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Sample records for her2-negative breast tumours

  1. Systemic treatment approaches in her2-negative advanced breast cancer—guidance on the guidelines

    PubMed Central

    Joy, A.A.; Ghosh, M.; Fernandes, R.; Clemons, M.J.

    2015-01-01

    Despite advancements in the treatment of early-stage breast cancer, many patients still develop disease recurrence; others present with de novo metastatic disease. For most patients with advanced breast cancer, the primary treatment intent is noncurative—that is, palliative—in nature. The goals of treatment should therefore focus on maximizing symptom control and extending survival. Treatments should be evaluated on an individualized basis in terms of evidence, but also with full respect for the wishes of the patient in terms of acceptable toxicity. Given the availability of extensive reviews on the roles of endocrine therapy and her2 (human epidermal growth factor receptor 2)–targeted therapies for advanced disease, we focus here mainly on treatment guidelines for the non-endocrine management of her2-negative advanced breast cancer in a Canadian health care context. PMID:25848337

  2. Blood Genome-Wide Transcriptional Profiles of HER2 Negative Breast Cancers Patients

    PubMed Central

    Balacescu, Ovidiu; Balacescu, Loredana; Gherman, Claudia; Drigla, Flaviu; Pop, Laura; Bolba-Morar, Gabriela; Tudoran, Oana; Berindan-Neagoe, Ioana

    2016-01-01

    Tumors act systemically to sustain cancer progression, affecting the physiological processes in the host and triggering responses in the blood circulating cells. In this study, we explored blood transcriptional patterns of patients with two subtypes of HER2 negative breast cancers, with different prognosis and therapeutic outcome. Peripheral blood samples from seven healthy female donors and 29 women with breast cancer including 14 triple-negative breast cancers and 15 hormone-dependent breast cancers were evaluated by microarray. We also evaluated the stroma in primary tumors. Transcriptional analysis revealed distinct molecular signatures in the blood of HER2− breast cancer patients according to ER/PR status. Our data showed the implication of immune signaling in both breast cancer subtypes with an enrichment of these processes in the blood of TNBC patients. We observed a significant alteration of “chemokine signaling,” “IL-8 signaling,” and “communication between innate and adaptive immune cells” pathways in the blood of TNBC patients correlated with an increased inflammation and necrosis in their primary tumors. Overall, our data indicate that the presence of triple-negative breast cancer is associated with an enrichment of altered systemic immune-related pathways, suggesting that immunotherapy could possibly be synergistic to the chemotherapy, to improve the clinical outcome of these patients. PMID:26884644

  3. Association between Ultrasound Features and the 21-Gene Recurrence Score Assays in Patients with Oestrogen Receptor-Positive, HER2-Negative, Invasive Breast Cancer.

    PubMed

    Chae, Eun Young; Moon, Woo Kyung; Kim, Hak Hee; Kim, Won Hwa; Cha, Joo Hee; Shin, Hee Jung; Choi, Woo Jung; Han, Wonshik; Noh, Dong-Young; Lee, Sae Byul; Ahn, Sei Hyun

    2016-01-01

    A multigene expression assay corresponds to the likelihood of breast cancer recurrence after the initial diagnosis and can be used to guide the decision for additional chemotherapy. However, only few studies have investigated the associations between the imaging features of breast cancer and the results of multigene expression assays. Our study was to identify the relationship between imaging features on ultrasound (US) and the recurrence score (RS) on a 21-gene expression assay in patients with oestrogen receptor (ER)-positive, HER2-negative breast cancer. 267 patients with ER-positive, HER-negative invasive breast cancer who underwent examinations using US and Oncotype DX assay were included. US images were independently reviewed by dedicated breast radiologists who were blind to the RS. Tumour roundness was measured using a laboratory-developed software program. The pathological data were reviewed, including immunohistochemistry results. Univariate analysis was performed to assess the associations between the RS and each variable. Multiple logistic regression analysis was used to identify independent predictors of high RS. Of 267 patients, 147 (55%) had low, 96 (36%) intermediate, and 24 (9%) had high RS. According to the univariate analysis, parallel orientation, presence of calcification in the mass, and tumour roundness were positively associated with high RS. Multiple logistic regression analysis showed that parallel orientation (OR = 5.53) and tumour roundness (OR = 1.70 per 10 increase) were associated with high RS. Parallel orientation and tumour roundness are independent variables that may predict high RS in patients with ER-positive, HER2-negative breast cancer. PMID:27362843

  4. Association between Ultrasound Features and the 21-Gene Recurrence Score Assays in Patients with Oestrogen Receptor-Positive, HER2-Negative, Invasive Breast Cancer

