, Jean-Yves; Bollet, Marc A.; Dieras, Veronique; Campana, Francois; Cottu, Paul; Fourquet, Alain; Kirova, Youlia M.

    2011-11-01

    Purpose: To assess the use of trastuzumab concurrently with whole brain radiotherapy (WBRT) for patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer. Methods and Materials: Between April 2001 and April 2007, 31 patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer were referred for WBRT with concurrent trastuzumab. At brain progression, the median age was 55 years (range, 38-73), and all patients had a performance status of 0-2. The patients received trastuzumab 2 mg/kg weekly (n = 17) or 6 mg/kg repeated every 21 days (n = 14). In 26 patients, concurrent WBRT delivered 30 Gy in 10 daily fractions. In 6 patients, other fractionations were chosen because of either poor performance status or patient convenience. Results: After WBRT, radiologic responses were observed in 23 patients (74.2%), including 6 (19.4%) with a complete radiologic response and 17 (54.8%) with a partial radiologic response. Clinical responses were observed in 27 patients (87.1%). The median survival time from the start of WBRT was 18 months (range, 2-65). The median interval to brain progression was 10.5 months (range, 2-27). No Grade 2 or greater acute toxicity was observed. Conclusion: The low toxicity of trastuzumab concurrently with WBRT should probably not justify delays. Although promising, these preliminary data warrant additional validation of trastuzumab as a potential radiosensitizer for WBRT in brain metastases from breast cancer in the setting of a clinical trial.

  4. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures.

    PubMed

    Oh, Djin-Ye; Dowling, David J; Ahmed, Saima; Choi, Hyungwon; Brightman, Spencer; Bergelson, Ilana; Berger, Sebastian T; Sauld, John F; Pettengill, Matthew; Kho, Alvin T; Pollack, Henry J; Steen, Hanno; Levy, Ofer

    2016-06-01

    Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles

  5. Imaging and biodistribution of Her2/neu expression in non-small cell lung cancer xenografts with Cu-labeled trastuzumab PET.

    PubMed

    Paudyal, Pramila; Paudyal, Bishnuhari; Hanaoka, Hirofumi; Oriuchi, Noboru; Iida, Yashuhiko; Yoshioka, Hiroki; Tominaga, Hideyuki; Watanabe, Satoshi; Watanabe, Shigeki; Ishioka, Noriko S; Endo, Keigo

    2010-04-01

    Non-small cell lung carcinomas (NSCLC) overexpress the Her2/neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/neu overexpressing breast cancer. However, its therapeutic use in Her2/neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of (64)Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/neu expression in NSCLC. Trastuzumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with (64)Cu. The molecular specificity of DOTA-trastuzumab was determined in NSCLC cell lines with Her2/neu overexpression (NCI-H2170) and negative expression (NCI-H520). Imaging of Her2/neu expression was performed in NCI-H2170 tumor-bearing mice with (64)Cu-DOTA-trastuzumab PET and (64)Cu-DOTA-IgG. In vitro studies revealed specific binding of DOTA-trastuzumab in the Her2/neu positive NCI-H2170 cells, while no binding was seen in the Her2/neu negative NCI-H520 cell line. Biodistribution and PET studies revealed a significantly high accumulation of (64)Cu-DOTA-trastuzumab in the Her2/neu overexpressing NCI-H2170 tumor at 24 and 48 h post-injection (21.4 +/- 1.4% and 23.2 +/- 5.1% injection dose/gram (% ID/g), respectively). PET imaging of Her2/neu negative NCI-H520 tumors showed much less uptake of (64)Cu-DOTA-trastuzumab (4.0% ID/g). The NCI-H2170 tumor uptake of (64)Cu-DOTA-trastuzumab was significantly higher than that of (64)Cu-DOTA-IgG (P < 0.0001). (64)Cu-DOTA-trastuzumab showed a very clear image of a Her2/neu positive tumor and appeared to be effective as a PET tracer for imaging of Her2/neu gene expression in NSCLC, suggesting its potential clinical use for identifying patients that might benefit from trastuzumab-based therapy. PMID:20219072

  6. A Pretherapy Biodistribution and Dosimetry Study of Indium-111-Radiolabeled Trastuzumab in Patients with Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer

    PubMed Central

    Raubitschek, Andrew; Yamauchi, Dave; Williams, Lawrence E.; Wu, Anna M.; Yazaki, Paul; Shively, John E.; Colcher, David; Somlo, George

    2010-01-01

    Abstract Purpose The purposes of this study were to evaluate the organ biodistribution, pharmacokinetics, immunogenicity, and tumor uptake of 111Indium (111In)-MxDTPA-trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers and to determine whether 90Y-MxDTPA-trastuzumab should be evaluated in subsequent clinical therapy trials. Experimental Design Patients with HER2-overexpressing breast cancers who were to undergo planned trastuzumab therapy first received unlabeled trastuzumab (4–8 mg/kg IV), followed 4 hours later by 5 mCi 111In-MxDTPA-trastuzumab (10 mg antibody). Serial blood samples, 24-hour urine collections, and nuclear scans were performed at defined time points for 7 days. Results Eight (8) patients received 111In-MxDTPA-trastuzumab, which was well tolerated with no adverse side-effects. Three (3) of 7 patients with known lesions demonstrated positive imaging on nuclear scans. No antiantibody responses were observed for 2 months postinfusion. Organ doses (cGy/mCi) assuming radiolabeling with 90Y were 19.9 for heart wall, 17.6 for liver, 4.6 for red marrow, and 2.8 for the whole body. Tumor doses ranged from 24 to 172 cGy/mCi. Conclusions In summary, results from this study indicate that 90Y-MxDTPA-trastuzumab is an appropriate agent to evaluate in therapy trials. No evidence of an immune response to 111In-MxDTPA-trastuzumab was detected, predicting for the ability to administer multiple cycles. With the exception of cardiac uptake, pharmacokinetics and organ biodistribution were comparable to other 90Y-labeled monoclonal antibodies previously evaluated in the clinic. Cardiac uptake was comparable to hepatic uptake and therefore predicted to not be prohibitively high as to result in dose-limiting cardiotoxicity. PMID:20707718

  7. Significant systemic therapeutic effects of high-LET immunoradiation by 212Pb-trastuzumab against prostatic tumors of androgen-independent human prostate cancer in mice.

    PubMed

    Tan, Zongqing; Chen, Pingping; Schneider, Nathan; Glover, Samuel; Cui, Lingling; Torgue, Julien; Rixe, Olivier; Spitz, Henry B; Dong, Zhongyun

    2012-06-01

    The purpose of this study was to determine therapeutic effects and systemic toxicity of 212Pb-trastuzumab in an orthotopic model of human prostate cancer cells in nude mice. TCMC-Trastuzumab was radiolabeled with 212Pb. The 212Pb-trastuzumab generated from the procedure was intact and had high binding affinity with a dissociation constant (of 3.9±0.99 nM. PC-3MM2 cells, which expressed a lower level of HER2 both in culture and in tumors, were used in therapy studies. A single intravenous injection of 212Pb-trastuzumab reduced tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the survival of tumor-bearing mice. Treatment with 212Pb-trastuzumab did not cause significant changes in body weight, serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), hematological profiles, and histological morphology of several major organs of tumor-bearing mice. These findings suggest that a systemic delivery of 212Pb-trastuzumab could be an effective modality for management of advanced human prostate cancer. PMID:22322558

  8. IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production.

    PubMed

    Jaime-Ramirez, Alena Cristina; Mundy-Bosse, Bethany L; Kondadasula, SriVidya; Jones, Natalie B; Roda, Julie M; Mani, Aruna; Parihar, Robin; Karpa, Volodymyr; Papenfuss, Tracey L; LaPerle, Krista M; Biller, Elizabeth; Lehman, Amy; Chaudhury, Abhik Ray; Jarjoura, David; Burry, Richard W; Carson, William E

    2011-03-15

    The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-γ production from NK cells and T cells. We hypothesized that coadministration of IL-12 with a murine anti-HER2/neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 μg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26(HER2/neu)) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN-γ, monokine induced by IFN-γ, and RANTES. Experiments with IFN-γ-deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4(+) or CD8(+) T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26(HER2/neu) tumor cells revealed that IFN-γ induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-γ production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs. PMID:21321106

  9. Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition.

    PubMed

    Dokmanovic, Milos; Wu, Yun; Shen, Yi; Chen, Jieqing; Hirsch, Dianne S; Wu, Wen Jin

    2014-08-01

    The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and the status of phosphorylated ErbB2-Y1248 (ErbB2-pY1248) may correlate with the sensitivity of breast cancers to trastuzumab. The mechanisms of which remain unclear. Here, we show that binding of trastuzumab to ErbB2 activates ErbB2 kinase activity and enhances ErbB2-Y1248 phosphorylation in trastuzumab-sensitive breast cancer cells. This in turn increases the interaction between ErbB2 and non-receptor Csk-homologous kinase (CHK), leading to growth inhibition of breast cancer cells. Overexpression of CHK mimics trastuzumab treatment to mediate ErbB2-Y1248 phosphorylation, Akt downregulation, and growth inhibition of trastuzumab-sensitive breast cancer cells. CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition. We further demonstrate that positive ErbB2-pY1248 staining in ErbB2-positive breast cancer biopsies correlates with the increased trastuzumab response in trastuzumab neoadjuvant settings. Collectively, this study highlights an important role for ErbB2-pY1248 in mediating trastuzumab-induced growth inhibition and trastuzumab-induced interactions between CHK and ErbB2-pY1248 is identified as a novel mechanism of action that mediates the growth inhibition of breast cancer cells. The novel mechanistic insights into trastuzumab action revealed by this study may impact the design of next generation of therapeutic monoclonal antibodies targeting receptor tyrosine kinases, as well as open new avenues to identify novel targets for the treatment of ErbB2-positive cancers. PMID:24835103

  10. Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

    PubMed Central

    Dokmanovic, Milos; Wu, Yun; Shen, Yi; Chen, Jieqing; Hirsch, Dianne S; Wu, Wen Jin

    2014-01-01

    The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and the status of phosphorylated ErbB2-Y1248 (ErbB2-pY1248) may correlate with the sensitivity of breast cancers to trastuzumab. The mechanisms of which remain unclear. Here, we show that binding of trastuzumab to ErbB2 activates ErbB2 kinase activity and enhances ErbB2-Y1248 phosphorylation in trastuzumab-sensitive breast cancer cells. This in turn increases the interaction between ErbB2 and non-receptor Csk-homologous kinase (CHK), leading to growth inhibition of breast cancer cells. Overexpression of CHK mimics trastuzumab treatment to mediate ErbB2-Y1248 phosphorylation, Akt downregulation, and growth inhibition of trastuzumab-sensitive breast cancer cells. CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition. We further demonstrate that positive ErbB2-pY1248 staining in ErbB2-positive breast cancer biopsies correlates with the increased trastuzumab response in trastuzumab neoadjuvant settings. Collectively, this study highlights an important role for ErbB2-pY1248 in mediating trastuzumab-induced growth inhibition and trastuzumab-induced interactions between CHK and ErbB2-pY1248 is identified as a novel mechanism of action that mediates the growth inhibition of breast cancer cells. The novel mechanistic insights into trastuzumab action revealed by this study may impact the design of next generation of therapeutic monoclonal antibodies targeting receptor tyrosine kinases, as well as open new avenues to identify novel targets for the treatment of ErbB2-positive cancers. PMID:24835103

  11. Extended Adjuvant Therapy for Breast Cancer

    Cancer.gov

    An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.

  12. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    Cancer.gov

    A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.

  13. [Rectal cancer and adjuvant chemotherapy: which conclusions?].

    PubMed

    Bachet, J-B; Rougier, P; de Gramont, A; André, T

    2010-01-01

    Adenocarcinoma of the rectum represents about a third of cases of colorectal cancer, with an annual incidence of 12,000 cases in France. On the contrary of colon cancer, the benefice of adjuvant chemotherapy in rectal cancer has not been definitively proved, more because this question was assessed in few recent studies than because negative results. Preoperative radiochemotherapy is now the reference treatment for mid and lower rectal cancers, and allow to increase the local control without improvement of progression free survival and overall survival. The data of the "historical studies" of adjuvant treatment in rectal cancer published before 1990, of the meta-analysis of adjuvant trials in rectal cancer and of the QUASAR study suggest that adjuvant chemotherapy with fluoropyrimidines (intravenous or oral), in absence of pre-operative treatment, decrease the risk of metastatic relapse after curative surgery for a rectal cancer of stage II or III. This benefice seems similar to the one observed in colon cancer. In the EORTC radiotherapy group trial 22921, an adjuvant chemotherapy with 5-fluorouracil and low dose of leucovorin was not associated with a significantly improvement of overall survival but, despite the fact that only 42.9% of patients received all planed cycles, the progression free survival was increased (not significantly) in groups receiving adjuvant chemotherapy. The French recommendations are to discuss the indication of adjuvant chemotherapy by fluoropyrimidines in cases of stage III rectal cancer on histopathologic reports and no chemotherapy in case of stade II. Despite the fact that none study have assessed a combination of fluoropyrimidines and oxaliplatin in adjuvant setting in rectal cancer, like in colon cancer, the Folfox4, modified Folfox6 or Xelox regimens are valid options in stage III (experts opinion). In cases of pathologic complete remission or in absence of involved nodes, the benefice of adjuvant chemotherapy is not assessed. In

  14. Applications of nanomaterials as vaccine adjuvants

    PubMed Central

    Zhu, Motao; Wang, Rongfu; Nie, Guangjun

    2014-01-01

    Vaccine adjuvants are applied to amplify the recipient's specific immune responses against pathogen infection or malignancy. A new generation of adjuvants is being developed to meet the demands for more potent antigen-specific responses, specific types of immune responses, and a high margin of safety. Nanotechnology provides a multifunctional stage for the integration of desired adjuvant activities performed by the building blocks of tailor-designed nanoparticles. Using nanomaterials for antigen delivery can provide high bioavailability, sustained and controlled release profiles, and targeting and imaging properties resulting from manipulation of the nanomaterials’ physicochemical properties. Moreover, the inherent immune-regulating activity of particular nanomaterials can further promote and shape the cellular and humoral immune responses toward desired types. The combination of both the delivery function and immunomodulatory effect of nanomaterials as adjuvants is thought to largely benefit the immune outcomes of vaccination. In this review, we will address the current achievements of nanotechnology in the development of novel adjuvants. The potential mechanisms by which nanomaterials impact the immune responses to a vaccine and how physicochemical properties, including size, surface charge and surface modification, impact their resulting immunological outcomes will be discussed. This review aims to provide concentrated information to promote new insights for the development of novel vaccine adjuvants. PMID:25483497

  15. Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results.

    PubMed

    Sorace, Anna G; Quarles, C Chad; Whisenant, Jennifer G; Hanker, Ariella B; McIntyre, J Oliver; Sanchez, Violeta M; Yankeelov, Thomas E

    2016-01-01

    To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter K (trans) ) and the extravascular extracellular volume fraction (v e ) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in K (trans) (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in v e (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically

  16. Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2

    PubMed Central

    Wu, Yifen; Li, Rong; Zhang, Junyi; Wang, Gang; Liu, Bin; Huang, Xiaofang; Zhang, Tao; Luo, Rongcheng

    2015-01-01

    Background Trastuzumab resistance in HER-2 positive breast cancer cells is closely related to overexpression of both epidermal growth factor receptor (EGFR) and human epidermal receptor (HER-2). SHP-1 has been demonstrated to downregulate tyrosine kinase activity including EGFR via its phosphatase function, but its effect on HER-2 activity is still unknown. Here, we examined the hypothesis that SHP-1 enhances the anticancer efficacy of trastuzumab in EGFR/HER-2 positive breast cancer cells through combining dual inhibition of EGFR and HER-2. Methods Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3cells in the presence of trastuzumab. The SHP-1 was ectopically expressed by stable transfection. The activity and expression of EGFR, HER-2, and downstream signaling pathways were tested by Western blot. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was examined by flow cytometry. The binding between SHP-1 and EGFR/HER-2 was evaluated by immunoprecipitation assay and bimolecular fluorescence complementation. The effects of SHP-1 on tumorigenicity and trastuzumab sensitivity were confirmed via in vivo xenograft model. Results Trastuzumab-resistant SKBr-3 cells showed aberrant co-expression of EGFR and HER-2. Introduction of wild-type SHP-1 inhibited cell proliferation, clone formation, and promoted the apoptosis induced by trastuzumab. Meanwhile, SHP-1 overexpression reduced phosphorylation levels of EGFR and HER-2 both in parental and trastuzumab-resistant SKBr-3 cells. In vivo study showed an increased antitumor effect of trastuzumab in SHP-1 overexpressed xenografts. At last, we discovered that SHP-1 can make complexes with both EGFR and HER-2, and both phospho-EGFR and phosphor-HER-2 levels in wild-type SHP-1 immunoprecipitates were less than those in phosphatase-inactive SHP-1 (C453S) immunoprecipitates, indicating that EGFR and HER-2 are

  17. Nab-paclitaxel and trastuzumab combination: a promising approach for neoadjuvant treatment in HER2-positive breast cancer

    PubMed Central

    Ricciardi, Giuseppina Rosaria Rita; Franchina, Tindara; Russo, Alessandro; Schifano, Silvia; Ferraro, Giuseppa; Adamo, Vincenzo

    2016-01-01

    Neoadjuvant therapy is a well-established approach for the treatment of locally advanced or inflammatory breast cancer (BC) and has been increasingly used in recent years not only as a management strategy but also as a research tool. Recently, nanoparticle albumin-bound paclitaxel (nab-paclitaxel)/trastuzumab combinations have been associated with promising activity in different clinical settings. In the present case, we report a complete pathological response after neoadjuvant treatment with the trastuzumab/nab-paclitaxel combination in a locally advanced human epidermal growth factor receptor 2 (HER2)-positive BC patient, with a good toxicity profile. This combination may represent a valid therapeutic option in the neoadjuvant therapy for HER2-positive locally advanced BC. PMID:27499629

  18. Influence of chelator and near-infrared dye labeling on biocharacteristics of dual-labeled trastuzumab-based imaging agents

    PubMed Central

    Aldrich, Melissa B; Yang, Zhi; Zhou, Nina; Xie, Qing; Liu, Chen; Sevick-Muraca, Eva

    2016-01-01

    Objective To investigate the effect of fluorescent dye labeling on the targeting capabilities of 111In- (DTPA)n-trastuzumab-(IRDye 800)m. Methods Trastuzumab-based conjugates were synthesized and conjugated with diethylenetriaminepentaacetic acid (DTPA) at molar ratios of 1, 2, 3 and 5 and with a fluorescent dye (IRDye 800CW) at molar ratios of 1, 3 and 5. Immunoreactivity and internalization were assessed on SKBR-3 cells, overexpressing human epidermal growth factor receptor 2. The stability in human serum and phosphate-buffered saline (PBS) was evaluated. The biodistribution of dual-labeled conjugates was compared with that of 111In-(DTPA)2-trastuzumab in a SKBR-3 xenograft model to evaluate the effect of dye-to-protein ratio. Results All trastuzumab-based conjugates exhibited a high level of chemical and optical purity. Flow cytometry results showed that increasing dye-to-protein ratios were associated with decreased immunoreactivity. Stability studies revealed that the conjugate was stable in PBS, while in human serum, increased degradation and protein precipitation were observed with increasing dye-to-protein ratios. At 4 h, the percentages of internalization of dual-labeled conjugates normalized by dye-to-protein ratio (m) were 24.88%±2.10%, 19.99%±0.59%, and 17.47%±1.26% for "m" equal to 1, 3, and 5, respectively. A biodistribution study revealed a progressive decrease in tumor uptake with an increase in the dye-to-protein ratios. The liver, spleen and kidney showed a marked uptake with increased dye-to-protein ratios, particularly in the latter. Conclusions With non-specific-site conjugation of the fluorescent dye with a protein based on imaging agent, the increase in dye-to-protein ratios negatively impacted the immunoreactivity and stability, indicating a reduced tumor uptake. PMID:27478322

  19. Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer

    PubMed Central

    Minuti, G; Cappuzzo, F; Duchnowska, R; Jassem, J; Fabi, A; O'Brien, T; Mendoza, A D; Landi, L; Biernat, W; Czartoryska-Arłukowicz, B; Jankowski, T; Zuziak, D; Zok, J; Szostakiewicz, B; Foszczyńska-Kłoda, M; Tempińska-Szałach, A; Rossi, E; Varella-Garcia, M

    2012-01-01

    Background: To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC). Methods: We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN. Results: MET FISH-positive cases (N=36, mean ⩾3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0% P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN ⩾3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8% P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately. Conclusion: High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC. PMID:22850551

  20. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma

    SciTech Connect

    Safran, Howard . E-mail: hsafran@lifespan.org; Di Petrillo, Thomas; Akerman, Paul; Ng, Thomas; Evans, Devon; Steinhoff, Margaret; Benton, David; Purviance, John; Goldstein, Lisa; Tantravahi, Umadevi; Kennedy, Teresa R.N.

    2007-02-01

    Purpose: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m{sup 2} and paclitaxel 50 mg/m{sup 2} weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. Results: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. Conclusions: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

  1. Adjuvant effects of saponins on animal immune responses*

    PubMed Central

    Rajput, Zahid Iqbal; Hu, Song-hua; Xiao, Chen-wen; Arijo, Abdullah G.

    2007-01-01

    Vaccines require optimal adjuvants including immunopotentiator and delivery systems to offer long term protection from infectious diseases in animals and man. Initially it was believed that adjuvants are responsible for promoting strong and sustainable antibody responses. Now it has been shown that adjuvants influence the isotype and avidity of antibody and also affect the properties of cell-mediated immunity. Mostly oil emulsions, lipopolysaccharides, polymers, saponins, liposomes, cytokines, ISCOMs (immunostimulating complexes), Freund’s complete adjuvant, Freund’s incomplete adjuvant, alums, bacterial toxins etc., are common adjuvants under investigation. Saponin based adjuvants have the ability to stimulate the cell mediated immune system as well as to enhance antibody production and have the advantage that only a low dose is needed for adjuvant activity. In the present study the importance of adjuvants, their role and the effect of saponin in immune system is reviewed. PMID:17323426

  2. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2.

    PubMed

    Varchetta, Stefania; Gibelli, Nadia; Oliviero, Barbara; Nardini, Elena; Gennari, Roberto; Gatti, Giovanna; Silva, Luzemira Santos; Villani, Laura; Tagliabue, Elda; Ménard, Sylvie; Costa, Alberto; Fagnoni, Francesco F

    2007-12-15

    Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective. Rather, susceptibility to develop ADCC was fairly predicted by test with trastuzumab before therapy and was correlated to the number of lymphocytes coexpressing CD16 and CD56. Phenotypic analysis at the end of ADCC evaluating down-regulation of CD16, and up-regulation of CD69 and CD107a, confirmed that natural killer (NK) cells and CD56(+) T cells were involved in productive engagement of trastuzumab. Also, the killing efficiency of CD16(+) lymphocytes was influenced by 158 V/F polymorphism of Fc gamma RIII (CD16), whereas variations of CD247 on NK cells were consistent with trends between ADCC before and after therapy. Complete pathologic response was observed in one patient showing ADCC of outstanding intensity, whereas four cases of partial response showed intermediate ADCC; none of the three patients unable to mount ADCC had significant tumor regression. These data indicate that quantity and lytic efficiency of CD16(+) lymphocytes are major factors for ADCC induction by trastuzumab, and confirm that breast cancer responses to short-term trastuzumab monotherapy may depend on involvement of the ADCC mechanism. PMID:18089830

  3. Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models

    PubMed Central

    Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Zhang, Nan; Murakami, Takashi; Maawy, Ali; Mii, Sumiyuki; Uehara, Fuminari; Yamamoto, Mako; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M.

    2015-01-01

    We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient’s cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer. PMID:26047477

  4. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    NASA Astrophysics Data System (ADS)

    Payne, Richard; McDonald, David; Byrne, Scott

    2015-10-01

    Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.

  5. Beyond antigens and adjuvants: formulating future vaccines.

    PubMed

    Moyer, Tyson J; Zmolek, Andrew C; Irvine, Darrell J

    2016-03-01

    The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next-generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines. PMID:26928033

  6. Systemic adjuvant therapies in renal cell carcinoma.

    PubMed

    Buti, Sebastiano; Bersanelli, Melissa; Donini, Maddalena; Ardizzoni, Andrea

    2012-10-01

    Renal cell carcinoma (RCC) is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to describe the results of past and ongoing phase III clinical trials in this field. We explored all the systemic treatments, including chemotherapy, immunotherapy and targeted drugs while alternative approaches have also been described. Appropriate selection of patients who would benefit from adjuvant therapies remains a crucial dilemma. Although the international guidelines do not actually recommend any adjuvant treatment after radical surgery for RCC, no conclusions have yet been drawn pending the results of the promising ongoing clinical trials with the target therapies. The significant changes that these new drugs have made on advanced disease outcome could represent the key to innovation in terms of preventing recurrence, delaying relapse and prolonging survival after radical surgery for RCC. PMID:25992216

  7. CpG DNA as mucosal adjuvant.

    PubMed

    McCluskie, M J; Davis, H L

    1999-09-01

    We have previously found synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs to be a potent adjuvant to protein administered by intramuscular injection or intranasal inhalation to BALB/c mice. Herein we have further evaluated the potential of CpG ODN as a mucosal adjuvant to purified hepatitis B surface antigen (HBsAg) when administered alone or with cholera toxin (CT). CpG ODN and CT both augmented systemic (humoral and cellular) and mucosal immune responses against HBsAg, and these could be further enhanced with higher doses of adjuvant or boosting. Overall, antibody isotypes with CT alone were predominantly IgG1 (Th2-like) whereas they were predominantly IgG2a (Th1-like) with CpG ODN alone or in combination with CT. Results from this study indicate that stimulatory CpG ODN are promising new adjuvants for mucosal vaccination strategies, whether used alone or in combination with other mucosal adjuvants. PMID:10506647

  8. Quantitative measurements of HER2 and phospho-HER2 expression: correlation with pathologic response to neoadjuvant chemotherapy and trastuzumab

    PubMed Central

    2014-01-01

    Background Preoperative therapy with chemotherapy and the HER2-targeted monoclonal antibody trastuzumab is valuable for patients with large or locally advanced HER2-positive (HER2+) breast cancers but traditional methods of measuring HER2 expression do not accurately stratify patients for likelihood of response. Quantitative immunofluorescent approaches have the potential to provide a mathematically continuous measure of HER2. Here we seek to determine whether quantitative measurement of HER2 or phospho-HER2 correlates with likelihood of response to trastuzumab- containing neoadjuvant therapy. Methods We evaluated core biopsy samples from 27 HER2+ breast cancer patients enrolled in a preoperative clinical trial using trastuzumab, nab-paclitaxel and carboplatin combination therapy (BrUOG BR-211B (NCT00617942)). Tumor core biopsies were taken before initiation of treatment and 9–13 days after patients received "run-in" doses of either single agent trastuzumab or nab-paclitaxel. The AQUA method of quantitative immunofluorescence was used for analysis of in situ protein expression. Patients then received 18 weeks of treatment, followed by surgery to assess pathologic response to the neoadjuvant regimen. Results A HER2 score of 2111 by AQUA analysis has been shown to be equivalent to HER2 3+ by immunohistochemical staining in previous studies. Of 20 evaluable patients, 10 cases who achieved a pathologic complete response (pathCR) with neoadjuvant treatment had a mean HER2 level of 10251 compared with 4766 in the patients without pathCR (p = 0.0021). Measurement of phospho-HER2 showed no difference in pathCR vs non-pathCR groups. In 9 patients who had HER2 levels repeated after a single treatment with trastuzumab there was no evidence of a reduction in the HER2 or phospho-HER2 levels following that exposure. Conclusions High levels of HER2 are associated with achievement of a pathCR in the preoperative setting, while levels of Phospho-HER2 were not predictive of

  9. Adjuvant radiation for soft tissue sarcomas.

    PubMed

    Dickie, Colleen I; Haas, Rick; O'Sullivan, Brian

    2015-01-01

    Over recent decades, limb-preservation surgery in combination with radiotherapy achieves local control rates exceeding 90% for extremity soft tissue sarcoma (STS). Local control is not as successful for retroperitoneal sarcoma (approximately 60%) despite aggressive surgical approaches including en bloc resection of uninvolved adjacent organs combined with intensity modulated radiotherapy (IMRT). This review will discuss the indications for adjuvant radiation therapy (RT) for primary presentation of soft tissue sarcoma: "What," referring to the type and manner of planning and delivery of RT; "When," referring to the timing and scheduling of RT; and "Why," referring to the rationale for the use of RT will be addressed. From a practical stand point, this Educational Chapter on "adjuvant RT" will focus on pre- and postoperative RT in the context of gross total resection for extremity and retroperitoneal soft tissue sarcoma, the two most frequent paradigms for the use of adjuvant RT. PMID:25993234

  10. Systemic immunotoxicity reactions induced by adjuvanted vaccines.

    PubMed

    Batista-Duharte, Alexander; Portuondo, Deivys; Pérez, O; Carlos, Iracilda Zeppone

    2014-05-01

    Vaccine safety is a topic of concern for the treated individual, the family, the health care personnel, and the others involved in vaccination programs as recipients or providers. Adjuvants are necessary components to warrant the efficacy of vaccines, however the overstimulation of the immune system is also associated with adverse effects. Local reactions are the most frequent manifestation of toxicity induced by adjuvanted vaccines and, with the exception of the acute phase response (APR), much less is known about the systemic reactions that follow vaccination. Their low frequency or subclinical expression meant that this matter has been neglected. In this review, various systemic reactions associated with immune stimulation will be addressed, including: APR, hypersensitivity, induction or worsening of autoimmune diseases, modification of hepatic metabolism and vascular leak syndrome (VLS), with an emphasis on the mechanism involved. Finally, the authors analyze the current focus of discussion about vaccine safety and opportunities to improve the design of new adjuvanted vaccines in the future. PMID:24607449

  11. For Some Breast Cancers, New Drug May Be Treatment Option

    Cancer.gov

    Results from an international clinical trial suggest that women with metastatic, HER2-positive breast cancer that is no longer responding to the targeted therapy trastuzumab (Herceptin) may soon have a new treatment option.