    PubMed Central

    Chae, Eun Young; Kim, Won Hwa; Cha, Joo Hee; Shin, Hee Jung; Choi, Woo Jung; Han, Wonshik; Noh, Dong-Young; Lee, Sae Byul; Ahn, Sei Hyun

    2016-01-01

    A multigene expression assay corresponds to the likelihood of breast cancer recurrence after the initial diagnosis and can be used to guide the decision for additional chemotherapy. However, only few studies have investigated the associations between the imaging features of breast cancer and the results of multigene expression assays. Our study was to identify the relationship between imaging features on ultrasound (US) and the recurrence score (RS) on a 21-gene expression assay in patients with oestrogen receptor (ER)-positive, HER2-negative breast cancer. 267 patients with ER-positive, HER-negative invasive breast cancer who underwent examinations using US and Oncotype DX assay were included. US images were independently reviewed by dedicated breast radiologists who were blind to the RS. Tumour roundness was measured using a laboratory-developed software program. The pathological data were reviewed, including immunohistochemistry results. Univariate analysis was performed to assess the associations between the RS and each variable. Multiple logistic regression analysis was used to identify independent predictors of high RS. Of 267 patients, 147 (55%) had low, 96 (36%) intermediate, and 24 (9%) had high RS. According to the univariate analysis, parallel orientation, presence of calcification in the mass, and tumour roundness were positively associated with high RS. Multiple logistic regression analysis showed that parallel orientation (OR = 5.53) and tumour roundness (OR = 1.70 per 10 increase) were associated with high RS. Parallel orientation and tumour roundness are independent variables that may predict high RS in patients with ER-positive, HER2-negative breast cancer. PMID:27362843

  5. Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-07-22

    BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  6. Phase I clinical trial of nintedanib plus paclitaxel in early HER-2-negative breast cancer (CNIO-BR-01-2010/GEICAM-2010-10 study)

    PubMed Central

    Quintela-Fandino, M; Urruticoechea, A; Guerra, J; Gil, M; Gonzalez-Martin, A; Marquez, R; Hernandez-Agudo, E; Rodriguez-Martin, C; Gil-Martin, M; Bratos, R; Escudero, M J; Vlassak, S; Hilberg, F; Colomer, R

    2014-01-01

    Introduction: Previous small-molecule antiangiogenics have compromised chemotherapy dose intensity in breast cancer. We present a phase I trial of a novel selective agent, nintedanib, plus standard chemotherapy in early breast cancer. Methods: Her-2-negative breast cancer patients with tumours larger than 2 cm were eligible for dose-escalation trial (classic 3+3 method). Results: The recommended phase II dose (RP2D) was 150 mg BID of nintedanib combined with standard dose of weekly paclitaxel followed by adriamycin plus cyclophosphamide. The dose-limiting toxicity was transaminase elevation. At the RP2D, the dose intensity was ∼100%. The pathologic complete response was 50%. Conclusions: The combination allows the delivery of full-dose intensity, while efficacy seems promising. PMID:25058346

  7. Capecitabine Monotherapy: Review of Studies in First-Line HER-2-Negative Metastatic Breast Cancer

    PubMed Central

    Kaufmann, Manfred; Siedentopf, Friederike; Dalivoust, Philippe; Debled, Marc; Robert, Nicholas J.; Harbeck, Nadia

    2012-01-01

    The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2–negative MBC. PMID:22418569

  8. Low Concordance between Gene Expression Signatures in ER Positive HER2 Negative Breast Carcinoma Could Impair Their Clinical Application

    PubMed Central

    Laas, Enora; Mallon, Peter; Duhoux, Francois P.; Hamidouche, Amina; Rouzier, Roman; Reyal, Fabien

    2016-01-01

    Background Numerous prognostic gene expression signatures have been recently described. Among the signatures there is variation in the constituent genes that are utilized. We aim to evaluate prognostic concordance among eight gene expression signatures, on a large dataset of ER positive HER2 negative breast cancers. Methods We analysed the performance of eight gene expression signatures on six different datasets of ER+ HER2- breast cancers. Survival analyses were performed using the Kaplan–Meier estimate of survival function. We assessed discrimination and concordance between the 8 signatures on survival and recurrence rates The Nottingham Prognostic Index (NPI) was used to to stratify the risk of recurrence/death. Results The discrimination ability of the whole signatures, showed fair discrimination performances, with AUC ranging from 0.64 (95%CI 0.55–0.73 for the 76-genes signatures, to 0.72 (95%CI 0.64–0.8) for the Molecular Prognosis Index T17. Low concordance was found in predicting events in the intermediate and high-risk group, as defined by the NPI. Low risk group was the only subgroup with a good signatures concordance. Conclusion Genomic signatures may be a good option to predict prognosis as most of them perform well at the population level. They exhibit, however, a high degree of discordance in the intermediate and high-risk groups. The major benefit that we could expect from gene expression signatures is the standardization of proliferation assessment. PMID:26895349