  12. Targeted Agents Active Against Breast Cancer: Q&A

    Cancer.gov

    ALTTO was a clinical trial designed to determine whether the combination of the monoclonal antibody trastuzumab (Herceptin) and the drug lapatinib (Tykerb) was more effective in treating HER2/ErbB2-positive breast cancer when combined with chemotherapy.

  13. [Adjuvant chemotherapy of adults soft tissue sarcomas].

    PubMed

    Bui-Nguyen, B; Italiano, A; Delva, F; Toulmond, M

    2010-06-01

    The main progress in the management of soft tissue sarcomas have been obtained in the field of local control. Although the main evolutive, vital, risk of these diseases is metastatic dissemination, efficacy of adjuvant chemotherapy remains a controversial issue. Thus, adjuvant chemotherapy cannot be considered as a standard for any situation. The last results of clinical trials, meta-analysis and population studies are presented and discussed in this article. New therapeutic strategies are to be developed to prevent metastases in soft tissue sarcomas. This needs a better understanding of the biology of those tumors, of metastases risk factors and of the determinants of systemic therapies efficacy in these tumors. PMID:20547481

  14. [ADJUVANTED INFLUENZA VACCINES: DATA FROM DIRECT COMPARATIVE STUDIES].

    PubMed

    Chernikova, M I; Vasiliev, Yu M

    2015-01-01

    Vaccines are the cornerstone of influenza control, however available vaccines are subject to certain limitations. Adjuvanted vaccines are a promising approach, however available adjuvants have a suboptimal effectiveness and safety profile. Data from direct comparative trials are necessary for selection of optimal adjuvants among currently available and search for novel safe and effective adjuvants for next generation influenza vaccines. Data from published direct comparative studies of adjuvants for influenza vaccines are summarized, a lack of such studies is noted, especially those using adequate methods and designs and comparing adjuvants of major groups (nature/source and mechanism of action). Several promising approaches of adjuvant research and development could be identified: chitosan-based adjuvants, oil-in-water emulsions and multi-component formulations (depot + immune modulating components). PMID:26829860

  15. Collagen density and alignment in responsive and resistant trastuzumab-treated breast cancer xenografts

    NASA Astrophysics Data System (ADS)

    Walsh, Alex J.; Cook, Rebecca S.; Lee, Jae H.; Arteaga, Carlos L.; Skala, Melissa C.

    2015-02-01

    Tumor collagen characteristics influence tumor malignancy, invasion, and metastasis. This study investigates the effects of trastuzumab (Tz) on the collagen of Tz-responsive (BT474) and Tz-resistant (HR6) breast cancer xenografts. Collagen content was assessed by in vivo second harmonic generation (SHG) imaging and histological trichrome staining of tumor sections. Collagen SHG imaging of control BT474 and HR6 tumors demonstrated increased collagen density after 14 days of treatment (p<0.05). Trichrome staining revealed decreased collagen in Tz-treated BT474 and HR6 tumors at 2, 5, and 14 days of treatment, suggesting that Tz affects the tumor microenvironment independent of epithelial cell response. Additionally, collagen alignment analysis revealed significantly less aligned collagen in the Tz-treated BT474 tumors at day 14 compared with control BT474 tumors. There was no correlation between SHG endpoints (collagen density and alignment) and trichrome staining (p>0.05), consistent with the physically distinctive nature of these measurements. There was also no correlation between tumor size and collagen endpoints (p>0.05). These results identify changes within the collagen compartment of the tumor microenvironment following Tz treatment, which are independent from the tumor cell response to Tz, and demonstrate that intravital collagen SHG imaging is capable of measuring dynamic changes in tumor microenvironment following treatment that complements trichrome staining.

  16. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 582.99...

  17. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 582.99...

  18. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 182.99...

  19. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  20. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 182.99...

  1. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 582.99...

  2. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 582.99...

  3. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  4. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Adjuvants for pesticide use dilutions. 172.710... Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower or applicant prior to application to...

  5. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 182.99...

  6. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  7. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) SUBSTANCES GENERALLY RECOGNIZED AS SAFE General Provisions § 182.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 182.99...

  8. Effectiveness of spray adjuvants on reduction of spray drift

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Five new drift control adjuvants were sele...

  9. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  10. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Adjuvants for pesticide chemicals. 582.99...

  11. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide chemicals. 182.99...

  12. Induction of lupus autoantibodies by adjuvants

    USGS Publications Warehouse

    Satoh, M.; Kuroda, Y.; Yoshida, H.; Behney, K.M.; Mizutani, A.; Akaogi, J.; Nacionales, D.C.; Lorenson, T.D.; Rosenbauer, R.J.; Reeves, W.H.

    2003-01-01

    Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNF?? production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies. The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines. ?? 2003 Elsevier Ltd. All rights reserved.

  13. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    SciTech Connect

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-08-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  14. Adjuvant steroids and relapse of typhoid fever.

    PubMed

    Cooles, P

    1986-10-01

    In a retrospective study, relapse after non-severe acute typhoid fever was highly significantly related to the use of adjuvant steroid in the initial illness. The steroid was given late and in small doses when compared with other studies. Caution should be observed when using steroids in this way as relapse though often mild may be a severe illness. PMID:3795323

  15. Aluminum vaccine adjuvants: are they safe?

    PubMed

    Tomljenovic, L; Shaw, C A

    2011-01-01

    Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue. PMID:21568886

  16. Is administration of trastuzumab an independent risk factor for developing osteonecrosis of the jaw among metastatic breast cancer patients under zoledronic acid treatment?

    PubMed

    Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

    2015-05-01

    One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect.Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients' ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits.Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13-82) and the mean number of ZA infusions was 38 (range: 15-56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively).The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab. PMID:25950681

  17. Is Administration of Trastuzumab an Independent Risk Factor for Developing Osteonecrosis of the Jaw Among Metastatic Breast Cancer Patients Under Zoledronic Acid Treatment?

    PubMed Central

    Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

    2015-01-01

    Abstract One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect. Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients’ ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits. Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13–82) and the mean number of ZA infusions was 38 (range: 15–56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively). The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab. PMID:25950681

  18. Vitamins as influenza vaccine adjuvant components.

    PubMed

    Quintilio, Wagner; de Freitas, Fábio Alessandro; Rodriguez, Dunia; Kubrusly, Flavia Saldanha; Yourtov, Dimitri; Miyaki, Cosue; de Cerqueira Leite, Luciana Cezar; Raw, Isaias

    2016-10-01

    A number of adjuvant formulations were assayed in mice immunized with 3.75 µg of A/California/7/2009 (H1N1) pdm09 influenza vaccine with vitamins A, D and/or E in emulsions or B2 and/or B9 combined with Bordetella pertussis MPLA and/or alum as adjuvants. Squalene was used as positive control, as well as MPLA with alum. The immune response was evaluated by a panel of tests, including a hemagglutination inhibition (HAI) test, ELISA for IgG, IgG1, and IgG2a and IFN-γ, IL-2, IL-6 and IL-10 quantification in splenocyte culture supernatant after stimulus with influenza antigen. Immunological memory was evaluated using a 1/10 dose booster 60 days after the first immunization followed by assessment of the response by HAI, IgG ELISA, and determination of the antibody affinity index. The highest increases in HAI, IgG1 and IgG2a titers were obtained with the adjuvant combinations containing vitamin E, or the hydrophilic combinations containing MPLA and alum or B2 and alum. The IgG1/IgG2a ratio indicates that the response to the combination of B2 with alum would have more Th2 character than the combination of MPLA with alum. In an assay to investigate the memory response, a significant increase in HAI titer was observed with a booster vaccine dose at 60 days after immunization with vaccines containing MPLA with alum or B2 with alum. Overall, of the 27 adjuvant combinations, MPLA with alum and B2 with alum were the most promising adjuvants to be evaluated in humans. PMID:27449155

  19. New generation adjuvants--from empiricism to rational design.

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

    Adjuvants are an essential component of modern vaccine development. Despite many decades of development, only a few types of adjuvants are currently included in vaccines approved for human use. In order to better understand the reasons that development of some adjuvants succeeded while many others failed, we discuss some of the common attributes of successful first generation adjuvants. Next, we evaluate current trends in the development of second generation adjuvants, including the potential advantages of rationally designed synthetic immune potentiators appropriately formulated. Finally, we discuss desirable attributes of next generation adjuvants. Throughout, we emphasize that the importance of formulation and analytical characterization in all aspects of vaccine adjuvant development is often underappreciated. We highlight the formulation factors that must be evaluated in order to optimize interactions between vaccine antigens, immune potentiators, and particulate formulations, and the resulting effects on safety, biological activity, manufacturability, and stability. PMID:26022561

  20. Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27.

    PubMed

    Chapman, Judith-Anne W; Shepherd, Lois E; Ingle, James N; Muss, Hyman B; Pritchard, Kathleen I; Gelmon, Karen A; Whelan, Timothy J; Elliott, Catherine; Goss, Paul E

    2016-04-01

    Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death. PMID:27006189

  1. Differential Response of Immunohistochemically Defined Breast Cancer Subtypes to Anthracycline-Based Adjuvant Chemotherapy with or without Paclitaxel

    PubMed Central

    Fountzilas, George; Dafni, Urania; Bobos, Mattheos; Batistatou, Anna; Kotoula, Vassiliki; Trihia, Helen; Malamou-Mitsi, Vassiliki; Miliaras, Spyros; Chrisafi, Sofia; Papadopoulos, Savvas; Sotiropoulou, Maria; Filippidis, Theodoros; Gogas, Helen; Koletsa, Triantafyllia; Bafaloukos, Dimitrios; Televantou, Despina; Kalogeras, Konstantine T.; Pectasides, Dimitrios; Skarlos, Dimosthenis V.; Koutras, Angelos; Dimopoulos, Meletios A.

    2012-01-01

    -enriched tumors. Conclusions Triple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment. PMID:22679488

  2. The adjuvancy of silicones: dependency on compartmentalization.

    PubMed

    Klykken, P C; White, K L

    1996-01-01

    Studies have been conducted in mice (B6C3F1) and rats (Sprague Dawley, Fischer 344) to investigate the adjuvancy potential of silicone mammary gel and the low molecular weight silicone fluid, octamethylcyclotetrasiloxane (D4). Dependent on the experimental conditions employed, a divergent data profile emerges. If the antigen (bovine serum albumin, BSA) is emulsified with either the gel or the D4 prior to intramuscular immunization, an amplified anti-BSA IgG antibody response, as measured by multipoint ELISA methodology, is noted over the 8 week measurement period. In parallel studies, a variety of non-silicone personal care ingredients (lanolin, white mineral oil, isopropyl palmitate) were also capable of amplifying this humoral response relative to the non-adjuvant phosphate buffered saline control. These observations are consistent with the empirical knowledge that hydrophobic substances tend to augment immune responses. However, under conditions in which the antigen is not blended with the silicone prior to immunization, normal immune responses are noted. In short (10 day) and long (180 day) term gel implant studies, the optimal IgM and IgG antibody responses, as determined in the antibody forming cell assay, were equivalent between the gel implanted and control animals. Moreover, under similar exposure conditions, no adjuvancy was noted in the three Host Resistance models (B16F10 Melanoma, Listeria monocytogenes, and Streptococcus pneumoniae) tested. Antibody forming cell studies conducted after 28 days of oral or inhalation exposure to D4 have also yielded responses similar to the non-silicone exposed vehicle controls. Collectively, these data suggest that in the absence of premixing the antigen with the silicone test material, there does not appear to be any silicone induced adjuvant response. PMID:8565549

  3. Psychosocial and Physical Effects of Adjuvant Chemotherapy

    PubMed Central

    Hislop, Thomas Gregory; Elwood, J. Mark; Waxler-Morrison, Nancy; Ragaz, Joseph; Skippen, Diane Hazel; Turner, I.D.

    1991-01-01

    Breast cancer patients younger than 55 completed a questionnaire on psychosocial factors and physical side effects shortly after diagnosis and 9 to 15 months after diagnosis. Those who had used adjuvant chemotherapy were more likely than those who had not to report physical side effects; there was little difference in psychosocial factors. Recent users were more likely than ex-users to report physical side effects, difficulties with domestic chores, and improvement in psychosocial factors. PMID:21229020

  4. Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Show a Largely Reduced Affinity for the Target Antigen.

    PubMed

    Selis, Fabio; Focà, Giuseppina; Sandomenico, Annamaria; Marra, Carla; Di Mauro, Concetta; Saccani Jotti, Gloria; Scaramuzza, Silvia; Politano, Annalisa; Sanna, Riccardo; Ruvo, Menotti; Tonon, Giancarlo

    2016-01-01

    PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and stability toward proteases, however their size lowers to some extent their potential because of a reduced ability to penetrate tissues, especially those of tumor origin. Fab or otherwise engineered smaller fragments are an alternative but are less stable and are much less well retained in circulation. We have here investigated the effects of various PEGylations on the binding properties and in vivo half-life of Fab fragments derived from the enzymatic splitting of Trastuzumab. We find that PEGylation increases the half-life of the molecules but also strongly affects the ability to recognize the target antigen in a way that is dependent on the extent and position of the chemical modification. Data thus support the concept that polyethylene glycol (PEG) conjugation on Trastuzumab Fabs increases half-life but reduces their affinity and this is a fine balance, which must be carefully considered for the design of strategies based on the use of antibody fragments. PMID:27043557

  5. Trastuzumab and target-therapy side effects: Is still valid to differentiate anthracycline Type I from Type II cardiomyopathies?

    PubMed Central

    Riccio, Gennaro; Coppola, Carmela; Piscopo, Giovanna; Capasso, Immacolata; Maurea, Carlo; Esposito, Emanuela; De Lorenzo, Claudia; Maurea, Nicola

    2016-01-01

    ABSTRACT The improvement in cancer therapy and the increasing number of long term survivors unearth the issue of cardiovascular side effects of anticancer treatments. As a paradox in cancer survivors, delayed cardiotoxicity has emerged as a significant problem. Two categories of cardiotoxic side effects of antineoplastic drugs have been previously proposed: Type I cardiotoxicity, defined as permanent cardiotoxicity, is usually caused by anthracyclines; Type II cardiotoxicity, considered as reversible cardiotoxicity, has been mainly related to monoclonal antibodies. The cardiotoxicity of antibodies has been associated to trastuzumab, a humanized anti-ErbB2 monoclonal antibody currently in clinical use for the therapy of breast carcinomas, which induces cardiac dysfunction when used in monotherapy, or in combination with anthracyclines. Furthermore, recent retrospective studies have shown an increased incidence of heart failure and/or cardiomyopathy in patients treated with trastuzumab, that can persist many years after the conclusion of the therapy, thus suggesting that the side toxic effects are not always reversible as it was initially proposed. On the other hand, early detection and prompt therapy of anthracycline associated cardiotoxicity can lead to substantial recovery of cardiac function. On the basis of these observations, we propose to find a new different classification for cardiotoxic side effects of drugs used in cancer therapy. PMID:26836985

  6. Study of the Interaction of Trastuzumab and SKOV3 Epithelial Cancer Cells Using a Quartz Crystal Microbalance Sensor

    PubMed Central

    Elmlund, Louise; Käck, Camilla; Aastrup, Teodor; Nicholls, Ian A.

    2015-01-01

    Analytical methods founded upon whole cell-based assays are of importance in early stage drug development and in fundamental studies of biomolecular recognition. Here we have studied the binding of the monoclonal antibody trastuzumab to human epidermal growth factor receptor 2 (HER2) on human ovary adenocarcinoma epithelial cancer cells (SKOV3) using quartz crystal microbalance (QCM) technology. An optimized procedure for immobilizing the cells on the chip surface was established with respect to fixation procedure and seeding density. Trastuzumab binding to the cell decorated sensor surface was studied, revealing a mean dissociation constant, KD, value of 7 ± 1 nM (standard error of the mean). This study provides a new perspective on the affinity of the antibody-receptor complex presented a more natural context compared to purified receptors. These results demonstrate the potential for using whole cell-based QCM assay in drug development, the screening of HER2 selective antibody-based drug candidates, and for the study of biomolecular recognition. This real time, label free approach for studying interactions with target receptors present in their natural environment afforded sensitive and detailed kinetic information about the binding of the analyte to the target. PMID:25763651

  7. Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Show a Largely Reduced Affinity for the Target Antigen

    PubMed Central

    Selis, Fabio; Focà, Giuseppina; Sandomenico, Annamaria; Marra, Carla; Di Mauro, Concetta; Saccani Jotti, Gloria; Scaramuzza, Silvia; Politano, Annalisa; Sanna, Riccardo; Ruvo, Menotti; Tonon, Giancarlo

    2016-01-01

    PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and stability toward proteases, however their size lowers to some extent their potential because of a reduced ability to penetrate tissues, especially those of tumor origin. Fab or otherwise engineered smaller fragments are an alternative but are less stable and are much less well retained in circulation. We have here investigated the effects of various PEGylations on the binding properties and in vivo half-life of Fab fragments derived from the enzymatic splitting of Trastuzumab. We find that PEGylation increases the half-life of the molecules but also strongly affects the ability to recognize the target antigen in a way that is dependent on the extent and position of the chemical modification. Data thus support the concept that polyethylene glycol (PEG) conjugation on Trastuzumab Fabs increases half-life but reduces their affinity and this is a fine balance, which must be carefully considered for the design of strategies based on the use of antibody fragments. PMID:27043557

  8. A phase I dose-escalation study of a biosimilar trastuzumab in Chinese metastasis breast cancer patients.

    PubMed

    Zhou, Xinna; Yu, Jing; Wang, Wenmiao; Song, Guohong; Wang, Xiaoli; Ren, Jun; Di, Lijun; Wang, Xinghe

    2015-01-01

    Trastuzumab has been widely used among the breast cancer patients with human epidermal growth factor receptor 2 (HER2) overexpression. The genetically engineered trastuzumab traded as Cipterbin® was developed in China since 2003. We have disclosed the phase I clinical trial data of safety, pharmacokinetic profile (PK) in patients with metastasis breast cancer. Subjects identified as HER2 strong positive received single intravenously doses of 100, 250 or 500 mg Cipterbin® in dose-escalation manner. The safety evaluations were recorded and plasma concentration profiles for the drug were analyzed. 27 Chinese metastatic breast cancer patients were enrolled in this study. Patients in each group of different dosage were well-tolerated. The most frequently drug-related adverse events were fever (59.3 %), transaminase increased (22.2 %), chills (18.5 %) and arrhythmia (18.5 %). Only one patient with severe adverse event was observed in 250 mg group revealing brachycardia. PK profile analysis showed that sera steady concentration could be reached in dose-proportional manner, except volume of distribution (Vd) and clearance (CL), which reached peak values at 250 mg administration cohort. This genetically engineered HER2-target antibody had demonstrated the accepted safety with well-tolerated. PMID:26702392

  9. Melanoma and IFN alpha: potential adjuvant therapy.

    PubMed

    Bottoni, U; Clerico, R; Paolino, G; Corsetti, P; Ambrifi, M; Brachini, A; Richetta, A; Nisticò, S; Pranteda, G; Calvieri, S

    2014-01-01

    Interferon alpha (IFNalpha) is the most used adjuvant treatment in clinical practice for melanoma (MEL) high-medium risk patients; however, the use of IFNalpha has yielded conflicting data on Overall Survival (OS) and disease free survival (DFS) rates. Starting from these considerations, we carried out an analysis on our MEL patients who received adjuvant IFNalpha therapy, in order to identify possible predictors for their outcome. A total of 140 patients were included in our analysis. Patients with Breslow thickness ≤2.00 mm presented a significantly longer mean DFS than patients with Breslow ≥2.01 mm (p = 0.01). Using non- parametric Spearman’s Coefficient test we found association between DFS and Breslow thickness (p < 0.001) and between DFS and ulceration (p = 0.03). Performing Multiple Regression test, Breslow thickness (p < 0.001) remained the only statistically significant predictor. From the OS analysis we found that patients with lower Breslow values ≤ 2.00 mm (p < 0.0001), and absence of ulceration (p <0.004) showed a significantly better long-term survival. From the current analysis we found that the use of low dose IFNalpha is justified only for cutaneous melanoma ≤ 4.01 mm that was not ulcerated; patients with Breslow ≥ 4.01 mm, in our opinion, should not carry out adjuvant treatment with low dose IFNalpha, because its side effects could be higher than the its benefits. PMID:25001659

  10. Utility of adjuvant systemic therapy in melanoma

    PubMed Central

    Eggermont, A. M. M.; Testori, A.; Marsden, J.; Hersey, P.; Quirt, I.; Petrella, T.; Gogas, H.; MacKie, R. M.; Hauschild, A.

    2009-01-01

    The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing. PMID:19617295

  11. Adjuvant and neoadjuvant treatment in pancreatic cancer

    PubMed Central

    Herreros-Villanueva, Marta; Hijona, Elizabeth; Cosme, Angel; Bujanda, Luis

    2012-01-01

    Pancreatic adenocarcinoma is one of the most aggressive human malignancies, ranking 4th among causes for cancer-related death in the Western world including the United States. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy. Currently there is no consensus around the world on what constitutes “standard” adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat with regard to geography and economy, for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe. Regardless of the efforts in adjuvant and neoadjuvant improved therapy, the major goal to combat pancreatic cancer is to find diagnostic markers, identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients. In this review, authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients. PMID:22529684

  12. Efficacy of live adjuvanted mesogenic Newcastle disease vaccine in chickens.

    PubMed

    Roy, P; Venugopalan, A T; Koteeswaran, A

    1999-06-01

    120 white leghorn chickens primed with a lentogenic Newcastle disease (ND) live vaccine at 7 days of age were divided into three equal groups of 8 weeks of age and vaccinated with a live mesogenic ND vaccine (NDV). One group received only Newcastle disease mesogenic vaccine (RDVK) in normal saline, the second group received RDVK with groundnut oil as adjuvant and the third group received RDVK with liquid paraffin as adjuvant. Sera were collected at different time points for the assessment of antibody level against ND virus (NDV) by the haemagglutination inhibition (HI) test. The commonly used non-adjuvanted RDVK could not evince 100% protective HI titre beyond 11 weeks of age but in both the adjuvanted groups 100% protective HI titre was evident up to 20 weeks of age. On challenge at 20 weeks of age both the adjuvanted groups withstood challenge but in the non-adjuvanted group 80% of chickens withstood the challenge. A significant difference in immune response between the adjuvanted and non-adjuvanted groups was seen but not between both the adjuvanted groups. The advantage of vegetable oil (groundnut oil) as an adjuvant for live mesogenic ND vaccine has been discussed. PMID:10418918

  13. Recent Advances of Vaccine Adjuvants for Infectious Diseases

    PubMed Central

    Nguyen, Minh Trang

    2015-01-01

    Vaccines are the most effective and cost-efficient method for preventing diseases caused by infectious pathogens. Despite the great success of vaccines, development of safe and strong vaccines is still required for emerging new pathogens, re-emerging old pathogens, and in order to improve the inadequate protection conferred by existing vaccines. One of the most important strategies for the development of effective new vaccines is the selection and usage of a suitable adjuvant. Immunologic adjuvants are essential for enhancing vaccine potency by improvement of the humoral and/or cell-mediated immune response to vaccine antigens. Thus, formulation of vaccines with appropriate adjuvants is an attractive approach towards eliciting protective and long-lasting immunity in humans. However, only a limited number of adjuvants is licensed for human vaccines due to concerns about safety and toxicity. We summarize current knowledge about the potential benefits of adjuvants, the characteristics of adjuvants and the mechanisms of adjuvants in human vaccines. Adjuvants have diverse modes of action and should be selected for use on the basis of the type of immune response that is desired for a particular vaccine. Better understanding of current adjuvants will help exploring new adjuvant formulations and facilitate rational design of vaccines against infectious diseases. PMID:25922593

  14. Prognostic relevance of HER2/neu in acute lymphoblastic leukemia and induction of NK cell reactivity against primary ALL blasts by trastuzumab.

    PubMed

    Haen, Sebastian P; Schmiedel, Benjamin J; Rothfelder, Kathrin; Schmied, Bastian J; Dang, Truong-Minh; Mirza, Nora; Möhle, Robert; Kanz, Lothar; Vogel, Wichard; Salih, Helmut R

    2016-03-15

    The epidermal growth factor receptor HER2/neu is expressed on various cancers and represents a negative prognostic marker, but is also a target for the therapeutic monoclonal antibody Trastuzumab. In about 30% of cases, HER2/neu is expressed on acute lymphoblastic leukemia (ALL) cells and was proposed to be associated with a deleterious prognosis. Here we evaluated clinical data from 65 ALL patients (HER2/neu+, n = 17; HER2/neu-, n = 48) with a median follow-up of 19.4 months (range 0.6-176.5 months) and observed no association of HER2/neu expression with response to chemotherapy, disease free or overall survival. In vitro, treatment of primary ALL cells (CD20+HER2/neu+, CD20+HER2/neu- and CD20-HER2/neu-) with Rituximab and Trastuzumab led to activation of NK cells in strict dependence of the expression of the respective antigen. NK reactivity was more pronounced with Rituximab as compared to Trastuzumab, and combined application could lead to additive effects in cases where both antigens were expressed. Besides providing evidence that HER2/neu expression is no risk factor in ALL patients, our data demonstrates that HER2/neu can be a promising target for Trastuzumab therapy in the subset of ALL patients with the potential to improve disease outcome. PMID:26887048

  15. Ki-67 index as a prognostic factor of subsequent lapatinib-based therapy in HER2-positive metastatic breast cancer with resistance to trastuzumab

    PubMed Central

    Bian, Li; Wang, Tao; Zhang, Shao-hua; Zhang, Hui-qiang; Guo, Yun-fei; Du, Ge; Li, Wang; Wu, Shi-kai; Song, San-tai; Jiang, Ze-fei

    2014-01-01

    Prognostic factor analysis has been conducted to determine whether the parameters of clinical data and biomarkers would predict differential progression-free survival (PFS) or overall survival (OS) from lapatinib-based therapy in patients with primary or acquired resistance to trastuzumab. Treatment with lapatinib plus capecitabine for HER2-positive metastatic breast cancer (MBC) with primary or acquired resistance to trastuzumab was analyzed retrospectively. Tumor biomarkers, which came from the biopsies before the starting of lapatinib therapy, were evaluated by immunohistochemistry (IHC). Prognostic factors related to PFS or OS of the lapatinib therapy were assessed by univariate and multivariate analysis. Ki-67 index and liver metastases were the significant prognostic factors for predicting PFS of subsequent lapatinib therapy in the univariate analysis and the multivariate analysis. The risk for disease progression in patients who had a Ki-67 index < 40% was 59% less than that in patients had Ki-67 ≥ 40 (HR = 0.41, 95% CI, 0.23–0.74, P = 0.003). TTP of prior trastuzumab therapy, liver metastases, and the number of metastatic sites were three independent prognostic factors of subsequent lapatinib therapy. Ki-67 index was the significant prognostic factors for predicting PFS of the subsequent second line targeted therapy in patients with trastuzumab resistance. PMID:24424115

  16. Ultrasound Targeted Apoptosis Imaging in Monitoring Early Tumor Response of Trastuzumab in a Murine Tumor Xenograft Model of Her-2–Positive Breast Cancer11

    PubMed Central

    Wei, Xi; Li, Ying; Zhang, Sheng; Gao, Xiujun; Luo, Yi; Gao, Ming

    2014-01-01

    OBJECTIVE: Our study aimed to monitor the trastuzumab therapy response of murine tumor xenograft model with human epidermal growth factor receptor 2 (Her-2)–positive breast cancer using ultrasound targeted apoptosis imaging. METHODS: We prepared targeted apoptosis ultrasound probes by nanobubble (NB) binding with Annexin V. In vitro, we investigated the binding rate of NB–Annexin V with breast cancer apoptotic cells after the trastuzumab treatment. In vivo, tumor-bearing mice underwent ultrasound targeted imaging over 7 days. After imaging was completed, the tumors were excised to determine Her-2 and caspase-3 expression by immunohistochemistry (IHC). The correlation between parameters of imaging and histologic results was then analyzed. RESULTS: For seeking the ability of targeted NB binding with apoptotic tumor cells (Her-2 positive), we found that binding rate in the treatment group was higher than that of the control group in vitro (P = .001). There were no differences of tumor sizes in all groups over the treatment process in vivo (P = .98). However, when using ultrasound imaging to visualize tumors by targeted NB in vivo, we observed that the mean and peak intensities from NBs gradually increased in the treatment group after trastuzumab therapy (P = .001). Furthermore, these two parameters were significantly associated with caspase-3 expression of tumor excised samples (P = .0001). CONCLUSION: Ultrasound targeted apoptosis imaging can be a non-invasive technique to evaluate the early breast tumor response to trastuzumab therapy. PMID:24685547

  17. Predictive Factors of Lapatinib and Capecitabine Activity in Patients with HER2-Positive, Trastuzumab-Resistant Metastatic Breast Cancer: Results from the Italian Retrospective Multicenter HERLAPAC Study

    PubMed Central

    Gori, Stefania; Inno, Alessandro; Rossi, Valentina; Turazza, Monica; Fiorio, Elena; Fabi, Alessandra; Bisagni, Giancarlo; Foglietta, Jennifer; Santini, Daniele; Pavese, Ida; Pellegrino, Arianna; Zambelli, Alberto; Vici, Patrizia; Leonardi, Vita; Barni, Sandro; Saracchini, Silvana; Bogina, Giuseppe; Marchetti, Fabiana; Duranti, Simona; Lunardi, Gianluigi; Montemurro, Filippo

    2016-01-01

    Background There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. Methods Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. Results At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p<0.001). Multivariate analysis revealed the benefit of lapatinib-based therapy in terms of PFS and OS was significantly associated with time-to-progression (TTP) on prior first-line trastuzumab-based therapy. In particular, each additional month on first-line trastuzumab based therapy was associated with a reduction in hazard of progression and death after the initiation of lapatinib-based therapy of 2% and 4%, respectively. Conclusions A longer TTP to first line trastuzumab seems to predict a prolonged PFS and OS with subsequent lapatinib and capecitabine. PMID:27224517

  18. A multicentre Phase II study of non-pegylated liposomal doxorubicin in combination with trastuzumab and docetaxel as first-line therapy in metastatic breast cancer.

    PubMed

    Venturini, M; Bighin, C; Puglisi, F; Olmeo, N; Aitini, E; Colucci, G; Garrone, O; Paccagnella, A; Marini, G; Crinò, L; Mansutti, M; Baconnet, B; Barbato, A; Del Mastro, L

    2010-10-01

    To evaluate the cardiotoxicity, general toxicity, and activity of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first-line therapy in metastatic breast cancer. Thirty-one patients with metastatic human epidermal growth factor receptor 2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50 mg/m(2)), docetaxel (75 mg/m(2)) and trastuzumab (2 mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) to below 45%, or a decrease in LVEF of at least 20% from baseline. Mean LVEF was maintained at baseline level also in the subset of patients who had received anthracycline previously. Cardiotoxicity developed in three patients during the treatment cycles, and in two further patients after the end of the study. The most common adverse events were haematological toxicity, alopecia, asthenia and fever. The best overall response rate was 65.5%. Median time to progression was 13.0 months. The combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab combines acceptable cardiac and general toxicity and promising activity as first-line therapy in metastatic breast cancer. PMID:20185313

  19. Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET.

    PubMed

    Mume, Eskender; Orlova, Anna; Malmström, Per-Uno; Lundqvist, Hans; Sjöberg, Stefan; Tolmachev, Vladimir

    2005-08-01

    Combining the specificity of radioimmunoscintigraphy and the high sensitivity of PET in an in vivo detection technique could improve the quality of nuclear diagnostics. Positron-emitting nuclide (76)Br (T(1/2)=16.2 h) might be a possible candidate for labeling monoclonal antibodies (mAbs) and their fragments, provided that the appropriate labeling chemistry has been established. For internalizing antibodies, such as the humanized anti-HER2 monoclonal antibody, trastuzumab, radiobromine label should be residualizing, i.e., ensuring that radiocatabolites are trapped intracellularly after the proteolytic degradation of antibody. This study evaluated the chemistry of indirect radiobromination of trastuzumab using N-succinimidyl 5-(tributylstannyl)-3-pyridinecarboxylate. Literature data indicated that the use of this method provided residualizing properties for iodine and astatine labels on some antibodies. An optimized "one-pot" procedure produced an overall labeling efficiency of 45.5+/-1.2% over 15 min. The bromine label was stable under physiological and denaturing conditions. The labeled trastuzumab retained its capacity to bind specifically to HER2-expressing SKOV-3 ovarian carcinoma cells in vitro (immunoreactivity more than 75%). However, in vitro cell test did not demonstrate that the radiobromination of trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate improves cellular retention of radioactivity in comparison with the use of N-succinimidyl 4-bromobenzoate. PMID:16026708

  20. Prognostic relevance of HER2/neu in acute lymphoblastic leukemia and induction of NK cell reactivity against primary ALL blasts by trastuzumab

    PubMed Central

    Schmied, Bastian J.; Dang, Truong-Minh; Mirza, Nora; Möhle, Robert; Kanz, Lothar; Vogel, Wichard; Salih, Helmut R.

    2016-01-01

    The epidermal growth factor receptor HER2/neu is expressed on various cancers and represents a negative prognostic marker, but is also a target for the therapeutic monoclonal antibody Trastuzumab. In about 30% of cases, HER2/neu is expressed on acute lymphoblastic leukemia (ALL) cells and was proposed to be associated with a deleterious prognosis. Here we evaluated clinical data from 65 ALL patients (HER2/neu+, n = 17; HER2/neu−, n = 48) with a median follow-up of 19.4 months (range 0.6-176.5 months) and observed no association of HER2/neu expression with response to chemotherapy, disease free or overall survival. In vitro, treatment of primary ALL cells (CD20+HER2/neu+, CD20+HER2/neu− and CD20−HER2/neu−) with Rituximab and Trastuzumab led to activation of NK cells in strict dependence of the expression of the respective antigen. NK reactivity was more pronounced with Rituximab as compared to Trastuzumab, and combined application could lead to additive effects in cases where both antigens were expressed. Besides providing evidence that HER2/neu expression is no risk factor in ALL patients, our data demonstrates that HER2/neu can be a promising target for Trastuzumab therapy in the subset of ALL patients with the potential to improve disease outcome. PMID:26887048

  1. Adjuvant chemotherapy for early-stage cervical cancer

    PubMed Central

    Asano, Hiroshi; Todo, Yukiharu; Watari, Hidemichi

    2016-01-01

    The aim of this review is to address the current status of adjuvant chemotherapy alone in early-stage cervical cancer treatments in the literature. At present, the therapeutic effect of adjuvant chemotherapy alone after radical surgery (RS) has not yet been established, and radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) is recommended as the standard adjuvant therapy after RS for early-stage cervical cancer in various guidelines. The main purpose of adjuvant therapy after RS, however, should be to reduce extrapelvic recurrence rather than local recurrence, although adjuvant RT or CCRT has survival benefits for patients with intermediate- or high-risk factors for recurrence. Moreover, several studies reported that adjuvant therapies including RT were associated with a higher incidence of complications, such as lymphedema, bowel obstruction and urinary disturbance, and a lower grade of long-term quality of life (QOL) or sexual functioning than adjuvant chemotherapy alone. The effect of adjuvant chemotherapy alone for early-stage cervical cancer with intermediate- or high-risk factors for recurrence were not fully investigated in prospective studies, but several retrospective studies suggest that the adjuvant effects of chemotherapy alone are at least similar to that of RT or CCRT in terms of recurrence rate, disease-free survival, or overall survival (OS) with lower incidence of complications. Whereas cisplatin based combination regimens were used in these studies, paclitaxel/cisplatin (TP) regimen, which is currently recognized as a standard chemotherapy regimen for patients with metastatic, recurrent or persistent cervical cancer by Gynecologic Oncology Group (GOG), had also survival benefit as an adjuvant therapy. Therefore, it may be worth considering a prospective randomized controlled trial (RCT) of adjuvant chemotherapy alone using TP regimen versus adjuvant RT as an alternative adjuvant therapy. Because early-stage cervical cancer is a curable

  2. The efficiency and safety of trastuzumab and lapatinib added to neoadjuvant chemotherapy in Her2-positive breast cancer patients: a randomized meta-analysis

    PubMed Central

    Chen, Zhe-Ling; Shen, Yan-Wei; Li, Shu-Ting; Li, Chun-Li; Zhang, Ling-Xiao; Yang, Jiao; Lv, Meng; Lin, Ya-Yun; Wang, Xin; Yang, Jin

    2016-01-01

    Background The addition of human epidermal growth factor receptor 2 (Her2) therapies to neoadjuvant chemotherapy (NAC) during treatment of Her2-positive breast cancer has been proposed as an effective way to improve the prognosis. However, the treatment outcomes of adding trastuzumab, lapatinib, or both to NAC were not unequivocal in randomized clinical trials. Based on these data, a meta-analysis was performed. Objective The main objective was to evaluate the efficiency and safety of trastuzumab and lapatinib added to NAC for treatment of Her2-positive breast cancer. Methods ClinicalTrials.gov and PubMed were searched for randomized clinical trials that compared trastuzumab, lapatinib, or both, added to NAC. The main endpoint was a pathologically complete response (pCR) rate, in breast only or in breast and lymph nodes. The drug safety and the influence of hormone-receptor status, comparing the clinical response and the rate of breast conservation, were evaluated. Results A total of eight publications were included in the primary analysis, designed as two or three subgroups. The cumulative cases were 2,349 and the analyses of all the clinical trials showed that the pCR rate was significantly higher in the group receiving trastuzumab than that in the group with lapatinib, either in breast only (P=0.001) or in breast and lymph nodes (P=0.0001). Similar results could be seen in comparisons of the combination versus trastuzumab group. Further studies of subgroups divided into hormone receptor-positive or-negative patients showed that the addition of trastuzumab or dual Her2-targeted therapy significantly improved the pCR rate in patients who were hormone-insensitive. Regarding the toxic effects, we found more grade 3 and 4 toxic effects, such as diarrhea, skin disorder, and hepatic biochemical changes in the lapatinib and combination groups. No temporally significant differences were found when the clinical response and the rate of breast conservation in the groups

  3. Evaluation of the anti-HER2 C6.5 diabody as a PET radiotracer to monitor HER2 status and predict response to trastuzumab treatment

    PubMed Central

    Reddy, Smitha; Shaller, Calvin C.; Doss, Mohan; Shchaveleva, Irina; Marks, James D.; Yu, Jian Q.; Robinson, Matthew K.

    2011-01-01

    Purpose The rapid tumor targeting and pharmacokinetic properties of engineered antibodies make them potentially suitable for use in imaging strategies to predict and monitor response to targeted therapies. This study aims to evaluate C6.5 diabody (C6.5db), a non-covalent anti-HER2 single chain-Fv dimer, as a radiotracer for predicting response to HER2-targeted therapies such as trastuzumab. Experimental Design Immunodeficient mice bearing established HER2-positive tumor xenografts were injected with radioiodinated C6.5db and imaged using PET/CT. Radiotracer biodistribution was quantified using biopsied tumor and normal tissues. Potential competition between trastuzumab and C6.5db was examined in vitro by flow cytometry and co-immunoprecipitations. Results Biodistribution analysis of mice bearing xenografts with varying HER2 density revealed that the tumor uptake of 125I-C6.5db correlates with HER2 tumor density. In vitro competition experiments suggest that the C6.5db targets an epitope on HER2 that is distinct from that bound by trastuzumab. Treatment of SK-OV-3-tumored mice with trastuzumab for 3 d caused a 42% (P=0.002) decrease in tumor uptake of 125I-C6.5db. This is consistent with a dramatic decrease in the tumor PET signal of 124I-C6.5db after trastuzumab treatment. Furthermore, BT-474-tumored mice showed a ∼60% decrease (P=0.0026) in C6.5db uptake after 6 d of trastuzumab treatment. Immunohistochemistry of excised xenograft sections and in vitro flow cytometry revealed that the decreased C6.5db uptake upon trastuzumab treatment is not associated with HER2 downregulation. Conclusions These studies suggest that 124I-C6.5db-based imaging can be used to evaluate HER2 levels as a predictor of respone to HER2-directed therapies. PMID:21177408

  4. The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells.

    PubMed

    Lyu, Hui; Yang, Xiao He; Edgerton, Susan M; Thor, Ann D; Wu, Xiaoying; He, Zhimin; Liu, Bolin

    2016-01-19

    Both erbB3 and IGF-1 receptor (IGF-1R) have been shown to play an important role in trastuzumab resistance. However, it remains unclear whether erbB3- and IGF-1R-initiated signaling pathways possess distinct effects on the sensitivity of lapatinib, a dual tyrosine kinase inhibitor against both EGFR and erbB2, in trastuzumab-resistant breast cancer. Here, we show that the trastuzumab-resistant SKBR3-pool2 and BT474-HR20 breast cancer sublines, as compared the parental SKBR3 and BT474 cells, respectively, exhibit refractoriness to lapatinib. Knockdown of erbB3 inhibited Akt in SKBR3-pool2 and BT474-HR20 cells, significantly increased lapatinib efficacy, and dramatically re-sensitized the cells to lapatinib-induced apoptosis. In contrast, specific knockdown of IGF-1R did not alter the cells' responsiveness to lapatinib. While the levels of phosphorylated Src (P-Src) were reduced upon IGF-1R downregulation, the P-Akt levels remained unchanged. Furthermore, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on SKBR3-pool2 and BT474-HR20 cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy. PMID:26621843

  5. Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting {sup 227}Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

    SciTech Connect

    Heyerdahl, Helen; Røe, Kathrine; Brevik, Ellen Mengshoel; Dahle, Jostein

    2013-09-01

    Purpose: The purpose of this study was to investigate the effect of α-particle-emitting {sup 227}Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of {sup 227}Th-trastuzumab. Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm{sup 3} (mean ± SEM) were treated with a single injection of either {sup 227}Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of {sup 227}Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Results: Significant increases of k{sub ep}, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and k{sub el,} the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of k{sub ep} and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after {sup 227}Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts.

  6. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

    PubMed Central

    Ray, Geoffrey L.; Baidoo, Kwamena E.; Keller, Lanea M. M.; Albert, Paul S.; Brechbiel, Martin W.; Milenic, Diane E.

    2011-01-01

    Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β−-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administeringescalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease. PMID:22229017

  7. Working together: interactions between vaccine antigens and adjuvants

    PubMed Central

    Kramer, Ryan M.; Barnes V, Lucien; Dowling, Quinton M.; Vedvick, Thomas S.

    2013-01-01

    The development of vaccines containing adjuvants has the potential to enhance antibody and cellular immune responses, broaden protective immunity against heterogeneous pathogen strains, enable antigen dose sparing, and facilitate efficacy in immunocompromised populations. Nevertheless, the structural interplay between antigen and adjuvant components is often not taken into account in the published literature. Interactions between antigen and adjuvant formulations should be well characterized to enable optimum vaccine stability and efficacy. This review focuses on the importance of characterizing antigen–adjuvant interactions by summarizing findings involving widely used adjuvant formulation platforms, such as aluminum salts, emulsions, lipid vesicles, and polymer-based particles. Emphasis is placed on the physicochemical basis of antigen–adjuvant associations and the appropriate analytical tools for their characterization, as well as discussing the effects of these interactions on vaccine potency. PMID:24757512

  8. Adjuvant chemotherapy for rectal cancer: Is it needed?

    PubMed Central

    Milinis, Kristijonas; Thornton, Michael; Montazeri, Amir; Rooney, Paul S

    2015-01-01

    Adjuvant chemotherapy has become a standard treatment of advanced rectal cancer in the West. The benefits of adjuvant chemotherapy after surgery alone have been well established. However, controversy surrounds the use adjuvant chemotherapy in patients who received preoperative chemoradiotherapy, despite it being recommended by a number of international guidelines. Results of recent multicentre randomised control trials showed no benefit of adjuvant chemotherapy in terms of survival and rates of distant metastases. However, concerns exist regarding the quality of the studies including inadequate staging modalities, out-dated chemotherapeutic regimens and surgical approaches and small sample sizes. It has become evident that not all the patients respond to adjuvant chemotherapy and more personalised approach should be employed when considering the benefits of adjuvant chemotherapy. The present review discusses the strengths and weaknesses of the current evidence-base and suggests improvements for future studies. PMID:26677436

  9. Trastuzumab Emtansine for Treating HER2-Positive, Unresectable, Locally Advanced or Metastatic Breast Cancer After Treatment with Trastuzumab and a Taxane: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

    PubMed

    Squires, Hazel; Stevenson, Matt; Simpson, Emma; Harvey, Rebecca; Stevens, John

    2016-07-01

    The National Institute for Health and Care Excellence (NICE) invited the manufacturer of trastuzumab emtansine (T-DM1) (Kadcyla(®); Roche) to submit evidence of its clinical and cost-effectiveness for treating human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield were the independent Evidence Review Group (ERG) who produced a critical review of the company's submission to NICE. The ERG also independently searched for relevant evidence and modified the submitted decision analytic model to produce a revised estimate of cost-effectiveness and examine the impact of altering some of the key assumptions. The clinical effectiveness data were taken from two randomised controlled trials that reported a significant advantage in progression-free survival (PFS) for T-DM1 over lapatinib in combination with capecitabine (EMILIA trial), and over the treatment of physician's choice (TH3RESA trial). A network meta-analysis suggested T-DM1 was the best treatment in terms of both overall survival and PFS compared with lapatinib in combination with capecitabine; trastuzumab in combination with capecitabine; and capecitabine monotherapy. Adverse event (AE) data were taken from a pooled analysis of additional trials of T-DM1 as a single agent. The most common grade 3 or greater AEs for T-DM1 were thrombocytopenia and hepatotoxicity. Following the clarification process, the manufacturer reported a deterministic incremental cost-effectiveness ratio (ICER) for T-DM1 compared with lapatinib in combination with capecitabine of £167,236, the latter of which was estimated to have an ICER of £49,798 compared with capecitabine monotherapy. The ERG produced similar values of £166,429 and £50,620 respectively. All other comparators were dominated. During the appraisal, the

  10. Rational design of small molecules as vaccine adjuvants.

    PubMed

    Wu, Tom Y-H; Singh, Manmohan; Miller, Andrew T; De Gregorio, Ennio; Doro, Francesco; D'Oro, Ugo; Skibinski, David A G; Mbow, M Lamine; Bufali, Simone; Herman, Ann E; Cortez, Alex; Li, Yongkai; Nayak, Bishnu P; Tritto, Elaine; Filippi, Christophe M; Otten, Gillis R; Brito, Luis A; Monaci, Elisabetta; Li, Chun; Aprea, Susanna; Valentini, Sara; Calabrό, Samuele; Laera, Donatello; Brunelli, Brunella; Caproni, Elena; Malyala, Padma; Panchal, Rekha G; Warren, Travis K; Bavari, Sina; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M

    2014-11-19

    Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants. PMID:25411473

  11. [Recent advance in adjuvant therapy for breast cancer].

    PubMed

    Shimizu, Chikako; Watanabe, Toru

    2002-12-01

    Adjuvant systemic therapy has contributed to a significant improvement of disease-free and overall survival in addition to surgery and irradiation to the local disease. The adjuvant therapy to a patient is determined integrating the information on estimated risk of recurrence, benefit and harm of the therapy and the patient's value. In this review, the state of the art of adjuvant therapy is discussed from several aspects, such as interpretation and evaluation of risk, the best available evidences on adjuvant systemic therapy, the future direction of primary therapy for breast cancer, and patient-oriented decision making. PMID:12506467

  12. Modern Vaccines/Adjuvants Formulation—Session 2 (Plenary II)

    PubMed Central

    Collin, Nicolas

    2013-01-01

    On the 15–17th May 2013, the Fourth International Conference on Modern Vaccines/Adjuvants Formulation was organized in Lausanne, Switzerland, and gathered stakeholders from academics and from the industry to discuss several challenges, advances and promises in the field of vaccine adjuvants. Plenary session 2 of the meeting was composed of four different presentations covering: (1) the recent set-up of an adjuvant technology transfer and training platform in Switzerland, (2) the proposition to revisit existing paradigms of modern vaccinology, (3) the properties of polyethyleneimine as potential new vaccine adjuvant, and (4) the progresses in the design of HIV vaccine candidates able to induce broadly neutralizing antibodies. PMID:23966098

  13. SU-C-201-05: Imaging 212Pb-TCMC-Trastuzumab for Alpha Radioimmunotherapy for Ovarian Cancer

    SciTech Connect

    Shen, S; Meredith, R; Azure, M; Yoder, D; Torgue, J; Banaga, E

    2015-06-15

    Purpose: To support the phase I trial for toxicity, biodistribution and pharmacokinetics of intra-peritoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy. A whole body gamma camera imaging method was developed for estimating amount of 212Pb-TCMC-trastuzumab left in the peritoneal cavity. Methods: {sup 212}Pb decays to {sup 212}Bi via beta emission. {sup 212}Bi emits an alpha particle at an average of 6.1 MeV. The 238.6 keV gamma ray with a 43.6% yield can be exploited for imaging. Initial phantom was made of saline bags with 212Pb. Images were collected for 238.6 keV with a medium energy general purpose collimator. There are other high energy gamma emissions (e.g. 511keV, 8%; 583 keV, 31%) that penetrate the septae of the collimator and contribute scatter into 238.6 keV. An upper scatter window was used for scatter correction for these high energy gammas. Results: A small source containing 212Pb can be easily visualized. Scatter correction on images of a small 212Pb source resulted in a ∼50% reduction in the full width at tenth maximum (FWTM), while change in full width at half maximum (FWHM) was <10%. For photopeak images, substantial scatter around phantom source extended to > 5 cm outside; scatter correction improved image contrast by removing this scatter around the sources. Patient imaging, in the 1st cohort (n=3) showed little redistribution of 212Pb-TCMC-trastuzumab out of the peritoneal cavity. Compared to the early post-treatment images, the 18-hour post-injection images illustrated the shift to more uniform anterior/posterior abdominal distribution and the loss of intensity due to radioactive decay. Conclusion: Use of medium energy collimator, 15% width of 238.6 keV photopeak, and a 7.5% upper scatter window is adequate for quantification of 212Pb radioactivity inside peritoneal cavity for alpha radioimmunotherapy of ovarian cancer. Research Support: AREVA Med, NIH 1UL1RR025777-01.

  14. Neoadjuvant Sequential Docetaxel Followed by High-Dose Epirubicin in Combination With Cyclophosphamide Administered Concurrently With Trastuzumab. The DECT Trial.

    PubMed

    Pizzuti, Laura; Barba, Maddalena; Giannarelli, Diana; Sergi, Domenico; Botti, Claudio; Marchetti, Paolo; Anzà, Michele; Maugeri-Saccà, Marcello; Natoli, Clara; Di Filippo, Simona; Catenaro, Teresa; Tomao, Federica; Amodio, Antonella; Carpano, Silvia; Perracchio, Letizia; Mottolese, Marcella; Di Lauro, Luigi; Sanguineti, Giuseppe; Di Benedetto, Anna; Giordano, Antonio; Vici, Patrizia

    2016-11-01

    To report the results of the DECT trial, a phase II study of locally advanced or operable HER2-positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA-IIIB HER2-positive BC, 18-75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m(2) intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3-weekly cycles of epirubicin 120 mg/m(2) and cyclophosphamide, 600 mg/m(2) , plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8-78). Four-year recurrence-free survival was 74.7% (95%CI, 58.2-91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541-2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. PMID:27187274

  15. Opioid and adjuvant analgesics: compared and contrasted.

    PubMed

    Khan, Mohammed Ilyas Ahmed; Walsh, Declan; Brito-Dellan, Norman

    2011-08-01

    An adjuvant (or co-analgesic) is a drug that in its pharmacological characteristic is not necessarily primarily identified as an analgesic in nature but that has been found in clinical practice to have either an independent analgesic effect or additive analgesic properties when used with opioids. The therapeutic role of adjuvant analgesics (AAs) is to increase the therapeutic index of opioids by a dose-sparing effect, add a unique analgesic action in opioid-resistant pain, or reduce opioid side effects. A notable difference between opioids and AAs is that unlike opioids some AAs are associated with permanent organ toxicity, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) and renal failure. It is impossible to predict in advance in a given individual what opioid dose they may require to control cancer pain. Most AAs have a ceiling effect for their analgesic actions, but often with continued dose-related toxicities and side effects (with the exception of glucocorticoids). The blood levels of opioids (and their metabolites) can be measured with great precision and accuracy. There is sometimes a role for drug blood levels of certain AAs, like tricyclic antidepressants or anticonvulsants when used for neuropathic pain. Age affects metabolism of most opioids. The therapeutic window of opioids is wide, with no ceiling effect. Most AAs (except corticosteroids) have a narrow therapeutic window. Naloxone is a pure opioid antagonist that competes and displaces opioids from their receptor sites. All clinically useful opioids are mu opioid receptor agonists. Not all routes of administration are available to all opioids. Adjuvant analgesics lack the versatility in routes of administration that opioids possess. Dosing flexibility is a major advantage when treating cancer-related pain with opioids. Dose flexibility is much less with AAs than opioids. Unlike opioids, the analgesic response is usually observed within hours to days of attaining an adequate dose with most

  16. Lack of a pharmacokinetic interaction between trastuzumab and carboplatin in the presence of docetaxel: results from a phase Ib study in patients with HER2-positive metastatic or locally advanced inoperable solid tumors.

    PubMed

    Eppler, Stephen; Gordon, Michael S; Redfern, Charles H; Trudeau, Caroline; Xu, Na; Han, Kelong; Lum, Bert L

    2015-04-01

    The objective of this study was to evaluate the potential for a pharmacokinetic (PK) drug-drug interaction (DDI) between trastuzumab and carboplatin and to evaluate the potential effect of trastuzumab on the electrocardiogram QT interval. Here, we report the results of the PK DDI assessment and an interim safety analysis. Patients with metastatic or locally advanced, inoperable, human epidermal growth factor receptor 2-positive cancer received docetaxel and carboplatin on cycle 1, day 1 and then on day 1 of each subsequent 3-weekly treatment cycle. Trastuzumab was administered by intravenous infusion, with an accelerated loading dose on cycle 1, day 2 and cycle 1, day 8, and then a maintenance dose on day 1 of each subsequent 3-weekly treatment cycle. Blood was collected at various time points to assess free (unbound) plasma carboplatin and serum trastuzumab PK. The study enrolled 59 patients. Carboplatin concentrations in the presence and absence of trastuzumab were similar, as demonstrated by the geometric mean ratios for PK parameters, which were close to 1.0 (no effect). The observed trastuzumab concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, computed using the actual sampling time. In this interim safety analysis, 84.5% of patients had experienced adverse events of grade three or higher, the most common of which were hematologic and as expected. The results suggest that there is no clinically relevant PK DDI between carboplatin and trastuzumab. The safety profile of trastuzumab plus carboplatin and docetaxel was consistent with the known safety profile of this combination. PMID:25643049

  17. Adjuvant Immunotherapy of Melanoma, and Development of New Approaches Using the Neo- Adjuvant Approach in Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad

    2013-01-01

    Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. While early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death–the latter approaching 70% or more at 5 years. In patients at high-risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse free and overall survival. Neo-adjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFNα. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neo-adjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neo-adjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFNα, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab [BMS], and BRAF inhibitor vemurafenib [Genentech]) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 [BMS, Merck, Curetech] and anti

  18. Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes

    PubMed Central

    2015-01-01

    Adjuvants improve the adaptive immune response to a vaccine antigen by modulating innate immunity or facilitating transport and presentation. The selection of an appropriate adjuvant has become vital as new vaccines trend toward narrower composition, expanded application, and improved safety. Functionally, adjuvants act directly or indirectly on antigen presenting cells (APCs) including dendritic cells (DCs) and are perceived as having molecular patterns associated either with pathogen invasion or endogenous cell damage (known as pathogen associated molecular patterns [PAMPs] and damage associated molecular patterns [DAMPs]), thereby initiating sensing and response pathways. PAMP-type adjuvants are ligands for toll-like receptors (TLRs) and can directly affect DCs to alter the strength, potency, speed, duration, bias, breadth, and scope of adaptive immunity. DAMP-type adjuvants signal via proinflammatory pathways and promote immune cell infiltration, antigen presentation, and effector cell maturation. This class of adjuvants includes mineral salts, oil emulsions, nanoparticles, and polyelectrolytes and comprises colloids and molecular assemblies exhibiting complex, heterogeneous structures. Today innovation in adjuvant technology is driven by rapidly expanding knowledge in immunology, cross-fertilization from other areas including systems biology and materials sciences, and regulatory requirements for quality, safety, efficacy and understanding as part of the vaccine product. Standardizations will aid efforts to better define and compare the structure, function and safety of adjuvants. This article briefly surveys the genesis of adjuvant technology and then re-examines polyionic macromolecules and polyelectrolyte materials, adjuvants currently not known to employ TLR. Specific updates are provided for aluminum-based formulations and polyelectrolytes as examples of improvements to the oldest and emerging classes of vaccine adjuvants in use. PMID:25648619

  19. The ALTTO Breast Cancer Trial

    Cancer.gov

    A collection of material about the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation, or ALTTO, study that will compare the targeted agents lapatinib and trastuzumab alone, in sequence, or in combination as adjuvant therapy for HER2-positive br

  20. E-cadherin expression on human carcinoma cell affects trastuzumab-mediated antibody-dependent cellular cytotoxicity through killer cell lectin-like receptor G1 on natural killer cells.

    PubMed

    Yamauchi, Chisako; Fujii, Satoshi; Kimura, Taichi; Kuwata, Takeshi; Wada, Noriaki; Mukai, Hirofumi; Matsumoto, Naoki; Fukayama, Masashi; Ochiai, Atsushi

    2011-05-01

    Trastuzumab is a recombinant antibody drug that is widely used for the treatment of HER2-overexpressing breast carcinoma. Despite encouraging clinical results, many HER2-overexpressing carcinomas are primarily resistant to trastuzumab. We attempted to explain trastuzumab resistance and search for solutions. Since the killer cell lectin-like receptor G1 (KLRG1), an inhibitory receptor expressed on subsets of natural killer (NK) cells recognizes E-cadherin as ligands and may inhibit immune responses by regulating the effector function of NK cells, we used HER2-overexpressing carcinoma cells which were expressing E-cadherin to investigate the role of antibody-dependent cellular cytotoxicity (ADCC) through KLRG1 on NK cells in vitro and vivo. The results indicated that HER2-overexpressing carcinoma cells were killed by trastuzumab-mediated ADCC and the ADCC activity was reflected the degree of E-cadherin expression on carcinoma cells. We found that expression of E-cadherin was shown to be a predictor of response to trastuzumab-based treatment for HER2-overexpressing carcinomas, furthermore, trastuzumab-mediated ADCC was markedly enhanced by KLRG1-negative peripheral blood mononuclear cells (PBMCs(KLRG1(-))). PMID:21387286

  1. Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification

    PubMed Central

    Disel, Umut; Germain, Alexis; Yilmazel, Bahar; Abali, Huseyin; Bolat, Filiz Aka; Yelensky, Roman; Elvin, Julia A.; Lipson, Doron; Chmielecki, Juliann; Wang, Kai; Stephens, Philip J.; Ross, Jeffrey S.; Miller, Vincent A.; Ali, Siraj M.; George, Thomas J.

    2015-01-01

    Somatic ERBB2 amplification or activating mutations occur in approximately 2–5% of metastatic colorectal adenocarcinomas and are presumed to be oncogenic drivers, but limited evidence exists to suggest these lesions are sensitive to targeted monotherapy in patients. Here we present the case of a patient with advanced CRC with pulmonary metastases, who had progressed on both standard of care cytotoxic chemotherapy and anti-EGFR targeted therapy. Comprehensive genomic profiling (FoundationOne®) identified amplification of ERBB2 and a TP53 mutation in the metastatic lesion. Treatment with trastuzumab with a chemotherapy backbone elicited stable disease/minor response in the patient over a one year course of therapy, reducing tumor burden and significantly improving quality of life. This report demonstrates the application of personalized targeted therapy guided by comprehensive genomic profiling in metastatic colorectal adenocarcinoma. PMID:26244165

  2. Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification.

    PubMed

    Disel, Umut; Germain, Alexis; Yilmazel, Bahar; Abali, Huseyin; Bolat, Filiz Aka; Yelensky, Roman; Elvin, Julia A; Lipson, Doron; Chmielecki, Juliann; Wang, Kai; Stephens, Philip J; Ross, Jeffrey S; Miller, Vincent A; Ali, Siraj M; George, Thomas J

    2015-01-01

    Somatic ERBB2 amplification or activating mutations occur in approximately 2-5% of metastatic colorectal adenocarcinomas and are presumed to be oncogenic drivers, but limited evidence exists to suggest these lesions are sensitive to targeted monotherapy in patients. Here we present the case of a patient with advanced CRC with pulmonary metastases, who had progressed on both standard of care cytotoxic chemotherapy and anti-EGFR targeted therapy. Comprehensive genomic profiling (FoundationOne(®)) identified amplification of ERBB2 and a TP53 mutation in the metastatic lesion. Treatment with trastuzumab with a chemotherapy backbone elicited stable disease/minor response in the patient over a one year course of therapy, reducing tumor burden and significantly improving quality of life. This report demonstrates the application of personalized targeted therapy guided by comprehensive genomic profiling in metastatic colorectal adenocarcinoma. PMID:26244165

  3. Development, Characterization and Validation of Trastuzumab-Modified Gold Nanoparticles for Molecularly Targeted Radiosensitization of Breast Cancer

    NASA Astrophysics Data System (ADS)

    Chattopadhyay, Niladri

    The overexpression of the human epidermal growth factor receptor-2 (HER-2) in 20--25% of human breast cancers was investigated as a target for development of a gold nanoparticle (AuNP) based radiosensitizer for improving the efficacy of neoadjuvant X-radiation therapy of the disease. HER-2 targeted AuNPs were developed by covalently conjugating trastuzumab, a Health Canada approved monoclonal antibody for the treatment of HER-2-overexpressing breast cancer, to 30 nm AuNPs. Trastuzumab conjugated AuNPs were efficiently internalized by HER-2-overexpressing breast cancer cells (as assessed by darkfield microscopy and transmission electron microscopy) and increased DNA damage from X-radiation in these cells by more than 5-fold. To optimize delivery of AuNPs to HER-2-overexpressing tumors, high resolution microSPECT/CT imaging was used to track the in vivo fate of 111In-labelled non-targeted and HER-2 targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and non-specific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to non-targeted AuNPs. This phenomenon could be attributed to Fc-mediated recognition and subsequent sequestration of trastuzumab conjugated AuNP by the reticuloendothelial system (RES). Blocking of the RES did not increase tumor uptake of either HER-2 targeted or non-targeted AuNPs. Following i.t. injection, our results suggest that Au-NTs redistribute over time and traffick to the liver via the ipsilateral axillary lymph node leading to comparable exposure as seen with i.v. administration. In contrast, targeted AuNPs are bound and internalized by HER-2

  4. Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab

    PubMed Central

    Holland, Jason P.; Caldas-Lopes, Eloisi; Divilov, Vadim; Longo, Valerie A.; Taldone, Tony; Zatorska, Danuta; Chiosis, Gabriela; Lewis, Jason S.

    2010-01-01

    Background The positron-emitting radionuclide 89Zr (t1/2 = 3.17 days) was used to prepare 89Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/neu-positive breast tumors. In addition, pharmacodynamic studies on HER2/neu expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted. Methodology/Principal Findings Trastuzumab was functionalized with desferrioxamine B (DFO) and radiolabeled with [89Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic nu/nu mice bearing sub-cutaneous BT-474 (HER2/neu positive) and/or MDA-MB-468 (HER2/neu negative) tumor xenografts were conducted. The change in 89Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET. 89Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3±2.1 MBq/mg (2.82±0.05 mCi/mg of mAb). In vitro assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87±0.07. In vivo biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68±13.06%ID/g; 71.71±10.35%ID/g and 85.18±11.10%ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of 89Zr-DFO-trastuzumab. Expression levels of HER2/neu were modulated during the first 24 and 48 h post-administration (29.75±4.43%ID/g and 41.42±3.64%ID/g, respectively). By 72 h radiotracer uptake (73.64±12.17%ID/g) and Western blot analysis demonstrated that HER2/neu expression recovered to baseline levels. Conclusions/Significance The results indicate that 89Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/neu positive tumors, and has

  5. Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes.

    PubMed

    Namboodiri, A M; Pandey, J P

    2011-12-01

    Antibody-dependent cell-mediated cytotoxicity (ADCC), which links the innate and the adaptive arms of immunity, is a major host immunosurveillance mechanism against tumours, as well as the leading mechanism underlying the clinical efficacy of therapeutic antibodies such as cetuximab and trastuzumab, which target tumour antigens, human epidermal growth factor receptor (HER)1 and HER2, respectively. Immunoglobulin (Ig)G antibody-mediated ADCC is triggered upon ligation of Fcγ receptor (FcγR) to the Fc region of IgG molecules. It follows that genetic variation in FcγR and Fc could contribute to the differences in the magnitude of ADCC. Genetic variation in FcγR is known to contribute to the differences in the magnitude of ADCC, but the contribution of natural genetic variation in Fc, GM allotypes, in this interaction has hitherto not been investigated. Using an ADCC inhibition assay, we show that IgG1 expressing the GM 3+, 1-, 2- allotypes was equally effective in inhibiting cetuximab- and trastuzumab-mediated ADCC of respective target cells, in the presence of natural killer (NK) cells expressing either valine or phenylalanine allele of FcγRIIIa. In contrast, IgG1 expressing the allelic GM 17+, 1+, 2+ allotypes was significantly more effective in inhibiting the ADCC - mediated by both monoclonal antibodies - when NK cells expressed the valine, rather than the phenylalanine, allele of FcγRIIIa. These findings have important implications for engineering antibodies (with human γ1 constant region) against malignancies characterized by the over-expression of tumour antigens HER1 and HER2 - especially for patients who, because of their FcγRIIIa genotype, are unlikely to benefit from the currently available therapeutics. PMID:22059994

  6. Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells.

    PubMed

    Oak, Prajakta S; Kopp, Florian; Thakur, Chitra; Ellwart, Joachim W; Rapp, Ulf R; Ullrich, Axel; Wagner, Ernst; Knyazev, Pjotr; Roidl, Andreas

    2012-12-15

    A major obstacle in the successful treatment of cancer is the occurrence of chemoresistance. Cancer cells surviving chemotherapy and giving rise to a recurrence of the tumor are termed cancer stem cells and can be identified by elevated levels of certain stem cell markers. Eradication of this cell population is a priority objective in cancer therapy. Here, we report elevated levels of stem cell markers in MCF-7 mammospheres. Likewise, an upregulation of HER2 and its differential expression within individual cells of mammospheres was observed. Sorting for HER2(high) and HER2(low) cells revealed an upregulation of stem cell markers NANOG, OCT4 and SOX2 in the HER2(low) cell fraction. Accordingly, HER2(low) cells also showed reduced proliferation, ductal-like outgrowths and an increased number of colonies in matrigel. Xenografts from subcutaneously injected HER2(low) sorted cells exihibited earlier onset but slower growth of tumors and an increase in stem cell markers compared to tumors developed from the HER2(high) fraction. Treatment of mammospheres with salinomycin reduced the expression of SOX2 indicating a selective targeting of cancer stem cells. Trastuzumab however, did not reduce the expression of SOX2 in mammospheres. Furthermore, a combinatorial treatment of mammospheres with trastuzumab and salinomycin was superior to single treatment with each drug. Thus, targeting HER2 expressing tumors with anti-HER2 therapies will not necessarily eliminate cancer stem cells and may lead to a more aggressive cancer cell phenotype. Our study demonstrates efficient killing of both HER2 positive cells and cancer stem cells, hence opening a possibility for a new combinatorial treatment strategy. PMID:22511343

  7. Mucosal adjuvants to improve wildlife rabies vaccination.

    PubMed

    Fry, Tricia; Van Dalen, Kaci; Hurley, Jerome; Nash, Paul

    2012-10-01

    RABORAL V-RG(®)a is a recombinant vaccine used in oral rabies vaccination (ORV) programs for wildlife in the United States. Vaccination rates for raccoons are substantially lower than vaccination rates for gray foxes and coyotes. Research suggests that the low viscosity of the oral vaccine may preclude animals from receiving an effective dose when biting into the vaccine bait delivery system. We evaluated the possibility of using two benign compounds, chitosan and N,N,N-trimethylated chitosan (TMC), to increase the viscosity of the vaccine and potentially act as adjuvants to improve the immune response in raccoons (Procyon lotor). Forty mildly sedated raccoons were orally vaccinated via needleless syringe with either RABORAL V-RG (n = 12), chitosan+RABORAL V-RG (n = 12), TMC+ RABORAL V-RG (n = 12), or no vaccine (n = 4), on day 0 and again on day 90. We collected sera every 2-4 wk for 4 mo and evaluated rabies virus-neutralizing antibodies (rVNA). Raccoons were considered responders if rVNA titers were ≥ 0.1 IU/mL. Eleven of 12 raccoons vaccinated with TMC+RABORAL V-RG responded after one dose of vaccine, as did eight of 12 vaccinated with RABORAL V-RG, and three of 12 vaccinated with chitosan+ RABORAL V-RG. Our results suggest that the inclusion of an adjuvant, such as TMC, could increase vaccine efficacy to aid in controlling rabies virus spread in wildlife reservoirs. PMID:23060506

  8. Neoadjuvant and Adjuvant Chemotherapy of Cervical Cancer.

    PubMed

    Mallmann, Peter; Mallmann, Christoph

    2016-01-01

    Neoadjuvant chemotherapy is indicated in patients who can tolerate the side effects of a chemotherapy and with preoperative presentation of one of the following clinical risk situations: bulky disease with a maximal tumor diameter of > 4 cm, suspicious lymph nodes in magnetic resonance imaging (MRI), computed tomography (CT) scan or endosonography, histopathologically confirmed lymph node metastasis, or histopathologically documented risk factors such as G3 and L1V1. A neoadjuvant chemotherapy followed by surgery should be performed with cisplatin at a dosage of > 25 mg/m2 per week and an application interval of < 14 days. The previously published data suggests an improved rate of complete resection and reduced incidences of positive lymph nodes and parametric infiltration. Accordingly, the percentage of patients in need for adjuvant radiochemotherapy after operation can be significantly reduced. Some studies demonstrated a prolongation of progression-free and overall survival. Following the previously published studies, adjuvant chemotherapy after operation or after radiochemotherapy has no significant effect on the overall survival and, following the current guidelines, should be avoided. PMID:27614740

  9. Adjuvant chemotherapy for soft tissue sarcoma.

    PubMed

    Casali, Paolo G

    2015-01-01

    Adjuvant chemotherapy is not standard treatment in soft tissue sarcoma (STS). However, when the risk of relapse is high, it is an option for shared decision making with the patient in conditions of uncertainty. This is because available evidence is conflicting, even if several randomized clinical trials have been performed for 4 decades and also have been pooled into meta-analyses. Indeed, available meta-analyses point to a benefit in the 5% to 10% range in terms of survival and distant relapse rate. Some local benefit also was suggested by some trials. Placing chemotherapy in the preoperative setting may help gain a local advantage in terms of the quality of surgical margins or decreased sequelae. This may be done within a personalized approach according to the clinical presentation. Attempts to personalize treatment on the basis of the variegated pathology and molecular biology of STS subgroups are ongoing as well, according to what is done in the medical treatment of advanced STS. Thus, decision making for adjuvant and neoadjuvant indications deserves personalization in clinical research and in clinical practice, taking profit from all multidisciplinary clinical skills available at a sarcoma reference center, though with a degree of subjectivity because of the limitations of available evidence. PMID:25993233

  10. Safety assessment of adjuvanted vaccines: Methodological considerations

    PubMed Central

    Da Silva, Fernanda Tavares; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

    2015-01-01

    Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines. PMID:26029975

  11. Safety assessment of adjuvanted vaccines: Methodological considerations.

    PubMed

    Da Silva, Fernanda Tavares; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

    2015-01-01

    Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines. PMID:26029975

  12. Adjuvant chemotherapy for endometrial cancer after hysterectomy

    PubMed Central

    Johnson, Nick; Bryant, Andrew; Miles, Tracie; Hogberg, Thomas; Cornes, Paul

    2014-01-01

    Background Endometrial adenocarcinoma (womb cancer) is a malignant growth of the lining (endometrium) of the womb (uterus). It is distinct from sarcomas (tumours of the uterine muscle). Survival depends the risk of microscopic metastases after surgery. Adjuvant (postoperative) chemotherapy improves survival from some other adenocarcinomas, and there is evidence that endometrial cancer is sensitive to cytotoxic therapy. This systematic review examines the effect of chemotherapy on survival after hysterectomy for endometrial cancer. Objectives To assess efficacy of adjuvant (postoperative) chemotherapy for endometrial cancer. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Selection criteria Randomised controlled trials (RCTs) comparing adjuvant chemotherapy with any other adjuvant treatment or no other treatment. Data collection and analysis We used a random-effects meta-analysis to assess hazard ratios (HR) for overall and progression-free survival and risk ratios (RR) to compare death rates and site of initial relapse. Main results Five RCTs compared no additional treatment with additional chemotherapy after hysterectomy and radiotherapy. Four trials compared platinum based combination chemotherapy directly with radiotherapy. Indiscriminate pooling of survival data from 2197 women shows a significant overall survival advantage from adjuvant chemotherapy (RR (95% CI) = 0.88 (0.79 to 0.99)). Sensitivity analysis focused on trials of modern platinum based chemotherapy regimens and found the relative risk of death to be 0.85 ((0.76 to 0.96); number needed to treat for an additional beneficial outcome (NNT) = 25; absolute risk reduction = 4% (1% to 8%)). The HR for overall survival is 0.74 (0.64 to 0.89), significantly

  13. Spray characteristics affected by physical properties of adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four drift adjuvants, Array, In-Place, Vector and Control, were tested and physical properties and spray spectrum parameters measured. Array had the highest conductivity, indicating a good potential for the electrostatic charging, and the highest shear viscosity. All adjuvants had very similar neut...

  14. Dispersion and evaporation of droplets amended with adjuvants on soybeans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Increased use of adjuvants to improve pesticide spray application efficiency is hindered by a lack of knowledge to enhance droplet adhesion. Dispersion and evaporation of single 300 µm droplets amended with four different spray adjuvants deposited at four different soybean plant locations were inves...

  15. Evaluating spray adjuvants to extend residual activity of microbiol pesticides`

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Based on requests to improve the residual efficacy of baculovirus applications, a commercial adjuvant (Nu-Film 17(R) and an experimental lignin adjuvant were evaluated for resistance to environmental degradation. Nu-Film is a commercial product derived from pine resin; and lignin is a by-product of...

  16. Current status of synthetic hemozoin adjuvant: A preliminary safety evaluation.

    PubMed

    Lee, Michelle Sue Jann; Igari, Yoshikatsu; Tsukui, Toshihiro; Ishii, Ken J; Coban, Cevayir

    2016-04-19

    Although adjuvants are a "must-have" component of successful vaccines, there are very few adjuvants licensed for use in humans, there is therefore an urgent need to develop new and safer adjuvants. Synthetic hemozoin (sHZ), a chemical analog of hemozoin which is produced by the malaria parasite, exhibits a potent adjuvant effect which enhances antigen-specific immune responses to vaccines. The potency of sHZ adjuvanticity is not limited to malaria specific vaccines, it has also been demonstrated to be effective in influenza and dog allergy models. While the synthesis of uniformly sized sHZ with consistent characteristics has proven difficult, we have recently successfully optimized the manufacture of sHZ product with an optimal adjuvant effect. Here, we summarize recent developments on the adjuvant properties of optimized sHZ adjuvant, including its good laboratory practice (GLP) non-clinical safety profile in animals. These studies ensure the safety of optimized sHZ product to be readily used as vaccine adjuvant beforehand in veterinary medicine. PMID:26976665

  17. Vaccine Adjuvants: from 1920 to 2015 and Beyond

    PubMed Central

    Di Pasquale, Alberta; Preiss, Scott; Tavares Da Silva, Fernanda; Garçon, Nathalie

    2015-01-01

    The concept of stimulating the body’s immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines. PMID:26343190

  18. Adjuvant Effects on Evaporation Time and Wetted Area of Droplets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Appropriate adjuvant selection for pesticide applications is central to improve spray performances on waxy leaves and to reduce off-target losses. Evaporation and deposition patterns of 500 µm sessile droplets with five classes of adjuvants on five different waxy plants were investigated. Droplets g...

  19. Vaccine adjuvant technology: from theoretical mechanisms to practical approaches.

    PubMed

    Schijns, V E J C; Tangerås, A

    2005-01-01

    Poorly immunogenic antigens depend on vaccine adjuvants to evoke an immune response. In addition, adjuvants largely determine the magnitude, quality, time of onset and the duration of immune responses to co-administered antigens. As late as 1989, Janeway aptly called adjuvants: "the immunologist's dirty little secret". This statement reflected the ignorance on the mechanisms of action of most known adjuvants. Yet, rational vaccine design involves a logical choice of adjuvant based on a knowledge of their mode of action and their effects on product efficacy and safety. However, even today the key processes critical for immune induction in general and those evoked by vaccine adjuvants in particular are being disputed among immunologists. This paper presents the four most important concepts likely to explain some of the mechanisms of vaccine adjuvants. They include: (i) the geographical concept of immune reactivity; (ii) the depot concept; (iii) the hypothesis of pathogen-structure recognition, and (iv) the damage/endogenous danger theory. These paradigms are based on observations gathered in mammalian species, largely in murine models. In aquatic animals the processes underlying immune induction will at least partly overlap those in mammals. However, due to inherent species differences, certain pathways may be different. Rational vaccine design, a difficult goal in mammals, is further hampered in aquatic animals by the lack of immunological tools in these species. Extensive trial and error-based approaches have yielded adjuvant candidates for various fish species, with acceptable safety and proven efficacy, some of which are presented. PMID:15962475

  20. In vitro interactions between macrophages and aluminum-containing adjuvants.

    PubMed

    Rimaniol, Anne-Cécile; Gras, Gabriel; Clayette, Pascal

    2007-09-17

    Intramuscular administration of aluminum-adjuvanted vaccines induces an infiltration of aluminum-containing macrophages between muscle fibers. In vitro stimulation of human monocyte-derived macrophages with aluminum hydroxide (AlOOH) induces similar intracellular crystalline inclusions as well as phenotypical and functional modifications. We compared in this study the ability of other adjuvants to exert similar changes in macrophages in vitro. All mineral salts, i.e. aluminic (AlOOH, AlPO(4)) and non-aluminic mineral adjuvants (CaPO(4), FePO(4)) but not emulsion were able to increase macrophages capacity to potentiate autologous memory T lymphocyte proliferation, while only aluminic adjuvants induced CD83 expression and increased CD86 on macrophages. All together, this suggests that aluminic and non-aluminic adjuvants exerted their immunoactivities by distinct mechanisms on macrophages. PMID:17689842

  1. Adjuvants in micro- to nanoscale: current state and future direction.

    PubMed

    Gupta, Ankur; Das, Soumen; Schanen, Brian; Seal, Sudipta

    2016-01-01

    Adjuvants have been used in vaccines for over 70 years to promote long-lived and sterilizing immunity. Since then, various adjuvant systems were developed by combining nanotechnology with natural and/or synthetic immunomodulatory molecules. These systems are biocompatible, immunogenic, and possess higher antigen carrying capacity. This article showcases advancements made in the adjuvant systems formulations, their synthesis routes, and the improvement of these adjuvants have brought in response to combat against ongoing global health threats such as malaria, hepatitis C, universal influenza, and human immunodeficiency virus. This review also highlights the interaction of adjuvants with the delivery of antigens to cells and unfolds mechanism of actions. In addition, this review discusses the physicochemical factors responsible for the efficient interaction of nanoadjuvants with antigen receptors to develop more effective, less reactogenic, and multifunctional systems for the next generation vaccines. PMID:26053286

  2. [Adjuvants--essential components of new generation vaccines].

    PubMed

    Dzierzbicka, Krystyna; Kołodziejczyk, Aleksander M

    2006-01-01

    Adjuvants are essential components of vaccines that augment an immunological reaction of organism. New vaccines based on recombinant proteins and DNA, are more save than traditional vaccines but they are less immunogenic. Therefore, there is an urgent need for the development of new, improved vaccine adjuvants. There are two classes of adjuvants: vaccine delivery systems (e.g. emulsions, microparticles, immune-stimulating complexes ISCOMs, liposomes) and immunostimulatory adjuvants (e.g. lipopolysaccharide, monophosphoryl lipid A, CpG DNA, or muramylpeptides). The discovery of more potent and safer adjuvants may allow to development better prophylactic and therapeutic vaccines against chronic infectious (e.g., HSV, HIV, HCV, HBV, HPV, or Helicobacter pylori) and noninfectious diseases as multiple sclerosis, insulin-dependent diabetes, rheumatoid arthritis, allergy and tumors (e.g., melanoma, breast, or colon cancer). PMID:17078510

  3. Update on Adjuvant Chemotherapy for Early Breast Cancer

    PubMed Central

    Rampurwala, Murtuza M; Rocque, Gabrielle B; Burkard, Mark E

    2014-01-01

    Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come. PMID:25336961

  4. Near-Infrared Laser Adjuvant for Influenza Vaccine

    PubMed Central

    Kashiwagi, Satoshi; Yuan, Jianping; Forbes, Benjamin; Hibert, Mathew L.; Lee, Eugene L. Q.; Whicher, Laura; Goudie, Calum; Yang, Yuan; Chen, Tao; Edelblute, Beth; Collette, Brian; Edington, Laurel; Trussler, James; Nezivar, Jean; Leblanc, Pierre; Bronson, Roderick; Tsukada, Kosuke; Suematsu, Makoto; Dover, Jeffrey; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C.

    2013-01-01

    Safe and effective immunologic adjuvants are often essential for vaccines. However, the choice of adjuvant for licensed vaccines is limited, especially for those that are administered intradermally. We show that non-tissue damaging, near-infrared (NIR) laser light given in short exposures to small areas of skin, without the use of additional chemical or biological agents, significantly increases immune responses to intradermal influenza vaccination without augmenting IgE. The NIR laser-adjuvanted vaccine confers increased protection in a murine influenza lethal challenge model as compared to unadjuvanted vaccine. We show that NIR laser treatment induces the expression of specific chemokines in the skin resulting in recruitment and activation of dendritic cells and is safe to use in both mice and humans. The NIR laser adjuvant technology provides a novel, safe, low-cost, simple-to-use, potentially broadly applicable and clinically feasible approach to enhancing vaccine efficacy as an alternative to chemical and biological adjuvants. PMID:24349390

  5. Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

    PubMed Central

    HogenEsch, Harm

    2013-01-01

    Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA, and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines. PMID:23335921

  6. Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer.

    PubMed

    Fleeman, Nigel; Bagust, Adrian; Beale, Sophie; Dwan, Kerry; Dickson, Rumona; Proudlove, Chris; Dundar, Yenal

    2015-01-01

    The National Institute for Health and Care Excellence (NICE) invited the manufacturer of pertuzumab (Roche) to submit evidence for the clinical and cost effectiveness of pertuzumab + trastuzumab + docetaxel for the treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic or locally recurrent unresectable breast cancer in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarises the ERG's review of the evidence submitted by the manufacturer and provides a summary of the Appraisal Committee's (AC) initial decision. At the time of writing, final guidance had not been published by NICE. The clinical evidence was mainly derived from an ongoing phase III randomised double-blind placebo-controlled international multicentre clinical trial (CLEOPATRA), designed to evaluate efficacy and safety in 808 patients, which compared pertuzumab + trastuzumab + docetaxel (pertuzumab arm) with placebo + trastuzumab + docetaxel (control arm). Both progression-free survival (PFS) and overall survival (OS) were analysed at two data cut-off points-May 2011 (median follow-up of 18 months) and May 2012 (median follow-up of 30 months). At both time points, PFS was significantly longer in the pertuzumab arm (18.5 months compared with 12.4 months in the control arm at the first data cut-off point and 18.7 versus 12.4 months at the second data cut-off point). Assessment of OS benefit suggested an improvement for patients in the pertuzumab arm with a strong trend towards an OS benefit at the second data cut-off point; however, due to the immaturity of the OS data, the magnitude of the OS benefit was uncertain. Importantly, cardiotoxicity was not increased in patients treated with a combination of pertuzumab + trastuzumab + docetaxel. The ERG's main concern with the

  7. D-amino acid peptide residualizing agents bearing N-hydroxysuccinimido-and maleimido- functional groups and their application for trastuzumab radioiodination

    PubMed Central

    Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan; Chitneni, Satish; Zalutsky, Michael R.

    2014-01-01

    Introduction Proteins that undergo receptor-mediated endocytosis are subject to lysosomal degradation, requiring radioiodination methods that minimize loss of radioactivity from tumor cells after this process occurs. To accomplish this, we developed the residualizing radioiodination agent N∊-(3-[*I]iodobenzoyl)-Lys5-Nα-maleimido-Gly1-d-GEEEK (Mal-d-GEEEK-[*I]IB), which enhanced tumor uptake but also increased kidney activity and necessitates generation of sulfhydryl moieties on the protein. The purpose of the current study was to synthesize and evaluate a new d-amino acid based agent that might avoid these potential problems. Methods Nα-(3-iodobenzoyl)-(5-succinimidyloxycarbonyl)-d-EEEG (NHS-IB-d-EEEG), which contains 3 d-glutamates to provide negative charge and a N-hydroxysuccinimide function to permit conjugation to unmodified proteins, and the corresponding tin precursor were produced by solid phase peptide synthesis and subsequent conjugation with appropriate reagents. Radioiodination of the anti-HER2 antibody trastuzumab using NHS-IB-d-EEEG and Mal-d-GEEEK-IB were compared. Paired-label internalization assays on BT474 breast carcinoma cells and biodistribution studies in athymic mice bearing BT474M1 xenografts were performed to evaluate the two radioiodinated d-peptide trastuzumab conjugates. Results NHS-[131I]IB-d-EEEG was produced in 53.8 ± 13.4 % and conjugated to trastuzumab in 39.5 ± 7.6 % yield. Paired-label internalization assays with trastuzumab-NHS-[131I]IB-d-EEEG and trastuzumab-Mal-d-GEEEK-[125I]IB demonstrated similar intracellular trapping for both conjugates at 1 h (131I, 84.4 ± 6.1%; 125I, 88.6 ± 5.2%) through 24 h (131I, 60.7 ± 6.8%; 125I, 64.9 ± 6.9 %). In the biodistribution experiment, tumor uptake peaked at 48 h (trastuzumab-NHS-[131I]IB-d-EEEG, 29.8 ± 3.6 %ID/g; trastuzumab-Mal-d-GEEEK-[125I]IB, 45.3 ± 5.3 %ID/g) and was significantly higher for 125I at all time points. In general, normal tissue levels were lower for

  8. Tumor dosimetry for I-131 trastuzumab therapy in a Her2+ NCI N87 xenograft mouse model using the Siemens SYMBIA E gamma camera with a pinhole collimator

    NASA Astrophysics Data System (ADS)

    Lee, Young Sub; Kim, Jin Su; Deuk Cho, Kyung; Kang, Joo Hyun; Moo Lim, Sang

    2015-07-01

    We performed imaging and therapy using I-131 trastuzumab and a pinhole collimator attached to a conventional gamma camera for human use in a mouse model. The conventional clinical gamma camera with a 2-mm radius-sized pinhole collimator was used for monitoring the animal model after administration of I-131 trastuzumab The highest and lowest radiation-received organs were osteogenic cells (0.349 mSv/MBq) and skin (0.137 mSv/MBq), respectively. The mean coefficients of variation (%CV) of the effective dose equivalent and effective dose were 0.091 and 0.093 mSv/MBq respectively. We showed the feasibility of the pinholeattached conventional gamma camera for human use for the assessment of dosimetry. Mouse dosimetry and prediction of human dosimetry could be used to provide data for the safety and efficacy of newly developed therapeutic schemes.

  9. Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts

    PubMed Central

    Whisenant, Jennifer G.; Sorace, Anna G.; McIntyre, J. Oliver; Kang, Hakmook; Sánchez, Violeta; Loveless, Mary E.; Yankeelov, Thomas E.

    2014-01-01

    We report longitudinal diffusion-weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced (DCE)-MRI (7 T) studies designed to identify functional changes, prior to volume changes, in trastuzumab-sensitive and resistant HER2 + breast cancer xenografts. Athymic mice (N = 33) were subcutaneously implanted with trastuzumab-sensitive (BT474) or trastuzumab-resistant (HR6) breast cancer cells. Tumor-bearing animals were distributed into four groups: BT474 treated and control, HR6 treated and control. DW- and DCE-MRI were conducted at baseline, day 1, and day 4; trastuzumab (10 mg/kg) or saline was administered at baseline and day 3. Animals were sacrificed on day 4 and tumors resected for histology. Voxel-based DW- and DCE-MRI analyses were performed to generate parametric maps of ADC, Ktrans, and ve. On day 1, no differences in tumor size were observed between any of the groups. On day 4, significant differences in tumor size were observed between treated vs. control BT474, treated BT474 vs. treated HR6, and treated vs. control HR6 (P < .0001). On day 1, ve was significantly higher in the BT474 treated group compared to BT474 control (P = .002) and HR6 treated (P = .004). On day 4, ve and Ktrans were significantly higher in the treated BT474 tumors compared to BT474 controls (P = .0007, P = .02, respectively). A significant decrease in Ki67 staining reinforced response in the BT474 treated group compared to BT474 controls (P = .02). This work demonstrated that quantitative MRI biomarkers have the sensitivity to differentiate treatment response in HER2 + tumors prior to changes in tumor size. PMID:25500087

  10. HER2-positive patients receiving trastuzumab treatment have a comparable prognosis with HER2-negative advanced gastric cancer patients: a prospective cohort observation.

    PubMed

    Qiu, Miao-Zhen; Li, Qian; Wang, Zhi-Qiang; Liu, Tian-Shu; Liu, Qing; Wei, Xiao-Li; Jin, Ying; Wang, De-Shen; Ren, Chao; Bai, Long; Zhang, Dong-Sheng; Wang, Feng-Hua; Li, Yu-Hong; Xu, Rui-Hua

    2014-05-15

    The monoclonal antibody trastuzumab has brought survival benefit to patients with advanced gastric cancer (AGC) that have human epidermal growth factor receptor 2 (HER2) over expression or amplification. This study was designed to compare the clinical outcomes of HER2-negative and HER2-positive AGC patients with or without trastuzumab treatment. There were three groups of patients enrolled for analysis. Group A was 51 HER2-positive AGC patients treated with trastuzumab and chemotherapy; group B was a matched control group of 47 HER2-positive patients who received chemotherapy only; group C was a matched group of 251 HER2-negative patients who received chemotherapy. All the patients were enrolled at Sun Yat-sen University Cancer Center or Zhongshan Hospital, Fudan University between January 2010 and December 2012. The primary endpoint was overall survival (OS). The Kaplan-Meier method and log-rank test were used for survival analysis. The median duration of follow-up was 13.5 months (range 5-18.6 months). The median OS of these three groups of patients was 14.8 months, 11.3 months and 14.4 months respectively (p < 0.001). The survival difference between group A and B was significant, p < 0.001. Similarly, there was significant difference between group B and C, p < 0.001. Moreover the survival between group A and C was comparable, p = 0.281. The median progression-free survival for these three groups was 7.4, 6.0 and 7.2 months. Multivariate analysis confirmed that trastuzumab treatment was an independent prognostic factor in group A and B patients (p = 0.017). HER2 positive was an independent adverse prognostic factor in group B and C patients (p = 0.013). PMID:24155030

  11. Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer

    PubMed Central

    2010-01-01

    Background We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC. Methods HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses. Results Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group. Conclusions These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC. PMID:20178580

  12. LC-MS/MS-Based Monitoring of In Vivo Protein Biotransformation: Quantitative Determination of Trastuzumab and Its Deamidation Products in Human Plasma.

    PubMed

    Bults, Peter; Bischoff, Rainer; Bakker, Hilde; Gietema, Jourik A; van de Merbel, Nico C

    2016-02-01

    An LC-MS/MS-based method is described for quantitatively monitoring the in vivo deamidation of the biopharmaceutical monoclonal antibody trastuzumab at a crucial position in its complementarity determining region (CDR). The multiplexed LC-MS/MS assay using selected reaction monitoring (SRM) allows simultaneous quantitation of five molecular species derived from trastuzumab after tryptic digestion: a stable signature peptide (FTISADTSK), a deamidation-sensitive signature peptide (IYPTNGYTR), its deamidated products (IYPTDGYTR and IYPTisoDGYTR), and a succinimide intermediate (IYPTsuccGYTR). Digestion of a 50 μL plasma sample is performed at pH 7 for 3 h at 37 °C, which combines a reasonable (>80%) digestion efficiency with a minimal (<1%) formation of deamidation products during digestion. Rapid in vitro deamidation was observed at higher pH, leading to a (large) overestimation of the concentrations of deamidation products in the original plasma sample. The LC-MS/MS method was validated in accordance with international bioanalytical guidelines over the clinically relevant range of 0.5 to 500 μg/mL with bias and CV values well below 15%. Deamidation of trastuzumab was observed in plasma both in a 56 day in vitro forced degradation study (up to 37% of the total drug concentration) and in samples obtained from breast cancer patients after treatment with the drug for several months (up to 25%). Comparison with a validated ELISA method for trastuzumab showed that deamidation of the drug at the CDR leads to a loss of recognition by the antibodies used in the ELISA assay. PMID:26713683

  13. Cardiac side effects of trastuzumab in breast cancer patients – single centere experiences

    PubMed Central

    Leś, Dominika; Sarzyczny-Słota, Danuta; Nowara, Elżbieta

    2013-01-01

    Aim of the study The aim of this study was to present our own experiences concerning risk factors for cardiac side effects in the study group. Material and methods The study was performed in 120 patients with HER2-overexpressing breast cancer who received immunotherapy in the Clinical and Experimental Oncology Department, between 2006 and 2011. Results LVEF reduction > 10% of the baseline fraction was observed in 10 (8%) patients. Symptomatic heart failure occurred in two individuals. Due to persistent cardiotoxicity five patients (4%) had to discontinue therapy prematurely. Risk factors for cardiac toxicity in the analyzed group included: previous radiotherapy to the left side of the chest (p = 0.05), higher BMI (p = 0.05), negative steroid receptor status (p = 0.045) and low baseline LVEF (p < 0.001). Patients receiving radiotherapy were more likely to develop cardiotoxicity if presenting older age (p = 0.0003). Conclusions Previous radiotherapy to the left side of the chest, negative steroid receptor status, high BMI and low baseline LVEF were associated with increased risk of cardiac dysfunction. There was no difference between patients receiving adjuvant therapy and those treated due to metastatic disease. PMID:23788989

  14. [HER2-Positive Advanced Gastric Cancer with Disseminated Intravascular Coagulation and Diffuse Bone Marrow Carcinomatosis Successfully Treated with S-1/Trastuzumab Chemotherapy--A Case Report].

    PubMed

    Senoo, Satoru; Mannami, Tomohiko; Tamura, Tomoki; Fujiwara, Nobukiyo; Ikeda, Genyo; Komoda, Minori; Ohtawa, Yasuyuki; Fujimoto, Yoshimi; Sato, Naohiro; Kambara, Takeshi; Waku, Toshihiko; Kenmotsu, Masaichi; Kurimoto, Etsuko; Okada, Toshiaki; Harita, Shingo; Sonobe, Hiroshi

    2015-12-01

    Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has been proven to result in a survival benefit for the treatment of patients with HER2-positive advanced gastric cancer (AGC). However, data are lacking for the treatment of those with disseminated intravascular coagulation (DIC) and diffuse bone marrow carcinomatosis. A 77-year-old woman presented with back pain and fatigue since 2 months. Esophagogastroduodenoscopy showed a scirrhous lesion in the gastric corpus, which was biopsied and identified as signet-ring cell carcinoma with HER2 overexpression on immunohistochemistry. Laboratory testing, bone scintigraphy, and bone marrow biopsy were conducted, and she was diagnosed with HER2-positive AGC with DIC and diffuse bone marrow carcinomatosis. She underwent chemotherapy with the following regimen: oral administration of 80 mg/m2 S-1 for 2 weeks and 6 mg/kg trastuzumab infusion on day 6 every 3 weeks, which significantly improved the DIC. She was discharged from the hospital 73 days after admission and survived for 438 days after diagnosis. To the best of our knowledge, this is the first case report in which HER2-positive AGC complicated by DIC with diffuse bone marrow carcinomatosis was successfully treated with combined chemotherapy consisting of S-1 plus trastuzumab. PMID:26809307

  15. HER2-positive, trastuzumab-resistant metastatic esophageal cancer presenting with brain metastasis after durable response to dual HER2 blockade: a case report

    PubMed Central

    Gelbspan, Deborah; Weitz, David; Markman, Maurie; Quan, Walter

    2014-01-01

    We here report a case of a patient diagnosed with human epithelial growth factor receptor 2 (HER2)-amplified esophageal adenocarcinoma. The patient responded well to trastuzumab-based chemotherapy initially, but progressed with liver metastases. Her treatment was then switched to dual HER2 blockade with both trastuzumab and lapatinib in combination with capecitabine. She tolerated therapy and responded remarkably well with radiographic resolution of liver metastases. Unfortunately, she developed multiple brain metastases in the absence of extracranial progression. Discordant negative expression of HER2 and subclonal mutations in brain lesions were discovered, which, at least in part, explained her brain metastases in the presence of capecitabine and lapatinib, as both agents are known to be able to cross the blood brain barrier. The potential mechanism for dual HER2 blockade is discussed in the context of HER2-positive, trastuzumab-resistant, advanced esophageal cancer. The incidence of brain metastasis in advanced gastro-esophageal cancer has been reported to be extremely low, but is expected to increase with more effective systemic therapy. The intratumoral heterogeneity between the metastases, local recurrences and the primary tumor is definitely noteworthy. PMID:25436131

  16. Glutamine synthetase predicts adjuvant TACE response in hepatocellular carcinoma

    PubMed Central

    Zhang, Bo; Liu, Kai; Zhang, Jian; Dong, Liwei; Jin, Zhichao; Zhang, Xinji; Xue, Feng; He, Jia

    2015-01-01

    Background: Adjuvant transcatheter arterial chemoembolization (TACE) is associated with better outcome and reduced tumor recurrence in hepatocellular carcinoma (HCC) patients. This study aimed to investigate the relationship between glutamine synthetase (GS) expression and survival of HCC patients after postoperative adjuvant TACE. Methods: We retrospectively analyzed 554 HCC patients in two independent cohorts who underwent curative resection. Immunohistochemistry assay was used to investigate the expression of GS protein and evaluate the association with survival and the response to adjuvant TACE. Results: In training cohort, patients with low GS expression who received postoperative adjuvant TACE showed a better overall survival (OS) (P<0.001) and less early phase recurrence (P=0.016). Adjuvant TACE was an independent prognostic factor for 5-year OS (HR=0.408, 95% CI 0.261-0.639, P<0.001) and early phase recurrence (HR=0.592, 95% CI 0.376-0.931, P=0.023). The same result was confirmed in validation cohort. Patients with high GS expression in both cohorts did not have a significant response to adjuvant TACE in OS and early phase recurrence. Conclusions: GS status in tumor might be a useful tool in the selection of HCC patients who would be likely to benefit from postoperative adjuvant TACE. PMID:26884995

  17. Antibody and T-cell responses to a virosomal adjuvanted H9N2 avian influenza vaccine: impact of distinct additional adjuvants.

    PubMed

    Radosević, Katarina; Rodriguez, Ariane; Mintardjo, Ratna; Tax, Dennis; Bengtsson, Karin Lövgren; Thompson, Catherine; Zambon, Maria; Weverling, Gerrit Jan; Uytdehaag, Fons; Goudsmit, Jaap

    2008-07-01

    A highly efficacious vaccine is required to counteract a threat of an avian influenza pandemic. Increasing the potency of vaccines by adjuvation is essential not only to overcome generally low immunogenicity of pandemic strains, but also to allow dose sparing and as such to make it feasible to satisfy huge global production demands. In this study we evaluated the ability of four distinct adjuvants to further increase immune responses to a virosomal adjuvanted avian H9N2 influenza vaccine in mice. Currently registered adjuvants aluminium phosphate, aluminium hydroxide and MF59, as well as a novel promising adjuvant MATRIX-M were included in the study. Our results demonstrate that all adjuvants significantly increased the H9N2 haemagglutinin (HA) inhibition and ELISA antibody titers induced with the virosomal adjuvanted vaccine. The adjuvants exhibited different effect on the isotype of virus specific antibodies, with MATRIX-M inducing the most pronounced skewing to IgG2a, i.e. towards Th1 type of response. While the virosomal adjuvanted pandemic influenza vaccine efficiently induced CD4(+) T-cell response, with no further increase upon adjuvation, the CD8(+) T-cell responses induced with virosomal adjuvanted vaccine could be significantly improved upon additional adjuvation with MATRIX-M or MF59. All adjuvants demonstrated a dose sparing effect, i.e. in combination with the virosomal adjuvanted pandemic influenza vaccine they increased immune responses to comparable level independent of the tested vaccine dose. In conclusion, our results demonstrate that immune responses to a virosomal adjuvanted pandemic influenza vaccine can be further enhanced by add-on adjuvants, with MATRIX-M being overall the most potent adjuvant in combination with virosomes, followed by MF59 and finally aluminium-based adjuvants. PMID:18514980

  18. Characterization of the in situ immunological responses to vaccine adjuvants.

    PubMed

    Horohov, D W; Dunham, J; Liu, C; Betancourt, A; Stewart, J C; Page, A E; Chambers, T M

    2015-03-15

    Adjuvants are included with many inactivated and some modified live vaccines to enhance immune responses to specific antigens. While early vaccines relied exclusively upon aluminum salts, still the major adjuvant used in human vaccines, other adjuvant products are used in veterinary medicine. In addition to enhancing antigen presentation, adjuvants can also enhance the development of specific immune responses. Thus, alum adjuvants often preferentially stimulate humoral immune responses. By contrast, lipid-based adjuvants are often more effective at stimulating cell-mediated immune responses. Metastim(®) is a lipid-based adjuvant reported to elicit both humoral and cellular immune responses, though the mechanism responsible for this activity remains unclear. In this study, we compared the ability of equine influenza virus vaccines containing either saline or Metastim(®) or an aluminum phosphate adjuvant to stimulate antigen presenting cell function in vivo. Six ponies were intradermally inoculated with inactivated equine influenza (KY97) mixed with either adjuvant or saline. Multiple sites were injected so that biopsies could be collected at different times post injection. The 4mm punch biopsies were formalin-fixed, paraffin-embedded, and stained with hematoxylin and eosin (H&E). Total RNA was isolated from 2mm punch biopsies for the determination of gene expression by real-time PCR. H&E staining revealed a variety of cells recruited to the injection sites, including lymphocytes, neutrophils, eosinophils and macrophages. Real-time PCR analysis of the injection site confirmed this cellular infiltration and identified increased expression of activation markers. Both vaccines also stimulated gene expressions of pro-inflammatory cytokines. The vaccine containing Metastim(®) elicited significantly higher gene expression of interferon-γ, IL-12, CD4 and CD83 compared to alum (p<0.05). While the greater induction of IFNγ-related gene expression indicates that Metastim

  19. Adjuvants for vaccines to drugs of abuse and addiction.

    PubMed

    Alving, Carl R; Matyas, Gary R; Torres, Oscar; Jalah, Rashmi; Beck, Zoltan

    2014-09-22

    Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA. PMID:25111169

  20. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer

    PubMed Central

    2014-01-01

    Introduction The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1). Methods Patients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n = 70) or T-DM1 (n = 67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction. Results HER2 mRNA levels were obtained for 116/137 patients (HT = 61; T-DM1 = 55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR) = 0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA ≥ median (HR = 0.39; 95% CI 0.18 to 0.85) versus < median (HR = 0.85; 95% CI 0.44 to 1.67). In the T-DM1 arm, median progression-free survival (PFS) was not reached in patients with HER2 mRNA ≥ median and was 10.6 months in patients with HER2 mRNA < median. In the HT arm, PFS was 8.8 versus 9.8 months in patients with HER2 mRNA ≥ median versus < median, respectively. The effect of HER2 mRNA expression on objective response rates was less pronounced. Conclusions This exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median. Trial registration ClinicalTrials.gov NCT00679341 PMID:24887458

  1. Chitosan as an adjuvant for a Helicobacter pylori therapeutic vaccine.

    PubMed

    Gong, Yanfeng; Tao, Liming; Wang, Fucai; Liu, Wei; Jing, Lei; Liu, Dongsheng; Hu, Sijun; Xie, Yong; Zhou, Nanjin

    2015-09-01

    The aim of the present study was to delineate the therapeutic effect of a Helicobacter pylori vaccine with chitosan as an adjuvant, as well as to identify the potential mechanism against H. pylori infection when compared with an H. pylori vaccine, with cholera toxin (CT) as an adjuvant. Mice were first infected with H. pylori and, following the establishment of an effective infection model, were vaccinated using an H. pylori protein vaccine with chitosan as an adjuvant. Levels of H. pylori colonization, H. pylori‑specific antibodies and cytokines were determined by enzyme‑linked immunosorbent assay. The TLR4 and Foxp3 mRNA and protein levels were determined by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. It was identified that the H. pylori elimination rate of the therapeutic vaccine with chitosan as an adjuvant (58.33%) was greater than the therapeutic vaccine with CT as an adjuvant (45.45%). The therapeutic H. pylori vaccine with chitosan as an adjuvant induced significantly greater antibody and cytokine levels when compared with the control groups. Notably, the IL‑10 and IL‑4 levels in the groups with chitosan as an adjuvant to the H. pylori vaccine were significantly greater than those in the groups with CT as an adjuvant. The mRNA expression levels of TLR4 and Foxp3 were significantly elevated in the mice that were vaccinated with chitosan as an adjuvant to the H. pylori vaccine, particularly in mice where the H. pylori infection had been eradicated. The H. pylori vaccine with chitosan as an adjuvant effectively increased the H. pylori elimination rate, the humoral immune response and the Th1/Th2 cell immune reaction; in addition, the therapeutic H. pylori vaccine regulated the Th1 and Th2 response. The significantly increased TLR4 expression and decreased CD4+CD25+Foxp3+Treg cell number contributed to the immune clearance of the H. pylori infection. Thus, the present findings demonstrate that in mice the H

  2. ER-Poor and HER2-Positive: A Potential Subtype of Breast Cancer to Avoid Axillary Dissection in Node Positive Patients after Neoadjuvant Chemo-Trastuzumab Therapy

    PubMed Central

    Chen, Can-ming; Hu, Zhen; Hou, Yi-feng; Di, Gen-hong; Wu, Jiong; Shen, Zhen-zhou; Shao, Zhi-ming; Liu, Guang-yu

    2014-01-01

    Purpose The study was to estimate the likelihood of axillary downstaging and to identify the factors predicting a pathologically node negative status after neoadjuvant chemotherapy (NAC) with or without trastuzumab in HER2-positive breast cancer. Methods Patients with HER2-positive, stage IIa-IIIc breast cancer were enrolled. Axillary status was evaluated by palpation and fine needle aspiration (FNA) before NAC. All patients received 4–6 cycles of PCrb (paclitaxel 80 mg/m2 and carboplatin AUC = 2 d1, 8, and 15 of a 28-day cycle, or paclitaxel 175 mg/m2 and carboplatin AUC = 6 every-3-week) and were non-randomly administered trastuzumab (2 mg/kg weekly or 6 mg/kg every-3-week) or not. After NAC, each patient underwent standard axillary lymph node dissection and breast-conserving surgery or mastectomy. And some patients received sentinel lymph node biopsy (SLNB) before axillary dissection. Results Between November-2007 and June-2013, 255 patients were enrolled. Of them, 157 were confirmed as axillary node positive by FNA (group-A) and 98 as axillary node negative either by FNA or impalpable (group-B). After axillary dissection, the overall pathologically node negative rates (pNNR) were 52.9% in group-A and 69.4% in group-B. The ER-poor/HER2-positive subtype acquired the highest pNNR (79.6% in group-A and 87.9% in group-B, respectively) and the lowest rate of residual with ≥4 nodes involvement (1.9% and 3%, respectively) after PCrb plus trastuzumab. In multivariate analysis, trastuzumab added and ER-poor status were independent factors in predicting a higher pNNR in HER2-positive breast cancer. Forty-six tested patients showed that the ER-poor/HER2-positive subtype acquired a considerable high pNNR and axillary status with SLNB was well macthed with the axillary dissection. Conclusions ER-poor/HER2-positive subtype of breast cancer is a potential candidate for undergoing sentinel lymph node biopsy instead of regional node dissection for accurate axillary

  3. Efficacy and safety of trastuzumab combined with chemotherapy for first-line treatment and beyond progression of HER2-overexpressing advanced breast cancer

    PubMed Central

    Shao, Bin; Yan,, Yin; Song, Guohong; Liu, Xiaoran; Wang, Jing; Liang, Xu

    2016-01-01

    Objective To observe the efficacy and safety of trastuzumab combined with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing advanced breast cancer. Methods A total of 90 patients with HER2-overexpressing advanced breast cancer were enrolled in this study. All patients were diagnosed with ductal invasive breast cancer by pathological analysis, and were aged between 31–73 years with a median of 51 years. HER2-positivity was defined as 3(+) staining in immunochemistry or amplification of fluorescence in situ hybridization (FISH, ratio ≥2.0). Trastuzumab was administered in combination with chemotherapy as first-line treatment and beyond progression as a secondline, third-line, and above treatment in 90, 34, 14, and 6 patients, respectively. The chemotherapy regimen was given according to normal clinical practice. The response rate was evaluated every two cycles, and the primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival curves were estimated by using Kaplan-Meier graphs and were compared by using log-rank test statistics. Multivariate analysis was done using Cox’s proportional hazards regression model, and the level of significance was P<0.05. Results All 90 patients received at least one dose of trastuzumab, and efficacy could be evaluated in 85 patients. The median follow-up was 50 months. In total, 72 (80.00%) patients had visceral metastasis, and 43 (47.78%) patients had progressed after one or more extensive chemotherapy regimens for metastatic diseases. The median PFS for first-line trastuzumab was 10 months (range, 2–59 months), and the median OS after metastasis or initially local advanced disease was 22 months (range, 2–116 months). Conclusions Trastuzumab combined with chemotherapy was active and well-tolerated as a first-line treatment and even beyond progression in HER2-overexpressing advanced breast cancer as a second-line or third-line treatment. However, its

  4. Adjuvant chemotherapy in early breast cancer.

    PubMed

    Ejlertsen, Bent

    2016-05-01

    these CMF regimens has not been compared within the context of a randomised trial. Shifting from the 77B's classic CMF regimen to the 82B four-weekly IV regimen or the 89B three-weekly IV regimen was associated with a 30% increased risk of a DFS event in a multivariate analysis of a population-based cohort study. Furthermore, the four-weekly regimen used in 82B was associated with a 40% increase in mortality. The strengths of the design include identical selection criteria, uniform and prospective registration of treatment, tumour and patient characteristics. Caution is still required due to the non-experimental design of the comparison. Another finding was a substantial difference in the risk of amenorrhoea; and while 15% of patients aged 40 or younger in 77B had regular menses throughout chemotherapy, the corresponding percentage was 37 in 82B and 47 in 89B. The DBCG in collaboration with a Swedish and a Dutch centre participating in the DBCG trial 89B compared CMF with ovarian ablation in premenopausal high-risk breast cancer patients with ER-positive tumours. No significant differences were found in DFS or OS in the preplanned analysis, suggesting that the benefits of CMF may, at least in part, be explained by ovarian suppression in premenopausal patients with ER-positive tumours. However, these results are not clinically useful by themselves as other chemotherapy regimens have been more efficacious, and knowledge is still lacking regarding the benefits from adding ovarian suppression to chemotherapy plus tamoxifen. The results from the DBCG 77B and 82C are in accordance with other large adjuvant trials and the EBCTCG meta-analyses. The benefits obtained with any individual anticancer drug are largely determined by the cancer (somatic) genome; and by being a molecular target of anthracyclines, TOP2A aberrations could obviously be associated with cancer drug benefits. In the DBCG 89D, a significant heterogeneity was observed between a beneficial effect on DFS and OS

  5. [A case of effective trastuzumab plus gemcitabine therapy for human epidermal growth factor receptor 2-positive breast cancer].

    PubMed

    Yabe, Nobushige; Murai, Shinji; Shimizu, Hirotomo; Kitasato, Kenjiro; Yoshikawa, Takahisa; Oto, Ippei; Nakadai, Junpei; Jinno, Hiromitsu; Kitagawa, Yuko

    2013-11-01

    A 71-year-old postmenopausal woman was undergoing treatment for depression. She visited the hospital with a chief complaint of fibrosclerosis of the entire left breast 8 years previously. She was diagnosed as having stage IV( T3N1M1b) left breast cancer (papillotubular>scirrhous carcinoma, g+, f+, estrogen receptor [ER]-negative, progesterone receptor [PgR]-negative, and human epidermal growth factor receptor 2[ HER2/neu]-positive[ 3+]). Synchronous bone metastases were detected in the left tenth rib, the eleventh dorsal vertebra, and in the area spanning the lower lumbar to sacral vertebrae. First-line treatment was systemic therapy with 4 cycles of Adriamycin and cyclophosphamide (AC) followed by 4 cycles of trastuzumab and paclitaxel. The breast mass initially observed on clinical imaging disappeared and only calcifications were observed. Bone metastases were detected only in the left tenth rib. As an additional therapy, 3-dimensional radiotherapy( 50 Gy/25 fractions), which irradiated the left mammary gland, axilla, and supraclavicular fossa, was administered. The tumor was well controlled for approximately 3 years. However, a gradual increase in the level of carcinoembryonic antigen( CEA) was accompanied by an increase in the left breast mass and enlargement of left axillary lymph nodes. Modified radical mastectomy (Bt+Ax [level I]) was performed for this condition 3 years ago. Papillotubular-type invasive ductal carcinoma (INF β, ly3, v0, g+, f+, s+, nuclear grade 3 [atypia 3+mitosis 3]) was diagnosed histopathologically. Lymph node metastases were also detected. As histopathological examination of the bone metastatic lesion showed no progression, administration of lapatinib and capecitabine was initiated. After 15 cycles of treatment, enlarged right axillary lymph nodes were observed and local excision was performed. Histopathological examination revealed recurrence of the breast cancer. The patient was diagnosed as having grade 3( atypia 3, mitosis 2

  6. Adjuvant therapy for gastric cancer: Current and future directions

    PubMed Central

    Foo, Marcus; Leong, Trevor

    2014-01-01

    The management of gastric cancer continues to evolve. Whilst surgery alone is effective when tumours present early, a large proportion of patients are diagnosed with loco-regionally advanced disease, resulting in high loco-regional and distant relapse rates, with subsequent poor survival. Early attempts at improving outcomes following resection were disappointing; however, randomized trials have now established either post-operative chemoradiotherapy (INT0116) or peri-operative chemotherapy as standard adjuvant therapies in the Western world. There remain, however, significant differences in the approach to management between the West and East. In Asia, where there is the highest incidence of gastric cancer, extended resection followed by adjuvant chemotherapy represents the standard of care. This review discusses current standard adjuvant therapy in gastric adenocarcinoma, as well as recent and ongoing trials investigating novel (neo)adjuvant approaches, which hope to build on the successes of previous studies. PMID:25320509

  7. Adjuvants and Inactivated Polio Vaccine: A Systematic Review

    PubMed Central

    Hawken, Jennifer; Troy, Stephanie B.

    2012-01-01

    Poliomyelitis is nearing universal eradication; in 2011, there were 650 cases reported globally. When wild polio is eradicated, global oral polio vaccine (OPV) cessation followed by universal use of inactivated polio vaccine (IPV) is believed to be the safest vaccination strategy as IPV does not mutate or run the risk of vaccine derived outbreaks that OPV does. However, IPV is significantly more expensive than OPV. One strategy to make IPV more affordable is to reduce the dose by adding adjuvants, compounds that augment the immune response to the vaccine. No adjuvants are currently utilized in stand-alone IPV; however, several have been explored over the past six decades. From aluminum, used in many licensed vaccines, to newer and more experimental adjuvants such as synthetic DNA, a diverse group of compounds has been assessed with varying strengths and weaknesses. This review summarizes the studies to date evaluating the efficacy and safety of adjuvants used with IPV. PMID:23041122

  8. Activity of glycated chitosan and other adjuvants to PDT vaccines

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Banáth, Judit; Čiplys, Evaldas; Szulc, Zdzislaw; Bielawska, Alicja; Chen, Wei R.

    2015-03-01

    Glycated chitosan (GC), a water soluble galactose-conjugated natural polysaccharide, has proven to be an effective immunoadjuvant for treatment of tumors based on laser thermal therapy. It was also shown to act as adjuvant for tumor therapy with high-intensity ultrasound and in situ photodynamic therapy (PDT). In the present study, GC was examined as potential adjuvant to PDT-generated cancer vaccine. Two other agents, pure calreticulin protein and acid ceramidase inhibitor LCL521, were also tested as prospective adjuvants for use in conjunction with PDT vaccines. Single treatment with GC, included with PDT vaccine cells suspension, improved the therapeutic efficacy when compared to vaccine alone. This attractive prospect of GC application remains to be carefully optimized and mechanistically elucidated. Both calreticulin and LCL521 proved also effective adjuvants when combined with PDT vaccine tumor treatment.

  9. Postoperative adjuvant radiotherapy for patients with gastric adenocarcinoma.

    PubMed

    Lim, Do Hoon

    2012-12-01

    In gastric adenocarcinoma, high rates of loco-regional recurrences have been reported even after complete resection, and various studies have been tried to find the role of postoperative adjuvant therapy. Among them, Intergroup 0116 trial was a landmark trial, and demonstrated the definite survival benefit in adjuvant chemoradiotherapy, compared with surgery alone. However, the INT 0116 trial had major limitation for global acceptance of the INT 0116 regimen as an adjuvant treatment modality because of the limited lymph node dissection. Lately, several randomized studies that were performed to patients with D2-dissected gastric cancer were published. This review summarizes the data about patterns of failure after surgical resection and the earlier prospective studies, including INT 0116 study. Author will introduce the latest studies, including ARTIST trial and discuss whether external beam radiotherapy should be applied to patients receiving extended lymph node dissection and adjuvant chemotherapy. PMID:23346491

  10. Cytotoxic T cell adjuvant effects of three Salmonella enterica flagellins

    PubMed Central

    Braga, Catarina J.M.; Massis, Liliana M.; Alencar, Bruna C.G.; Rodrigues, Maurício M.; Sbrogio-Almeida, M.E.; Ferreira, Luís C.S.

    2008-01-01

    Bacterial flagellins are important virulence-associated factors and strong inducers of inflammatory responses in mammalian hosts. Flagellins have also been investigated as potential vaccine adjuvants, either for induction of humoral or cellular immune responses, to different target antigens. In this study we investigated the adjuvant properties of three Salmonella enterica flagellins types (FliCd, FliCi and FljB) to an ovalbumin-derived CD8+ T cell-restricted epitope (OVA257–264). Although mice immunized with the three tested flagellins elicited antigen-specific activated CD8+ T cells, only animals immunized with FliCi and FliCd flagellins admixed with ovalbumin mounted specific in vivo cytotoxic responses to peptide-pulsed target cells. The present results indicate that Salmonella flagellins are endowed with type-specific adjuvant effects toward murine CD8+ T cells, a feature that may impact their use as adjuvants for prophylatic or therapeutic vaccines. PMID:24031176

  11. Learning Impairment in Honey Bees Caused by Agricultural Spray Adjuvants

    PubMed Central

    Ciarlo, Timothy J.; Mullin, Christopher A.; Frazier, James L.; Schmehl, Daniel R.

    2012-01-01

    Background Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s). The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. Methodology/Principal Findings An improved, automated version of the proboscis extension reflex (PER) assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants) were investigated in this study. Learning was impaired after ingestion of 20 µg organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. Conclusions/Significance A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many social interactions

  12. Roles of adjuvant and salvage radiotherapy for desmoplastic melanoma.

    PubMed

    Oliver, Daniel E; Patel, Kirtesh R; Switchenko, Jeffrey; Parker, Douglas; Lawson, David H; Delman, Keith A; Kudchadkar, Ragini R; Khan, Mohammad K

    2016-02-01

    Current guidelines are unclear as to the precise role of radiotherapy (RT) in patients with desmoplastic melanoma (DM). The purpose of this study was to evaluate our institutional outcomes in patients with DM, and to explore the roles of both adjuvant and salvage RT in these patients. We identified 100 patients with a histopathologic diagnosis of DM who received treatment at our institution from 2000 to 2014. Local control, distant metastasis-free survival, and overall survival (OS) were evaluated in the 95 patients managed surgically with or without adjuvant and/or salvage RT. The overall rate of local recurrence (LR) was 10%. There was no LR in either adjuvant or salvage RT cohort. Adjuvant RT did not significantly improve LR-free survival at 5 years (100 vs. 81%, P=0.59), despite the RT patients having worse pathological features. Four of seven (57%) salvage patients developed distant metastases, despite 100% local control. Adjuvant RT did not significantly impact 5-year overall survival (86 vs. 82%, P=0.43). RT shows a trend towards improved local control in both the adjuvant and salvage settings for patients with DM, and likely overcomes adverse risk factors after surgery in appropriately selected patients. Future prospective studies are needed to better address the optimal management for these patients. PMID:26397051

  13. Roles of adjuvant and salvage radiotherapy for desmoplastic melanoma

    PubMed Central

    Oliver, Daniel E.; Patel, Kirtesh R.; Switchenko, Jeffrey; Parker, Douglas; Lawson, David H.; Delman, Keith A.; Kudchadkar, Ragini R.; Khan, Mohammad K.

    2016-01-01

    Current guidelines are unclear as to the precise role of radiotherapy (RT) in patients with desmoplastic melanoma (DM). The purpose of this study was to evaluate our institutional outcomes in patients with DM, and to explore the roles of both adjuvant and salvage RT in these patients. We identified 100 patients with a histopathologic diagnosis of DM who received treatment at our institution from 2000 to 2014. Local control, distant metastasis-free survival, and overall survival (OS) were evaluated in the 95 patients managed surgically with or without adjuvant and/or salvage RT. The overall rate of local recurrence (LR) was 10%. There was no LR in either adjuvant or salvage RT cohort. Adjuvant RT did not significantly improve LR-free survival at 5 years (100 vs. 81%, P = 0.59), despite the RTpatients having worse pathological features. Four of seven (57%) salvage patients developed distant metastases, despite 100% local control. Adjuvant RT did not significantly impact 5-year overall survival (86 vs. 82%, P = 0.43). RT shows a trend towards improved local control in both the adjuvant and salvage settings for patients with DM, and likely overcomes adverse risk factors after surgery in appropriately selected patients. Future prospective studies are needed to better address the optimal management for these patients. PMID:26397051

  14. Chitosan-based mucosal adjuvants: Sunrise on the ocean.

    PubMed

    Xia, Yufei; Fan, Qingze; Hao, Dongxia; Wu, Jie; Ma, Guanghui; Su, Zhiguo

    2015-11-01

    Mucosal vaccination, which is shown to elicit systemic and mucosal immune responses, serves as a non-invasive and convenient alternative to parenteral administration, with stronger capability in combatting diseases at the site of entry. The exploration of potent mucosal adjuvants is emerging as a significant area, based on the continued necessity to amplify the immune responses to a wide array of antigens that are poorly immunogenic at the mucosal sites. As one of the inspirations from the ocean, chitosan-based mucosal adjuvants have been developed with unique advantages, such as, ability of mucosal adhesion, distinct trait of opening the junctions to allow the paracellular transport of antigen, good tolerability and biocompatibility, which guaranteed the great potential in capitalizing on their application in human clinical trials. In this review, the state of art of chitosan and its derivatives as mucosal adjuvants, including thermo-sensitive chitosan system as mucosal adjuvant that were newly developed by author's group, was described, as well as the clinical application perspective. After a brief introduction of mucosal adjuvants, chitosan and its derivatives as robust immune potentiator were discussed in detail and depth, in regard to the metabolism, safety profile, mode of actions and preclinical and clinical applications, which may shed light on the massive clinical application of chitosan as mucosal adjuvant. PMID:26271831

  15. Adjuvant therapy for ampullary carcinomas: The Mayo Clinic experience

    SciTech Connect

    Bhatia, Sumita; Miller, Robert C. . E-mail: miller.robert@mayo.edu; Haddock, Michael G.; Donohue, John H.; Krishnan, Sunil

    2006-10-01

    Purpose: To determine the effects of adjuvant radiotherapy and chemotherapy for carcinoma of the ampulla of Vater. Methods and Materials: We retrospectively reviewed the records of 125 patients who underwent definitive surgery for carcinomas involving the ampulla of Vater between April 1977 and February 2005 and who survived more than 50 days after surgery. Twenty-nine of the patients also received adjuvant radiotherapy (median dose, 50.4 Gy in 28 fractions) with concurrent 5-fluorouracil chemotherapy. Adverse prognostic factors were investigated, and overall survival (OS) and local and distant failure were estimated. Results: Adverse prognostic factors for decreased OS by univariate analysis included lymph node (LN) involvement, locally advanced tumors (T3/T4), and poor histologic grade. By multivariate analysis, positive LN status (p = 0.02) alone was associated with decreased OS. The addition of adjuvant radiotherapy and chemotherapy improved OS for patients with positive LN (p = 0.01). Median survival for positive LN patients receiving adjuvant therapy was 3.4 years, vs. 1.6 years for those with surgery alone. Conclusions: The addition of adjuvant radiotherapy and 5-fluorouracil chemotherapy may improve OS in patients with LN involvement. The effect of adjuvant therapy on outcomes for patients with poor histologic grade or T3/T4 tumors without LN involvement could not be assessed.

  16. Communicating the role and value of vaccine adjuvants.

    PubMed

    Gellin, Bruce G; Salisbury, David M

    2015-06-01

    Despite the inclusion of adjuvants in many routinely used vaccines to improve the immune response, their presence and role are neither clear in product details such as the packaging or in the Summaries of Product Characteristics, nor understood by health professionals or the public. For many vaccines the adjuvant may simply be described as 'Adsorbed' without clarification that the adsorbing onto a material such as aluminium hydroxide adjuvants the antigens. As many future vaccines are likely to be adjuvanted, the presence of adjuvants, either those used in existing vaccines or novel formulations, may raise public and professional concerns unless communication materials are prepared in advance to allay anxieties such as those that have arisen over some present vaccine ingredients such as thiomersal. This raises a dilemma about how active such communications should be: over-promotion of the presence of a new adjuvant may cause unneeded anxieties; under-promotion may raise concerns over concealment of information. Research is needed and appropriate communication materials should be prepared. PMID:26022567

  17. Adjuvant postoperative radiation therapy for colonic carcinoma.

    PubMed Central

    Willett, C G; Tepper, J E; Skates, S J; Wood, W C; Orlow, E C; Duttenhaver, J R

    1987-01-01

    One hundred thirty-three patients with Stage B2, B3, and C colonic carcinoma had resection for curative intent followed by adjuvant postoperative radiotherapy to the tumor bed. The 5-year actuarial local control and disease-free survival rates for these 133 patients were 82% and 61%, respectively. Stage for stage, the development of local regional failure was reduced for patients receiving postoperative radiotherapy compared with a historic control series. Local recurrence occurred in 8%, 21%, and 31% of patients with Stage B3, C2, and C3 tumors who had radiation therapy, respectively, whereas the local failure rates were 31%, 36%, and 53% in patients treated with surgery alone. There was a 13% and 12% improvement in the 5-year disease-free survival rate in the patients with Stage B3 and C3 lesions who had radiotherapy compared with the historic controls. For patients with Stage C disease, local control and disease-free survival rates decreased progressively with increasing nodal involvement; however, local control and disease-free survival rates were higher in the patients who had radiotherapy than in those who had surgery alone. Failure patterns in the patients who had radiotherapy did not show any notable changes compared with those for patients who had surgery alone. Postoperative radiation therapy for Stage B3, C2, and C3 colonic carcinoma is a promising treatment approach that deserves further investigation. PMID:3689006

  18. Cost-effectiveness of trastuzumab in metastatic breast cancer: mainly a matter of price in the EU?

    PubMed

    Garattini, Livio; van de Vooren, Katelijne; Curto, Alessandro

    2015-02-01

    Trastuzumab (TR), a monoclonal antibody approved by EMA in 2000 and one of the first examples of "targeted therapy", is indicated to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. TR, whose patent will expire in 2015 in Europe, has been judged positively for reimbursement by most public authorities in the EU. Here we critically review the existing evidence on TR in metastatic breast cancer (MBC), in line with the multidisciplinary health technology assessment (HTA) approach, to assess whether the existing evidence supports TR positive reimbursement decisions taken in MBC by EU health authorities. We did a literature search for the main HTA topics (efficacy, quality of life and ethics) on the PubMed international database (2000-2013). Then, we did a specific literature search to select the full economic evaluations (FEEs) conducted in EU countries focused on TR as first-line innovative therapy in MBC. We retrieved scant evidence in the literature to support TR reimbursement in MBC. We found only two clinical trials and their results were unclear because of the large proportion of patients who crossed over. Moreover, the quality of methods was poor in all four European FEEs selected. This example of HTA exercise on a mature monoclonal antibody in a specific indication casts doubts on how often the reimbursement decisions taken by EU health authorities in emotional pathologies like cancer are rational. These decisions should at least be reconsidered periodically on the basis of the latest evidence. PMID:25523144

  19. Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

    PubMed Central

    Kulhari, Hitesh; Pooja, Deep; Shrivastava, Shweta; Kuncha, Madhusudana; Naidu, V. G. M.; Bansal, Vipul; Sistla, Ramakrishna; Adams, David J.

    2016-01-01

    Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem. PMID:27052896

  20. Purification of the therapeutic antibody trastuzumab from genetically modified plants using safflower Protein A-oleosin oilbody technology.

    PubMed

    McLean, Michael D; Chen, Rongji; Yu, Deqiang; Mah, Kor-Zheng; Teat, John; Wang, Haifeng; Zaplachinski, Steve; Boothe, Joseph; Hall, J Christopher

    2012-12-01

    Production of therapeutic monoclonal antibodies using genetically modified plants may provide low cost, high scalability and product safety; however, antibody purification from plants presents a challenge due to the large quantities of biomass that need to be processed. Protein A column chromatography is widely used in the pharmaceutical industry for antibody purification, but its application is limited by cost, scalability and column fouling problems when purifying plant-derived antibodies. Protein A-oleosin oilbodies (Protein A-OB), expressed in transgenic safflower seeds, are relatively inexpensive to produce and provide a new approach for the capture of monoclonal antibodies from plants. When Protein A-OB is mixed with crude extracts from plants engineered to express therapeutic antibodies, the Protein A-OB captures the antibody in the oilbody phase while impurities remain in the aqueous phase. This is followed by repeated partitioning of oilbody phase against an aqueous phase via centrifugation to remove impurities before purified antibody is eluted from the oilbodies. We have developed this purification process to recover trastuzumab, an anti-HER2 monoclonal antibody used for therapy against specific breast-cancers that over express HER2 (human epidermal growth factor receptor 2), from transiently infected Nicotiana benthamiana. Protein A-OB overcomes the fouling problem associated with traditional Protein A chromatography, allowing for the development of an inexpensive, scalable and novel high-resolution method for the capture of antibodies based on simple mixing and phase separation. PMID:22382463

  1. Serum level of hepatocyte growth factor is a novel marker of predicting the outcome and resistance to the treatment with trastuzumab in HER2-positive patients with metastatic gastric cancer

    PubMed Central

    Takahashi, Naoki; Furuta, Koh; Taniguchi, Hirokazu; Sasaki, Yusuke; Shoji, Hirokazu; Honma, Yoshitaka; Iwasa, Satoru; Okita, Natsuko; Takashima, Atsuo; Kato, Ken; Hamaguchi, Tetsuya; Shimada, Yasuhiro; Yamada, Yasuhide

    2016-01-01

    HER2-overexpression in tumor tissue is observed in 6 to 23% of advanced gastric cancer (GC) cases, and trastuzumab is an active molecular drug for these patients. There are no data available on whether serum levels of ligands are associated with the response and resistance to trastuzumab in HER2-positive patients with metastatic GC. HER2 screening of 502 patients with advanced gastric cancer was performed in our institution. Among these patients, 84 patients (16.8%) were diagnosed as HER2-positive, and those who were treated with trastuzumab and met the inclusion criteria were enrolled in the present study. Serum levels of ligands that affect the HER2 signal pathway were measured by an enzyme-linked immunosorbent assay. Forty-six HER2-positive patients were enrolled in this study, and 26 patients (56.5%) achieved a partial response to treatment with trastuzumab. Among several ligands, the serum level of hepatocyte growth factor (HGF) was significantly lower in responders compared with that in non-responders (p = 0.014). Multivariate analyses showed that a high level of serum HGF was a poor prognostic factor for overall survival (OS) compared with low levels of HGF (adjusted HR: 3.857, 95% CI: 1.309–11.361, p = 0.014). Among 25 patients without initial disease progression on the treatment with trastuzumab, the mean value of serum HGF at disease progression was significantly higher than that at pre-treatment (p = 0.041). As novel findings, our study indicated that serum level of HGF was associated with tumor shrinkage and time to progression of trastuzumab in HER2-positive patients with metastatic GC. PMID:26716644

  2. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines

    PubMed Central

    Savelkoul, Huub F. J.; Ferro, Valerie A.; Strioga, Marius M.; Schijns, Virgil E. J. C.

    2015-01-01

    The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines. PMID:26344951

  3. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines.

    PubMed

    Savelkoul, Huub F J; Ferro, Valerie A; Strioga, Marius M; Schijns, Virgil E J C

    2015-01-01

    The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines. PMID:26344951

  4. Altered S-nitrosothiol homeostasis provides a survival advantage to breast cancer cells in HER2 tumors and reduces their sensitivity to trastuzumab.

    PubMed

    Cañas, Amanda; López-Sánchez, Laura M; Peñarando, Jon; Valverde, Araceli; Conde, Francisco; Hernández, Vanessa; Fuentes, Elena; López-Pedrera, Chary; de la Haba-Rodríguez, Juan R; Aranda, Enrique; Rodríguez-Ariza, Antonio

    2016-04-01

    The monoclonal antibody trastuzumab against HER2/neu, which is overexpressed in 15-20% of breast cancers, has clinical efficacy but many patients do not respond to initial treatment or develop resistance during treatment. Nitric oxide (NO) regulates cell signaling by targeting specific cysteine residues in proteins, forming S-nitrosothiols (SNO) in a process known as S-nitrosylation. We previously reported that molecular characteristics in breast cancer may dictate the tumor response to impaired SNO homeostasis. In the present study, we explored the role of SNO homeostasis in HER2 breast tumors. The antiproliferative action of trastuzumab in HER2-overexpressing BT-474 and SKBR-3 cells was suppressed when S-nitrosoglutathione reductase (GSNOR/ADH5) activity, which plays a key role in SNO homeostasis, was specifically inhibited with the pyrrole derivative compound N6022. Moreover, GSNOR inhibition restored the activation of survival signaling pathways involved in the resistance to anti-HER2 therapies (AKT, Src and c-Abl kinases and TrkA/NRTK1, TrkB/NRTK2, EphA1 and EphA3 receptors) and reduced the apoptotic effect of trastuzumab. Accordingly, GSNOR inhibition augmented the S-nitrosylation of apoptosis-related proteins, including Apaf-1, pSer73/63 c-Jun, calcineurin subunit α and HSF1. In agreement with in vitro data, immunohistochemical analyses of 51 breast tumors showed that HER2 expression was associated with lower expression of GSNOR protein. Moreover, gene expression analysis confirmed that high ADH5/GSNOR gene expression was associated with high patient survival rates in HER2 tumors. In conclusion, our data provide evidence of molecular mechanisms contributing to the progression of HER2+ breast cancers and could facilitate the development of therapeutic options to counteract resistance to anti-HER2 therapies. PMID:26854735

  5. The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells

    PubMed Central

    Koziel, Jillian E.; Herbert, Brittney-Shea

    2015-01-01

    Purpose Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2+ breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2+ breast cancer cell lines. Methods The effects of imetelstat on CSC populations of HER2+ breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Results Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting imetelstat acts on the CSC subpopulation in telomere length independent and dependent mechanisms. Conclusions Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population. PMID:25627551

  6. The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells.

    PubMed

    Koziel, Jillian E; Herbert, Brittney-Shea

    2015-02-01

    Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2(+) breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. The effects of imetelstat on CSC populations of HER2(+) breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population. PMID:25627551

  7. Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells

    PubMed Central

    Ravacci, Graziela Rosa; Brentani, Maria Mitzi; Tortelli, Tharcisio Citrângulo; Torrinhas, Raquel Suzana M. M.; Santos, Jéssica Reis; Logullo, Angela Flávia; Waitzberg, Dan Linetzky

    2015-01-01

    In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of “de novo” FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA. PMID:26640797

  8. Monitor Therapeutic Response of Human Ovarian Cancer to 17-DMAG by Non-invasive PET imaging with 64Cu-DOTA-Trastuzumab

    PubMed Central

    Niu, Gang; Li, Zibo; Cao, Qizhen; Chen, Xiaoyuan

    2012-01-01

    Purposes 17-DMAG, a heat shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to non-invasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice. Methods The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression of SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using 64Cu-DOTA-trastuzumab and 18F-FDG. Biodistribution studies, immunofluorescence staining were performed to validate the microPET results. Results SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose dependent manner, with an IC50 value of 68.7 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that 64Cu-DOTA-trastuzumab had prominent tumor activity accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment. Conclusion The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using 64Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment. PMID:19440708

  9. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments.

    PubMed

    Loganzo, Frank; Tan, Xingzhi; Sung, Matthew; Jin, Guixian; Myers, Jeremy S; Melamud, Eugene; Wang, Fang; Diesl, Veronica; Follettie, Maximillian T; Musto, Sylvia; Lam, My-Hanh; Hu, William; Charati, Manoj B; Khandke, Kiran; Kim, Kenny Sung Kyoo; Cinque, Mike; Lucas, Judy; Graziani, Edmund; Maderna, Andreas; O'Donnell, Christopher J; Arndt, Kim T; Gerber, Hans-Peter

    2015-04-01

    Antibody-drug conjugates (ADC) are emerging as clinically effective therapy. We hypothesized that cancers treated with ADCs would acquire resistance mechanisms unique to immunoconjugate therapy and that changing ADC components may overcome resistance. Breast cancer cell lines were exposed to multiple cycles of anti-Her2 trastuzumab-maytansinoid ADC (TM-ADC) at IC80 concentrations followed by recovery. The resistant cells, 361-TM and JIMT1-TM, were characterized by cytotoxicity, proteomic, transcriptional, and other profiling. Approximately 250-fold resistance to TM-ADC developed in 361-TM cells, and cross-resistance was observed to other non-cleavable-linked ADCs. Strikingly, these 361-TM cells retained sensitivity to ADCs containing cleavable mcValCitPABC-linked auristatins. In JIMT1-TM cells, 16-fold resistance to TM-ADC developed, with cross-resistance to other trastuzumab-ADCs. Both 361-TM and JIMT1-TM cells showed minimal resistance to unconjugated mertansine (DM1) and other chemotherapeutics. Proteomics and immunoblots detected increased ABCC1 (MRP1) drug efflux protein in 361-TM cells, and decreased Her2 (ErbB2) in JIMT1-TM cells. Proteomics also showed alterations in various pathways upon chronic exposure to the drug in both cell models. Tumors derived from 361-TM cells grew in mice and were refractory to TM-ADC compared with parental cells. Hence, acquired resistance to trastuzumab-maytansinoid ADC was generated in cultured cancer cells by chronic drug treatment, and either increased ABCC1 protein or reduced Her2 antigen were primary mediators of resistance. These ADC-resistant cell models retain sensitivity to other ADCs or standard-of-care chemotherapeutics, suggesting that alternate therapies may overcome acquired ADC resistance. Mol Cancer Ther; 14(4); 952-63. ©2015 AACR. PMID:25646013

  10. Clinicopathological characteristics of patients with HER2-positive breast cancer and the efficacy of trastuzumab in the People’s Republic of China

    PubMed Central

    Zhou, Ping; Jiang, Yi-Zhou; Hu, Xin; Sun, Wei; Liu, Yi-Rong; Liu, Fang; Luo, Rong-Cheng; Shao, Zhi-Ming

    2016-01-01

    Objective The aim of this study was to describe the clinical features and outcomes of Chinese patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Method The clinical data and survival statuses of 732 patients with operable HER2-positive breast cancer who were treated at the Department of Breast Surgery of the Shanghai Cancer Center from January 1, 2007, to December 31, 2011, were collected. The patients were divided into two groups according to treatment with and without trastuzumab. Disease-free survival (DFS) and overall survival were calculated using the Kaplan–Meier method and log-rank test. The associations of the patient characteristics with prognosis were analyzed via Cox regression. Results A total of 732 women with HER2-positive breast cancer were included in this study, among whom 258 (35.2%) received trastuzumab. The median follow-up duration was 41 months. By the end of the follow-up period, 86 (12%) women experienced local recurrence or metastasis. Patients who received both anti-HER2 therapy and chemotherapy exhibited a longer DFS than those who received chemotherapy alone (P=0.001). Tumor size, lymph node status, and family history of breast cancer were associated with median DFS, and tumor size, lymph node status, clinical stage, age, and body mass index were associated with median overall survival. Patients who received both neoadjuvant chemotherapy and trastuzumab exhibited a higher rate of pathological complete remission. In the neoadjuvant group, the patients who received both anti-HER2 therapy and chemotherapy exhibited a longer DFS than those who received chemotherapy alone (P=0.049). Conclusion Significant clinical features were observed in the Chinese patients with HER2-positive breast cancer. Furthermore, targeted anti-HER2 therapy may improve the prognosis of these patients. PMID:27143924

  11. Paclitaxel and Trastuzumab as Maintenance Therapy in Patients with HER2-Positive Metastatic Breast Cancer Who Underwent High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation.

    PubMed

    Cheng, Yee Chung; Rondón, Gabriela; Anderlini, Paolo; Khouri, Issa F; Champlin, Richard E; Ueno, Naoto T

    2013-01-01

    We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (AHST) for patients with HER2-positive metastatic breast cancer. Ten patients (9 women and 1 man) were enrolled in the study. The median age was 46.5 years (range, 27-65 years). The median follow-up time was 1003 days (range, 216-2526 days). All patients had metastatic disease, but 2 had only bone metastasis. One patient had complete response, 6 had partial response and 3 had stable disease to the standard-dose chemotherapy prior to transplantation. The conditioning regimen consisted of cyclophosphamide, carmustine, and thiotepa. After AHST, patients received weekly paclitaxel for 12 doses and trastuzumab every 3 weeks for 1 year as maintenance therapy. All patients experienced successful engraftment. The only grade 4 toxic effects observed were leukopenia and thrombocytopenia. The most common grade 3 toxic effect was neutropenic fever. No treatment-related deaths were observed. The median progression-free survival time was 441 days, and the median overall survival time was 955 days. Two patients died in accidents while their disease remained in remission. Five patients died with disease progression. At the time of this report, 3 patients are alive with stable disease, 1 of whom has remained free of disease progression for 2526 days since transplantation. Our findings indicate that paclitaxel plus trastuzumab as maintenance therapy after HDC with AHST for patients with HER2-positive metastatic breast cancer not only is feasible and safe but also results in survival outcomes similar to historical results. PMID:24155780

  12. Predictive markers of safety and immunogenicity of adjuvanted vaccines.

    PubMed

    Mastelic, Beatris; Garçon, Nathalie; Del Giudice, Giuseppe; Golding, Hana; Gruber, Marion; Neels, Pieter; Fritzell, Bernard

    2013-11-01

    Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/. PMID:24071553

  13. Role of Adjuvant Chemoradiotherapy for Resected Extrahepatic Biliary Tract Cancer

    SciTech Connect

    Kim, Tae Hyun; Han, Sung-Sik; Park, Sang-Jae Lee, Woo Jin; Woo, Sang Myung; Moon, Sung Ho; Yoo, Tae; Kim, Sang Soo; Kim, Seong Hoon; Hong, Eun Kyung; Kim, Dae Yong; Park, Joong-Won

    2011-12-01

    Purpose: To evaluate the effect of adjuvant chemoradiotherapy (CRT) on locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) for patients with extrahepatic biliary tract cancer treated with curative resection. Methods and Materials: The study involved 168 patients with extrahepatic biliary tract cancer undergoing curative resection between August 2001 and April 2009. Of the 168 patients, 115 received adjuvant CRT (CRT group) and 53 did not (no-CRT group). Gender, age, tumor size, histologic differentiation, pre- and postoperative carbohydrate antigen 19-9 level, resection margin, vascular invasion, perineural invasion, T stage, N stage, overall stage, and the use of adjuvant CRT were analyzed to identify the prognostic factors associated with LRC, DFS, and OS. Results: For all patients, the 5-year LRC, DFS, and OS rate was 54.8%, 30.6%, and 33.9%, respectively. On univariate analysis, the 5-year LRC, DFS, and OS rates in the CRT group were significantly better than those in the no-CRT group (58.5% vs. 44.4%, p = .007; 32.1% vs. 26.1%, p = .041; 36.5% vs. 28.2%, p = .049, respectively). Multivariate analysis revealed that adjuvant CRT was a significant independent prognostic factor for LRC, DFS, and OS (p < .05). Conclusion: Our results have suggested that adjuvant CRT helps achieve LRC and, consequently, improves DFS and OS in patients with extrahepatic biliary tract cancer.

  14. Adjuvant chemotherapy for gastric cancer: Current evidence and future challenges

    PubMed Central

    Miceli, Rosalba; Tomasello, Gianluca; Bregni, Giacomo; Di Bartolomeo, Maria; Pietrantonio, Filippo

    2014-01-01

    Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e., limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that disease-free survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment. PMID:24782604

  15. Novel adjuvants & delivery vehicles for vaccines development: A road ahead

    PubMed Central

    Mohan, Teena; Verma, Priyanka; Rao, D. Nageswara

    2013-01-01

    The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines. PMID:24434331

  16. Environmental adjuvants, apoptosis and the censorship over autoimmunity.

    PubMed

    Rovere-Querini, Patrizia; Manfredi, Angelo A; Sabbadini, Maria Grazia

    2005-11-01

    Alterations during apoptosis lead to the activation of autoreactive T cells and the production of autoantibodies. This article discusses the pathogenic potential of cells dying in vivo, dissecting the role of signals that favor immune responses (adjuvants) and the influence of genetic backgrounds. Diverse factors determine whether apoptosis leads or not to a self-sustaining, clinically apparent autoimmune disease. The in vivo accumulation of uncleared dying cells per se is not sufficient to cause disease. However, dying cells are antigenic and their complementation with immune adjuvants causes lethal diseases in predisposed lupus-prone animals. At least some adjuvant signals directly target the function and the activation state of antigen presenting cells. Several laboratories are aggressively pursuing the molecular identification of endogenous adjuvants. Sodium monourate and the high mobility group B1 protein (HMGB1) are, among those identified so far, well known to rheumatologists. However, even the complementation of apoptotic cells with potent adjuvant signals fail to cause clinical autoimmunity in most strains: autoantibodies generated are transient, do not undergo to epitope/spreading and do not cause disease. Novel tools for drug development will derive from the molecular identification of the constraints that prevent autoimmunity in normal subjects. PMID:16214095

  17. Novel adjuvants & delivery vehicles for vaccines development: a road ahead.

    PubMed

    Mohan, Teena; Verma, Priyanka; Rao, D Nageswara

    2013-11-01

    The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines. PMID:24434331

  18. Optimizing Adherence to Adjuvant Imatinib in Gastrointestinal Stromal Tumor

    PubMed Central

    Tetzlaff, Eric D.; Davey, Monica P.

    2013-01-01

    The increasing use of patient-administered oral anticancer drugs is paralleled by new challenges in maintaining treatment adherence. These challenges are particularly significant with adjuvant therapies for prevention of disease recurrence, where the benefits of ongoing treatment are not readily apparent to patients. Nurse practitioners and physician assistants (collectively referred to as advanced practitioners) play integral roles in providing education on disease and treatment to patients that can increase adherence to oral therapies and ideally improve outcomes. For patients with gastrointestinal stromal tumor (GIST), the oral targeted therapy imatinib has become the mainstay of treatment for advanced and recurrent disease and as adjuvant therapy following surgical resection. Recent data indicate significantly improved overall survival with 3 years vs. 1 year of adjuvant imatinib therapy. Continuous dosing with imatinib is needed for optimal efficacy and to limit additional health-care costs associated with management of disease progression in GIST. However, longer duration of therapy increases the risk of nonadherence. Imatinib adherence rates, as well as factors contributing to nonadherence to adjuvant therapy in routine clinical practice, are discussed in this review. Also explored are practical approaches for improving adherence to adjuvant imatinib therapy through greater patient education, in light of the increased duration of therapy in select patients. PMID:25032004

  19. Who benefits most from adjuvant interferon treatment for melanoma?

    PubMed

    Gogas, Helen; Abali, Huseyin; Ascierto, Paolo A; Demidov, Lev; Pehamberger, Hubert; Robert, Caroline; Schachter, Jacob; Eggermont, Alexander M M; Hauschild, Axel; Espinosa, Enrique

    2015-01-01

    Metastatic melanoma has a poor prognosis; the median survival for patients with stage IV melanoma ranges from 8 to 18 months after diagnosis. Interferon-α provides significant improvement in disease-free survival at the cost of poor tolerability. Identifying patients who benefit the most may improve the cost:benefit ratio. In addition, no data exist for the role of adjuvant therapy in noncutaneous melanoma. Molecular profiles may help to identify patients who benefit the most from adjuvant interferon therapy. In this review, the American Joint Commission on Cancer 2009 staging criteria and emerging biomarker data to guide adjuvant treatment decisions will be discussed. Several criteria to guide selection of patients are discussed in detail. These include Breslow thickness, number of positive lymph nodes, whether or not the primary lesion has ulcerated, immunologic markers, and cytokine profiles. Substantial progress has been made in deciding which patients benefit from interferon-α adjuvant therapy. Interferon-α is the only agent currently approved for the adjuvant treatment of this deadly disease, despite its side effect profile. More effective drugs with better tolerability are needed. PMID:24176884

  20. Transition probabilities of HER2-positive and HER2-negative breast cancer patients treated with Trastuzumab obtained from a clinical cancer registry dataset

    PubMed Central

    Pobiruchin, Monika; Bochum, Sylvia; Martens, Uwe M.; Kieser, Meinhard; Schramm, Wendelin

    2016-01-01

    Records of female breast cancer patients were selected from a clinical cancer registry and separated into three cohorts according to HER2-status (human epidermal growth factor receptor 2) and treatment with or without Trastuzumab (a humanized monoclonal antibody). Propensity score matching was used to balance the cohorts. Afterwards, documented information about disease events (recurrence of cancer, metastases, remission of local/regional recurrences, remission of metastases and death) found in the dataset was leveraged to calculate the annual transition probabilities for every cohort. PMID:27054173

  1. Transition probabilities of HER2-positive and HER2-negative breast cancer patients treated with Trastuzumab obtained from a clinical cancer registry dataset.

    PubMed

    Pobiruchin, Monika; Bochum, Sylvia; Martens, Uwe M; Kieser, Meinhard; Schramm, Wendelin

    2016-06-01

    Records of female breast cancer patients were selected from a clinical cancer registry and separated into three cohorts according to HER2-status (human epidermal growth factor receptor 2) and treatment with or without Trastuzumab (a humanized monoclonal antibody). Propensity score matching was used to balance the cohorts. Afterwards, documented information about disease events (recurrence of cancer, metastases, remission of local/regional recurrences, remission of metastases and death) found in the dataset was leveraged to calculate the annual transition probabilities for every cohort. PMID:27054173

  2. Overall survival benefit with pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer in CLEOPATRA, a randomised Phase 3 study

    PubMed Central

    Swain, Sandra M.; Kim, Sung-Bae; Cortés, Javier; Ro, Jungsil; Semiglazov, Vladimir; Campone, Mario; Ciruelos, Eva; Ferrero, Jean-Marc; Schneeweiss, Andreas; Knott, Adam; Clark, Emma; Ross, Graham; Benyunes, Mark C.; Baselga, José

    2013-01-01

    Summary Background Primary results from the randomised, double-blind phase 3 study CLEOPATRA demonstrated significantly improved median progression-free survival (PFS) with pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer (MBC). Overall survival (OS) data at the primary analysis showed a strong trend in favour of the pertuzumab arm but did not reach statistical significance. Here we report confirmatory OS results after one additional year of follow-up. Methods Patients were randomly assigned to study treatment. OS and investigator-assessed PFS were analysed using the Kaplan-Meier approach and log-rank tests stratified by geographic region and prior treatment status. This trial is registered with ClinicalTrials.gov, NCT00567190. Findings In the intent-to-treat population (808 patients), 267 deaths had occurred at data cut-off (placebo arm: 154 of 406 [37·9%], pertuzumab arm: 113 of 402 [28·1%]). Treatment with pertuzumab plus trastuzumab plus docetaxel resulted in a 34% reduction in the risk of death during the course of the study (HR=0·66; 95% CI 0·52–0·84; p=0·0008). Median OS was 37·6 months in the placebo arm and was not yet reached in the pertuzumab arm. A descriptive follow-up analysis of investigator-assessed PFS showed a median PFS of 12·4 and 18·7 months in the placebo versus pertuzumab arm (HR=0·69; 95% CI 0·58–0·81). No new safety concerns were identified with one additional year of follow-up. Adverse events were similar to those reported at the primary analysis with respect to incidence, severity, and specificity. Interpretation This OS analysis demonstrated statistically significant and clinically meaningful survival benefit with pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive MBC. Updated analyses of investigator-assessed PFS and safety were consistent with the

  3. Cell Killing Mechanisms and Impact on Gene Expression by Gemcitabine and 212Pb-Trastuzumab Treatment in a Disseminated i.p. Tumor Model

    PubMed Central

    Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2016-01-01

    In pre-clinical studies, combination therapy with gemcitabine and targeted radioimmunotherapy (RIT) using 212Pb-trastuzumab showed tremendous therapeutic potential in the LS-174T tumor xenograft model of disseminated intraperitoneal disease. To better understand the underlying molecular basis for the observed cell killing efficacy, gene expression profiling was performed after a 24 h exposure to 212Pb-trastuzumab upon gemcitabine (Gem) pre-treatment in this model. DNA damage response genes in tumors were quantified using a real time quantitative PCR array (qRT-PCR array) covering 84 genes. The combination of Gem with α-radiation resulted in the differential expression of apoptotic genes (BRCA1, CIDEA, GADD45α, GADD45γ, IP6K3, PCBP4, RAD21, and p73), cell cycle regulatory genes (BRCA1, CHK1, CHK2, FANCG, GADD45α, GTSE1, PCBP4, MAP2K6, NBN, PCBP4, and SESN1), and damaged DNA binding and repair genes (BRCA1, BTG2, DMC1, ERCC1, EXO1, FANCG, FEN1, MSH2, MSH3, NBN, NTHL1, OGG1, PRKDC, RAD18, RAD21, RAD51B, SEMA4G, p73, UNG, XPC, and XRCC2). Of these genes, the expression of CHK1, GTSE1, EXO1, FANCG, RAD18, UNG and XRCC2 were specific to Gem/212Pb-trastuzumab administration. In addition, the present study demonstrates that increased stressful growth arrest conditions induced by Gem/212Pb-trastuzumab could suppress cell proliferation possibly by up-regulating genes involved in apoptosis such as p73, by down-regulating genes involved in cell cycle check point such as CHK1, and in damaged DNA repair such as RAD51 paralogs. These events may be mediated by genes such as BRCA1/MSH2, a member of BARC (BRCA-associated genome surveillance complex). The data suggest that up-regulation of genes involved in apoptosis, perturbation of checkpoint genes, and a failure to correctly perform HR-mediated DSB repair and mismatch-mediated SSB repair may correlate with the previously observed inability to maintain the G2/M arrest, leading to cell death. PMID:27467592

  4. MicroRNA-7 Inhibits Multiple Oncogenic Pathways to Suppress HER2Δ16 Mediated Breast Tumorigenesis and Reverse Trastuzumab Resistance

    PubMed Central

    Huynh, Felicia C.; Jones, Frank E.

    2014-01-01

    The oncogenic isoform of HER2, HER2Δ16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Δ16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2Δ16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2Δ16 oncogenic activity we investigated the contribution of altered microRNA expression to HER2Δ16 mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy comparing microRNA expression profiles of MCF-7 to MCF-7/HER2Δ16 cells, we found that expression of HER2Δ16 significantly altered expression of 16 microRNAs by 2-fold or more including a 4.8 fold suppression of the miR-7 tumor suppressor. Reestablished expression of miR-7 in the MCF-7/HER2Δ16 cell line caused a G1 cell cycle arrest and reduced both colony formation and cell migration activity to levels of parental MCF-7 cells. Suppression of miR-7 in the MCF-7 cell line resulted in enhanced colony formation activity but not cell migration, indicating that miR-7 suppression is sufficient to drive tumor cell proliferation but not migration. MiR-7 inhibited MCF-7/HER2Δ16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR. In contrast, miR-7 inhibition of MCF-7/HER2Δ16 cell proliferation involved a pathway where miR-7 expression resulted in the inactivation of Src kinase independent of suppressed EGFR expression. Also independent of EGFR suppression, reestablished miR-7 expression sensitized refractory MCF-7/HER2Δ16 cells to trastuzumab. Our results demonstrate that reestablished miR-7 expression abolishes HER2Δ16 induced cell proliferation and migration while sensitizing HER2Δ16 expressing cells to trastuzumab therapy. We propose that miR-7 regulated

  5. Targeted delivery of polyamidoamine-paclitaxel conjugate functionalized with anti-human epidermal growth factor receptor 2 trastuzumab

    PubMed Central

    Ma, Pengkai; Zhang, Xuemei; Ni, Ling; Li, Jinming; Zhang, Fengpu; Wang, Zheng; Lian, Shengnan; Sun, Kaoxiang

    2015-01-01

    Background Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB), which binds to human epidermal growth factor receptor 2 (HER2), was used as a targeting agent in a TMAB-polyamidoamine (PAMAM) conjugate carrying paclitaxel (PTX) specifically to cells overexpressing HER2. Methods TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG). PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively. Results Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was located in the cytoplasm. The in vitro cytotoxicity of TMAB-conjugated PAMAM was lower than free PTX due to the slow release of PTX from the conjugate. In vivo targeting further demonstrated that TMAB-conjugated PAMAM accumulated in the BT474 tumor model more efficiently than non-conjugated PAMAM. Conclusion TMAB can serve as an effective targeting agent

  6. Adjuvant Therapy for Renal Cell Carcinoma: Past, Present, and Future

    PubMed Central

    Pal, Sumanta K.

    2014-01-01

    At the present time, the standard of care for patients who have received nephrectomy for localized renal cell carcinoma (RCC) is radiographic surveillance. With a number of novel targeted agents showing activity in the setting of metastatic RCC, there has been great interest in exploring the potential of the same agents in the adjuvant setting. Herein, we discuss the evolution of adjuvant trials in RCC, spanning from the immunotherapy era to the targeted therapy era. Pitfalls of current studies are addressed to provide a context for interpreting forthcoming results. Finally, we outline avenues to incorporate promising investigational agents, such as PD-1 (programmed death-1) inhibitors and MNNG transforming gene inhibitors, in future adjuvant trials. PMID:24969163

  7. Adjuvant chemotherapy in elderly patients with breast cancer: key challenges.

    PubMed

    Pondé, Noam; Dal Lago, Lissandra; Azim, Hatem A

    2016-06-01

    Elderly women with early breast cancer (BC) form a heterogeneous and large subgroup (41.8% of women with BC are over 65). Decision making in this subgroup is made more difficult by lack of familiarity with their physical, cognitive and social issues. Adequate management depends on biological factors and accurate clinical evaluation through comprehensive geriatric assessment (CGA). CGA can help to better select and determine potential risks factors for patients who are candidates for adjuvant chemotherapy. It is still recently introduced in geriatric oncology and there is a lack of awareness of its importance. Available data on adjuvant chemotherapy for BC is limited but suggests it can be of benefit for well selected patients, though the risk of short and long-term toxicity is significant. Here we provide a discussion of the key practical issues in decision making in the setting of adjuvant chemotherapy for elderly BC patients. PMID:27010772

  8. Development of CpG ODN Based Vaccine Adjuvant Formulations.

    PubMed

    Gursel, Mayda; Gursel, Ihsan

    2016-01-01

    Development of effective vaccine mediated immune responses relies on the use of vaccine adjuvants capable of enhancing and directing the adaptive immune response to the antigen. When used as vaccine adjuvants, type I interferon inducing agents can elicit potent effector/memory T cell responses and humoral immunity. Distinct sequences of single stranded synthetic oligodeoxynucleotides containing unmethylated cytosine-phosphate-guanine oligodeoxynucleotide motifs (CpG ODN) can generate type I interferon production via a TLR9-MyD88-IRF7-mediated signaling pathway. Here, we describe two different methods of preparing CpG ODN-based vaccine adjuvant formulations that can induce a robust IFNα response from human peripheral blood mononuclear cells. PMID:27076306

  9. Old and new adjuvants for hepatitis B vaccines.

    PubMed

    Leroux-Roels, Geert

    2015-02-01

    The safety and immunogenicity profiles of currently available recombinant hepatitis B vaccines are excellent. However, it remains a real challenge to induce protective immunity in the target groups that respond poorly or not at all to conventional vaccines. Ideally, a hepatitis B vaccine can be developed that conveys lifelong protection against infection rapidly after the injection of a single dose. Although this goal is far from being reached, important improvements have been made. Novel vaccine adjuvants have been developed that enhance the immunogenicity of recombinant hepatitis B vaccines while maintaining a good safety profile. The different adjuvants and adjuvant systems that are discussed herein have all been thoroughly evaluated in clinical trials and some have reached or are close to reach the market. PMID:25523196

  10. The Safety of Adjuvanted Vaccines Revisited: Vaccine-Induced Narcolepsy.

    PubMed

    Ahmed, S Sohail; Montomoli, Emanuele; Pasini, Franco Laghi; Steinman, Lawrence

    2016-01-01

    Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1) pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed "black box" attitude towards all vaccines. The focus of this review article is to revisit this "black box" using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine. PMID:27228647

  11. [New options in adjuvant endocrine therapy in breast cancer].

    PubMed

    Saltel-Fulero, Aurélien; Donnadieu, Anne; Leman-Detours, Solenne; Cottu, Paul

    2016-01-01

    Endocrine therapy is a compulsory step in the adjuvant management of early breast cancer expressing the estrogen receptor, by reducing as much as possible serum and tissue levels of estrogens. Tamoxifen is the standard therapy for non-menopausal women. Ovarian function suppression, in addition to exemestane or tamoxifen, could be an alternative option for young women at high risk of recurrence and non menopausal after adjuvant or neo-adjuvant chemotherapy. Recent studies show a trend for improvement of overall survival and disease-free-survival with aromatase inhibitors among postmenopausal women. However, safety of aromatase inhibitors is controversial and adverse events may lead to switch for tamoxifen with no loss of efficacy. Extension therapy by tamoxifen or aromatase inhibitor after five years of tamoxifen and for a total duration of ten years significantly improves overall survival. There is to date no data supporting the extension therapy after five years of aromatase inhibitor. PMID:26675809

  12. Exosome removal as a therapeutic adjuvant in cancer.

    PubMed

    Marleau, Annette M; Chen, Chien-Shing; Joyce, James A; Tullis, Richard H

    2012-01-01

    Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30-100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles < 200 nm from the entire circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT™ device, the Hemopurifier®, to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible

  13. Management of Pediatric Myxopapillary Ependymoma: The Role of Adjuvant Radiation

    SciTech Connect

    Agbahiwe, Harold C.; Wharam, Moody; Batra, Sachin; Cohen, Kenneth; Terezakis, Stephanie A.

    2013-02-01

    Introduction: Myxopapillary ependymoma (MPE) is a rare tumor in children. The primary treatment is gross total resection (GTR), with no clearly defined role for adjuvant radiation therapy (RT). Published reports, however, suggest that children with MPE present with a more aggressive disease course. The goal of this study was to assess the role of adjuvant RT in pediatric patients with MPE. Methods: Sixteen patients with MPE seen at Johns Hopkins Hospital (JHH) between November 1984 and December 2010 were retrospectively reviewed. Fifteen of the patients were evaluable with a mean age of 16.8 years (range, 12-21 years). Kaplan-Meier curves and descriptive statistics were used for analysis. Results: All patients received surgery as the initial treatment modality. Surgery consisted of either a GTR or a subtotal resection (STR). The median dose of adjuvant RT was 50.4 Gy (range, 45-54 Gy). All patients receiving RT were treated at the involved site. After a median follow-up of 7.2 years (range, 0.75-26.4 years), all patients were alive with stable disease. Local control at 5 and 10 years was 62.5% and 30%, respectively, for surgery alone versus 100% at both time points for surgery and adjuvant RT. Fifty percent of the patients receiving surgery alone had local failure. All patients receiving STR alone had local failure compared to 33% of patients receiving GTR alone. One patient in the surgery and adjuvant RT group developed a distant site of recurrence 1 year from diagnosis. No late toxicity was reported at last follow-up, and neurologic symptoms either improved or remained stable following surgery with or without RT. Conclusions: Adjuvant RT improved local control compared to surgery alone and should be considered after surgical resection in pediatric patients with MPE.

  14. Chemotherapy: Does Neoadjuvant or Adjuvant Therapy Improve Outcomes?

    PubMed

    Canter, Robert J

    2016-10-01

    Since preoperative chemotherapy has been clearly shown to improve outcomes for patients with Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, practitioners have attempted to extend the use of adjuvant/neoadjuvant chemotherapy to other types of adult soft tissue sarcoma. Given the high risk of distant recurrence and disease-specific death for patients with soft tissue sarcoma tumors larger than 10 cm, these patients should be considered candidates for neoadjuvant chemotherapy as well as investigational therapies. Yet, potential toxicity from cytotoxic chemotherapy is substantial, and there remains little consensus and wide variation regarding the indications for use of chemotherapy in the adjuvant/neoadjuvant setting. PMID:27591503

  15. Knowns and Known Unknowns of Gastrointestinal Stromal Tumor Adjuvant Therapy.

    PubMed

    Martínez-Marín, Virginia; Maki, Robert G

    2016-09-01

    The first 15 years of management of gastrointestinal stromal tumor (GIST) have led to 3 lines of therapy for metastatic disease: imatinib, sunitinib, and regorafenib. In the adjuvant setting, imatinib is usually given for 3 years postoperatively to patients with higher-risk primary tumors that are completely resected. In this review, issues regarding GIST adjuvant therapy are discussed. It is hoped this review will help the reader understand the present standard of care to improve upon it in years to come. PMID:27546844

  16. Biotinylated polyacrylamide-based metal-chelating polymers and their influence on antigen recognition following conjugation to a trastuzumab Fab fragment.

    PubMed

    Liu, Peng; Boyle, Amanda J; Lu, Yijie; Reilly, Raymond M; Winnik, Mitchell A

    2012-09-10

    We report the synthesis and characterization of metal-chelating polymers (MCPs) with a terminal biotin and a polyacrylamide backbone harboring multiple diethylenetriaminepentaacetic acid (DTPA) chelating sites. These polymers are conjugated to a streptavidin (SAv)-modified Fab fragment of trastuzumab (tmFab) and subsequently complexed with (111)In through DTPA. Trastuzumab has specific targeting ability toward human epidermal growth factor receptor-2 (HER2), which is overexpressed on some types of breast cancer cells and ovarian cancer cells. (111)In can generate Auger electrons which cause lethal DNA double strand breaks. The radioimmunoconjugates (RICs) were designed to target HER2 overexpressing cancer cells and carry multiple copies of (111)In to these cells. The mole maximum specific activities of these polymers were investigated by loading the polymers with (111)In at an increasing (111)In to polymer ratio. The polymers show 55-fold to 138-fold higher maximum specific activity than DTPA modified tmFab-SAv. Moreover, the HER2 immunoreactivities of these RICs were evaluated by measuring their specific binding ability toward HER2 overexpressing SKOV-3 ovarian cancer cells. The results demonstrate that although in the presence of polymer there is increased nonspecific binding, HER2 targeting ability was retained, ensuring the radionuclide delivery ability of these RICs. PMID:22871127

  17. Qualification and application of a liquid chromatography-quadrupole time-of-flight mass spectrometric method for the determination of trastuzumab in rat plasma.

    PubMed

    Park, Min-Ho; Lee, Min-Woo; Shin, Young G

    2016-04-01

    An liquid chromatography-quadrupole time-of-flight (QqTOF) mass spectrometric method was developed for the determination of humanized or human monoclonal antibodies in rat plasma at the early drug discovery stage. Trastuzumab was used as a model monoclonal antibody. The method consisted of immunoprecipitation followed by tryptic digestion for sample preparation and LC-TOF-MS/MS analysis of specific signature peptides in the positive ion mode using electrospray ionization for analysis. A stable isotope-labeled signature peptide was also used as internal standard. A quadratic regression (weighted 1/concentration(2) ), with an equation y = ax(2)  + bx + c, was used to fit calibration curves over the concentration range of 0.500-100 µg/mL for trastuzumab. Samples from a pharmacokinetic study in rat were analyzed by this qualified LC-TOF-MS/MS method and concentrations were compared with those generated by enzyme linked immunosorbent assays method. The LC-TOF-MS/MS method was accurate and precise, with quantitative results comparable with those of ELISA. The qualification run met the acceptance criteria of ±25% accuracy and precision values for quality control samples. Within-run accuracy ranged from 1.53 to 9.20% with precision values ≤10.29%. This LC-TOF-MS/MS method approach could be used as a complementary method for humanized or human monoclonal antibodies at the early drug discovery stage. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26317190

  18. Adjuvant High-Dose Interferon-α for Resected Melanoma in a Patient with HIV Infection

    PubMed Central

    Saba, Nakhle S.; George, Thomas J.

    2010-01-01

    Adjuvant interferon (IFN)-α remains the standard adjuvant therapy for intermediate and high-risk melanoma after definitive surgical resection. Data addressing the role and safety of adjuvant immunotherapy in HIV-infected patients with melanoma are lacking. We report on an HIV+ patient who received IFN-α as adjuvant treatment for high-risk melanoma. To our knowledge, this is the first reported case of such an approach. PMID:20555019

  19. Droplet evaporation and spread on waxy and hairy leaves associated with type and concentration of adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adjuvants can improve pesticide application efficiency and effectiveness. However, knowledge is lacking on quantitative behaviors of adjuvant-amended pesticide droplets on foliage. Evaporation rates and wetted areas of 500 µm diameter water droplets amended with four adjuvants applied to waxy and h...

  20. Schistosome Vaccine Adjuvants in Preclinical and Clinical Research

    PubMed Central

    Stephenson, Rachel; You, Hong; McManus, Donald; Toth, Istvan

    2014-01-01

    There is currently no vaccine available for human use for any parasitic infections, including the helminth disease, schistosomiasis. Despite many researchers working towards this goal, one of the focuses has been on identifying new antigenic targets. The bar to achieve protective efficacy in humans was set at a consistent induction of 40% protection or better by the World Health Organisation (WHO), and although this is a modest goal, it is yet to be reached with the six most promising schistosomiasis vaccine candidates (Sm28GST, IrV5, Sm14, paramyosin, TPI, and Sm23). Adjuvant selection has a large impact on the effectiveness of the vaccine, and the use of adjuvants to aid in the stimulation of the immune system is a critical step and a major variable affecting vaccine development. In addition to a comprehensive understanding of the immune system, level of protection and the desired immune response required, there is also a need for a standardised and effective adjuvant formulation. This review summarises the status of adjuvants that have been or are being employed in schistosomiasis vaccine development focusing on immunisation outcomes at preclinical and clinical stages. PMID:26344751

  1. Have adjuvant tyrosine kinase inhibitors lost their shine?

    PubMed Central

    Sabari, Joshua K.

    2016-01-01

    Despite broad advances in molecularly targeted therapies, lung cancer remains the leading cause of cancer related mortality in the United States. Epidermal growth factor receptor (EGFR) mutations occur in approximately 17% of advanced non-small cell lung cancer (NSCLC) in the US population. The remarkable efficacy of small-molecule EGFR tyrosine kinase inhibitors (TKIs) in this unique subset of patients has revolutionized the therapeutic approach to lung cancer. The success of these agents in the metastatic setting leads to the logical question of what role these drugs may have in the adjuvant setting for patients with earlier stage disease. RADIANT, an international randomized, double-blind, placebo controlled phase III study in patients with completely resected stage IB to IIIA NSLC whose tumors expressed EGFR by IHC and EGFR amplification by FISH, attempted to answer the question of whether erlotinib would improve disease free survival and overall survival in the adjuvant setting. While RADIANT does not conclude for or against adjuvant use of EGFR-TKIs, all data points towards benefit in a selected population. As clinicians, we must continue to enroll to potentially practice changing therapeutic neoadjuvant and adjuvant chemotherapy studies internationally. PMID:27568486

  2. Have adjuvant tyrosine kinase inhibitors lost their shine?

    PubMed

    Sabari, Joshua K; Chaft, Jamie E

    2016-08-01

    Despite broad advances in molecularly targeted therapies, lung cancer remains the leading cause of cancer related mortality in the United States. Epidermal growth factor receptor (EGFR) mutations occur in approximately 17% of advanced non-small cell lung cancer (NSCLC) in the US population. The remarkable efficacy of small-molecule EGFR tyrosine kinase inhibitors (TKIs) in this unique subset of patients has revolutionized the therapeutic approach to lung cancer. The success of these agents in the metastatic setting leads to the logical question of what role these drugs may have in the adjuvant setting for patients with earlier stage disease. RADIANT, an international randomized, double-blind, placebo controlled phase III study in patients with completely resected stage IB to IIIA NSLC whose tumors expressed EGFR by IHC and EGFR amplification by FISH, attempted to answer the question of whether erlotinib would improve disease free survival and overall survival in the adjuvant setting. While RADIANT does not conclude for or against adjuvant use of EGFR-TKIs, all data points towards benefit in a selected population. As clinicians, we must continue to enroll to potentially practice changing therapeutic neoadjuvant and adjuvant chemotherapy studies internationally. PMID:27568486

  3. Adjuvant Iodine131 Lipiodol after Resection of Hepatocellular Carcinoma

    PubMed Central

    Furtado, Ruelan V.; Ha, Leo; Clarke, Stephen; Sandroussi, Charbel

    2015-01-01

    Background. Survival after liver resection for HCC is compromised by a high rate of intrahepatic recurrence. Adjuvant treatment with a single, postoperative dose of intra-arterial I131 lipiodol has shown promise, as a means of prolonging disease-free survival (DFS). Methodology. DFS and overall survival (OS) after a single dose of postoperative I131 lipiodol were compared to liver resection alone, for treatment of hepatocellular carcinoma (HCC). Data were collected retrospectively for patients who had a curative resection for HCC between December 1993 and September 2011. Seventy-two patients were given I131 lipiodol after surgery and 70 patients had surgery alone. Results. The DFS at 1, 3, and 5 years was 72%, 43%, and 26% in the surgery group and 70%, 39%, and 29% in the adjuvant I131 lipiodol group (p = 0.75). The 1-, 3-, and 5-year OS was 83%, 64%, and 52% in the surgery group and 96%, 72%, and 61% in the adjuvant I131 lipiodol group (p = 0.16). Conclusion. This retrospective study has found no significant benefit to survival, after adjuvant treatment with I131 lipiodol. PMID:26713092

  4. Ready-to-use colloidal adjuvant systems for intranasal immunization.

    PubMed

    Lee, Jeong-Jun; Shim, Aeri; Lee, Song Yi; Kwon, Bo-Eun; Kim, Seong Ryeol; Ko, Hyun-Jeong; Cho, Hyun-Jong

    2016-04-01

    Adjuvant systems based on oil-in-water (o/w) microemulsions (MEs) for vaccination via intranasal administration were prepared and evaluated. A ready-to-use blank ME system composed of mineral oil (oil), Labrasol (surfactant), Tween 80 (cosurfactant), and water was prepared and blended with antigen (Ag) solution prior to use. The o/w ME system developed exhibited nano-size droplets within the tested range of Ag concentrations and dilution factors. The maintenance of primary, secondary, and tertiary structural stability of ovalbumin (OVA) in ME, compared with OVA in solution, was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), and fluorescence intensity measurements, respectively. The uptake efficiency in RAW 264.7 cells, evaluated by flow cytometry, of OVA in the ME group was significantly higher than that of the OVA solution group (p<0.05). In an intranasal immunization study with OVA ME in mice, elevated adjuvant effects in terms of mucosal immunization and Th1-dominant cell-mediated immune responses were identified. Given the convenience of use (simply mixing with Ag solution prior to use) and the adjuvant effects after intranasal immunization, the new o/w ME may be a practical and efficient adjuvant system for intranasal vaccination. PMID:26775242

  5. Vinegar: Application volumes and adjuvants for weed control

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vinegar has been identified as a potential organic herbicide, yet more information is needed to determine influence of application volume and use of additives (adjuvants) on weed control. Vinegar is a solution containing water and acetic acid, an organic acid produced through the natural fermentatio...

  6. Effect of adjuvant physical properties on spray characteristics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of adjuvant physical properties on spray characteristics were studied. Dynamic surface tension was measured with a Sensa Dyne surface tensiometer 6000 using the maximum bubble pressure method. Viscosity was measured with a Brookfield synchro-lectric viscometer model LVT using a UL adap...

  7. Molecular adjuvants and immunomodulators: new approaches to immunization.

    PubMed Central

    Johnson, A G

    1994-01-01

    Epitopes on microbial antigens responsible for protective immunity have begun to be identified and isolated, and their chemical structures have been determined. Ensuing knowledge of their weak immunizing capacity per se has led to an appreciation of the need for adjuvants to increase the immunogenicity of these low-molecular-weight synthetic structures. As such, a recent surge in adjuvant research has emerged. Accordingly, this review will highlight a number of those adjuvant substances whose activity in animals indicates a potential use in human vaccines. In addition, the potential of several well-defined substances, termed immunomodulators, which nonspecifically stimulate resistance of animals to multiple 50% lethal doses of microbial challenge is described. Among the most extensively characterized adjuvants of microbial origin discussed in detail are (i) the lipopolysaccharides isolated from gram-negative bacteria and their nontoxic analogs, (ii) the synthetic muramyl dipeptides and their multiple analogs, and (iii) the synthetic polyribonucleotide complexes, mimicking the interferon-inducing capacity of viruses. Discussed also are the heat-labile enterotoxin of Escherichia coli, the nonionic block copolymers, the saponins, a quinolamine derivative, and the hormone dihydroepiandrosterone. PMID:7923049

  8. Molecular adjuvants and immunomodulators: new approaches to immunization.

    PubMed

    Johnson, A G

    1994-07-01

    Epitopes on microbial antigens responsible for protective immunity have begun to be identified and isolated, and their chemical structures have been determined. Ensuing knowledge of their weak immunizing capacity per se has led to an appreciation of the need for adjuvants to increase the immunogenicity of these low-molecular-weight synthetic structures. As such, a recent surge in adjuvant research has emerged. Accordingly, this review will highlight a number of those adjuvant substances whose activity in animals indicates a potential use in human vaccines. In addition, the potential of several well-defined substances, termed immunomodulators, which nonspecifically stimulate resistance of animals to multiple 50% lethal doses of microbial challenge is described. Among the most extensively characterized adjuvants of microbial origin discussed in detail are (i) the lipopolysaccharides isolated from gram-negative bacteria and their nontoxic analogs, (ii) the synthetic muramyl dipeptides and their multiple analogs, and (iii) the synthetic polyribonucleotide complexes, mimicking the interferon-inducing capacity of viruses. Discussed also are the heat-labile enterotoxin of Escherichia coli, the nonionic block copolymers, the saponins, a quinolamine derivative, and the hormone dihydroepiandrosterone. PMID:7923049

  9. Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy.

    PubMed

    Kim, Su-Yeon; Joo, Hong-Gu

    2015-01-01

    Fucoidan is a sulfated polysaccharide derived from brown seaweed, including Fucus vesiculosus. This compound is known to have immunostimulatory effects on various types of immune cells including macrophages and dendritic cells. A recent study described the application of fucoidan as a vaccine adjuvant. Vaccination is regarded as the most efficient prophylactic method for preventing harmful or epidemic diseases. To increase vaccine efficacy, effective adjuvants are needed. In the present study, we determined whether fucoidan can function as an adjuvant using vaccine antigens. Flow cytometric analysis revealed that fucoidan increases the expression of the activation markers major histocompatibility complex class II, cluster of differentiation (CD)25, and CD69 in spleen cells. In combination with Bordetella bronchiseptica antigen, fucoidan increased the viability and tumor necrosis factor-α production of spleen cells. Furthermore, fucoidan increased the in vivo production of antigen-specific antibodies in mice inoculated with Mycoplasma hyopneumoniae antigen. Overall, this study has provided valuable information about the use of fucoidan as a vaccine adjuvant. PMID:25549218

  10. Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy

    PubMed Central

    Kim, Su-Yeon

    2015-01-01

    Fucoidan is a sulfated polysaccharide derived from brown seaweed, including Fucus vesiculosus. This compound is known to have immunostimulatory effects on various types of immune cells including macrophages and dendritic cells. A recent study described the application of fucoidan as a vaccine adjuvant. Vaccination is regarded as the most efficient prophylactic method for preventing harmful or epidemic diseases. To increase vaccine efficacy, effective adjuvants are needed. In the present study, we determined whether fucoidan can function as an adjuvant using vaccine antigens. Flow cytometric analysis revealed that fucoidan increases the expression of the activation markers major histocompatibility complex class II, cluster of differentiation (CD)25, and CD69 in spleen cells. In combination with Bordetella bronchiseptica antigen, fucoidan increased the viability and tumor necrosis factor-α production of spleen cells. Furthermore, fucoidan increased the in vivo production of antigen-specific antibodies in mice inoculated with Mycoplasma hyopneumoniae antigen. Overall, this study has provided valuable information about the use of fucoidan as a vaccine adjuvant. PMID:25549218

  11. [Expression and adjuvant effects of the fusion peptide TBP5].

    PubMed

    Wang, Chen; Guo, Xiangling; Li, Xiaokang; Wu, Tingcai; Li, Deyuan; Chen, Puyan

    2015-05-01

    Thymopentin (TP5) and bursopentin (BP5) are both immunopotentiators. To explore whether the TP5-BP5 fusion peptide (TBP5) has adjuvant activity or not, we cloned the TBP5 gene and confirmed that the TBP5 gene in a recombinant prokaryotic expression plasmid was successfully expressed in Escherichia coli BL21. TBP5 significantly promoted the proliferation of thymic and splenic lymphocytes of mice. The potential adjuvant activity of the TBP5 was examined in mice by coinjecting TBP5 and H9N2 avian influenza virus (AIV) inactivated vaccine. HI antibody titers, HA antibodies and cytokines levels (IL-4 and IFN-γ) were determined. We found that TBP5 markedly elevated serum HI titers and HA antibody levels, induced the secretion of both IL-4 and IFN-γ cytokines. Furthermore, virus challenge experiments confirmed that TBP5 contributed to inhibition replication of the virus [H9N2 AIV (A/chicken/Jiangsu/NJ07/05)] from mouse lungs. Altogether, these findings suggest that TBP5 may be an effective adjuvant for avian vaccine and that this study provides a reference for further research on new vaccine adjuvants. PMID:26571686

  12. Organic weed control with vinegar: Application volumes and adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Preliminary results have indicated that vinegar has potential as an organic herbicide, but further research is needed to increase our understanding of the relationship between acetic acid concentrations, application volumes, adjuvants, weed species, and weed maturity on effectiveness of vinegar to c...

  13. Inflence of air shear and adjuvants on spray atomization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Droplet size is critical to maximizing pesticide efficacy and mitigating off-target movement and correct selection and adjustment of nozzles and application equipment, as well as the use of adjuvants can aid in this process. However, in aerial applications air shear tends to be the dominate factor ...

  14. Vaccine adjuvants - Current status and prospects on controlled release adjuvancity.

    PubMed

    Sivakumar, S M; Safhi, Mohammed M; Kannadasan, M; Sukumaran, N

    2011-10-01

    The strategy of World Health Organization is to develop efficient and inexpensive vaccine against various infectious diseases amongst children's population. Vaccination is considered as the most cost effective health intervention known to public. Since 90 years various substances have been added in vaccine formulation but still alum is considered as the safest adjuvant for human use licensed by United States Food and Drug Administration. MF 59 and ASO4 are the adjuvants were developed recently and approved for human use. Due to poor adjuvancity, conventional vaccines require multiple recall injection at approximately time intervals to attain optimal immune response. For past approximately two decades the vaccine research has been focused towards the alternation of alum type of adjuvant in order to increase the immunogenicity. The development of new vaccines, is more efficacious or easier to deliver, or both have become an area of research that can certainly benefit from controlled release technology. Especially, the conversion of multiple administration vaccine into single administration vaccine may represent an improved advancement towards the betterment of human health care and welfare. Biodegradable polymer microparticles have been evaluated for delivering antigens in native form, sustained release keeping in mind the safety aspects. In this article we review the overall concept of adjuvants in vaccine technology with special focus towards the prospects of controlled release antigens. PMID:23960760

  15. Vaccine Adjuvants Alter TCR-Based Selection Thresholds

    PubMed Central

    Malherbe, Laurent; Mark, Linda; Fazilleau, Nicolas; McHeyzer-Williams, Louise J.; McHeyzer-Williams, Michael G.

    2009-01-01

    SUMMARY How TCR specificity evolves in vivo following protein vaccination is central to the development of T helper cell function. Most models of clonal selection in the T helper cell compartment favor TCR affinity-based thresholds. Here, we demonstrate that depot-forming vaccine adjuvants do not require TLR agonists to induce clonal dominance in antigen-specific T helper cell responses. However, readily dispersible adjuvants using TLR-9 and TLR-4 agonists skew TCR repertoire usage by increasing TCR selection thresholds and enhancing antigen-specific clonal expansion. In this manner, vaccine adjuvants control the local accumulation of T helper cells expressing TCR with the highest peptide MHC class II binding. Clonal composition was altered by mechanisms that blocked the local propagation of clonotypes independent of antigen dose and not as a consequence of inter-clonal competition. This capacity of adjuvants to modify antigen-specific Th cell clonal composition has fundamental implications for the design of future protein sub-unit vaccines. PMID:18450485

  16. Involvement of Numb-mediated HIF-1α inhibition in anti-proliferative effect of PNA-antimiR-182 in trastuzumab-sensitive and -resistant SKBR3 cells.

    PubMed

    Sajadimajd, Soraya; Yazdanparast, Razieh; Akram, Sadeghirizi

    2016-04-01

    Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2) that is overexpressed in about 25 % of breast cancer patients. However, primary and/or acquired resistance to trastuzumab develops in most affected persons. In this study, we explored the functional role of miR-182 inhibition with aiming the sensitization of SKBR3 cells to trastuzumab. Cell viability, apoptosis, colony formation, and migration capacities of SKBR3(S) (sensitive) and SKBR3(R) (resistant) cells were assessed to determine the anti-proliferative effects of PNA-antimiR-182. In addition, the expression levels of miR-182, mRNA of FOXO1, and Bim as well as the protein levels of HER2 and Notch1 signaling factors were evaluated by stem-loop RT-qPCR, RT-qPCR, and Western blot, respectively. The results indicated that miR-182 might play a causal role in the mechanism of trastuzumab. In line with that, PNA-antimiR-182 inhibited synergistically the viability of both the sensitive and resistant cell groups. Furthermore, the inhibitory effect of PNA-anitmiR-182 on migration in SKBR3 cells was more than the induction of apoptosis. In addition, PNA-antimiR-182 reduced the levels of NICD, Hes1, HIF-1α, and p-Akt in both cell groups, while it augmented the intracellular content of FOXO1 and Numb suppressor proteins. In other words, PNA-antimiR-182-mediated upregulation of Numb was associated with downregulation of HIF-1α and Hes1. Consequently, downregulation of miR-182 might find therapeutical value for overcoming trastuzumab resistance. Graphical Abstract The crosstalk between HER2 and Notch1 signaling pathway is mediated by miR-182. PMID:26563369

  17. Efficacy of Neo-Adjuvant Chemoradiotherapy for Resectable Pancreatic Adenocarcinoma

    PubMed Central

    Liu, Wei; Fu, Xue-Liang; Yang, Jian-Yu; Liu, De-Jun; Li, Jiao; Zhang, Jun-Feng; Huo, Yan-Miao; Yang, Min-Wei; Hua, Rong; Sun, Yong-Wei

    2016-01-01

    Abstract We have conducted a meta-analysis and systematic review to determine the overall survival, mortality rate, and complete resection rate of neo-adjuvant chemoradiotherapy (CRT) compared with pancreaticoduodenectomy alone in patients with pancreatic adenocarcinoma. Whether neo-adjuvant CRT is beneficial in the treatment of resectable pancreatic cancer or not, it is still a controversial issue. Medline and Cochrane were searched with relevant terms. Eight studies with a total of 833 participants were selected. The meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The analysis revealed neo-adjuvant group may have a benefit in the overall survival, as compared with the resection group, although it did not reach statistical significance (pooled hazard ratio = 0.87, 95% confidence interval [CI] = 0.75–1.00, P = 0.051). We found no difference in the in-hospital mortality rate (pooled odds ratio [OR] = 1.27, 95% CI = 0.35–4.58, P = 0.710). The complete resection rate was significantly higher in the neo-adjuvant group than in the resection group (pooled OR = 2.39, 95% CI = 1.21–4.74, P = 0.012). This meta-analysis found that there was no significant difference in the overall survival between patients treated with neo-adjuvant CRT or pancreaticduodenectomy. PMID:27082545

  18. Evaluation of Widely Consumed Botanicals as Immunological Adjuvants

    PubMed Central

    Ragupathi, Govind; Hood, Chandra; Yeung, K. Simon; Vickers, Andrew; Hood, Chandra; Deng, Gary; Cheung, Nai-Kong; Vickers, Andrew; Cassileth, Barrie; Livingston, Philip

    2008-01-01

    Background Many widely used botanical medicines are claimed to be immune enhancers. Clear evidence of augmentation of immune responses in vivo is lacking in most cases. To select botanicals for further study based on immune enhancing activity, we study them here mixed with antigen and injected subcutaneously (s.c.). Globo H and GD3 are cell surface carbohydrates expressed on glycolipids or glycoproteins on the cell surface of many cancers. When conjugated to keyhole limpet hemocyanin (KLH), mixed with an immunological adjuvant and administered s.c. the magnitude of the antibody responses against globo H, GD3 and KLH depend largely on the potency of the adjuvant. We describe here the results obtained using this s.c. immunization model with 7 botanicals purported to have immune stimulant effects. Methods Groups of 5–10 mice were immunized with globo H–KLH or GD3-KLH mixed with botanical, saline or positive control immunological adjuvant, s.c. 3 times at 1 week intervals. Antibody responses were measured 1 and 2 weeks after the 3rd immunization. The following seven botanicals and fractions were tested: (1) H-48 (Honso USA Co.), (2) Coriolus vesicolor raw water extract, purified polysaccharide-K (PSK) or purified polysaccharide-peptide (PSP) (Institute of Chinese Medicine (ICM)), (3) Maitake extract (Yukiguni Maitake Co Ltd. and Tradeworks Group), (4) Echinacea lipophilic, neutral and acidic extracts (Gaia Herbs), (5) Astragalus water, 50% or 95% ethanol extracts (ICM), (6) Turmeric supercritical (SC) or hydro-ethanolic (HE) extracts (New Chapter) or 60% ethanol extract (ICM) and (7) yeast β-glucan (Biotec Pharmacon). Purified saponin extract QS-21 (Antigenics) and semi-synthetic saponin GPI-0100 (Advanced BioTherapies) were used as positive control adjuvants. Sera were analyzed by ELISA against synthetic globo H ceramide or GD3 and KLH. Results Consistent significant adjuvant activity was observed after s.c vaccination with the Coriolus extracts (especially PSK

  19. Dendritic cell-targeting DNA-based mucosal adjuvants for the development of mucosal vaccines

    PubMed Central

    Kataoka, Kosuke; Fujihashi, Kohtaro

    2009-01-01

    In order to establish effective mucosal immunity against various mucosal pathogens, vaccines must be delivered via the mucosal route and contain effective adjuvant(s). Since mucosal adjuvants can simply mix with the antigen, it is relatively easy to adapt them for different types of vaccine development. Even in simple admixture vaccines, the adjuvant itself must be prepared without any complications. Thus, CpG oligodeoxynucleotides or plasmids encoding certain cDNA(s) would