  9. FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

    PubMed

    Beaver, Julia A; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia

    2015-11-01

    On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. PMID:26324739

  10. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer

    PubMed Central

    Liu, Mei-Ching; Lee, Soo Chin; Vanlemmens, Laurence; Ferrero, Jean-Marc; Tabei, Toshio; Pivot, Xavier; Iwata, Hiroji; Aogi, Kenjiro; Lugo-Quintana, Roberto; Harbeck, Nadia; Brickman, Marla J.; Zhang, Ke; Kern, Kenneth A.; Martin, Miguel

    2010-01-01

    This multicenter, randomized, open-label phase III trial (planned enrollment: 700 patients) was conducted to test the hypothesis that single-agent sunitinib improves progression-free survival (PFS) compared with capecitabine as treatment for advanced breast cancer (ABC). Patients with HER2-negative ABC that recurred after anthracycline and taxane therapy were randomized (1:1) to sunitinib 37.5 mg/day or capecitabine 1,250 mg/m2 (1,000 mg/m2 in patients >65 years) BID on days 1–14 q3w. The independent data-monitoring committee (DMC) determined during the first interim analysis (238 patients randomized to sunitinib, 244 to capecitabine) that the trial be terminated due to futility in reaching the primary endpoint. No statistical evidence supported the hypothesis that sunitinib improved PFS compared with capecitabine (one-sided P = 0.999). The data indicated that PFS was shorter with sunitinib than capecitabine (median 2.8 vs. 4.2 months, respectively; HR, 1.47; 95% CI, 1.16–1.87; two-sided P = 0.002). Median overall survival (15.3 vs. 24.6 months; HR, 1.17; two-sided P = 0.350) and objective response rates (11 vs. 16%; odds ratio, 0.65; P = 0.109) were numerically inferior with sunitinib versus capecitabine. While no new or unexpected safety findings were reported, sunitinib treatment was associated with higher frequencies and greater severities of many common adverse events (AEs) compared with capecitabine, resulting in more temporary discontinuations due to AEs with sunitinib (66 vs. 51%). The relative dose intensity was lower with sunitinib than capecitabine (73 vs. 95%). Based on these efficacy and safety results, sunitinib should not be used as monotherapy for patients with ABC. PMID:20339913

  11. Brief-exposure to preoperative bevacizumab reveals a TGF-β signature predictive of response in HER2-negative breast cancers.

    PubMed

    Varadan, Vinay; Kamalakaran, Sitharthan; Gilmore, Hannah; Banerjee, Nilanjana; Janevski, Angel; Miskimen, Kristy L S; Williams, Nicole; Basavanhalli, Ajay; Madabhushi, Anant; Lezon-Geyda, Kimberly; Bossuyt, Veerle; Lannin, Donald R; Abu-Khalaf, Maysa; Sikov, William; Dimitrova, Nevenka; Harris, Lyndsay N

    2016-02-01

    To best define biomarkers of response, and to shed insight on mechanism of action of certain clinically important agents for early breast cancer, we used a brief-exposure paradigm in the preoperative setting to study transcriptional changes in patient tumors that occur with one dose of therapy prior to combination chemotherapy. Tumor biopsies from breast cancer patients enrolled in two preoperative clinical trials were obtained at baseline and after one dose of bevacizumab (HER2-negative), trastuzumab (HER2-positive) or nab-paclitaxel, followed by treatment with combination chemo-biologic therapy. RNA-Sequencing based PAM50 subtyping at baseline of 46 HER2-negative patients revealed a strong association between the basal-like subtype and pathologic complete response (pCR) to chemotherapy plus bevacizumab (p ≤ 0.0027), but did not provide sufficient specificity to predict response. However, a single dose of bevacizumab resulted in down-regulation of a well-characterized TGF-β activity signature in every single breast tumor that achieved pCR (p ≤ 0.004). The TGF-β signature was confirmed to be a tumor-specific read-out of the canonical TGF-β pathway using pSMAD2 (p ≤ 0.04), with predictive power unique to brief-exposure to bevacizumab (p ≤ 0.016), but not trastuzumab or nab-paclitaxel. Down-regulation of TGF-β activity was associated with reduction in tumor hypoxia by transcription and protein levels, suggesting therapy-induced disruption of an autocrine-loop between tumor stroma and malignant cells. Modulation of the TGF-β pathway upon brief-exposure to bevacizumab may provide an early functional readout of pCR to preoperative anti-angiogenic therapy in HER2-negative breast cancer, thus providing additional avenues for exploration in both preclinical and clinical settings with these agents. PMID:26284485

  12. Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer.

    PubMed

    Clemens, Michael R; Gladkov, Oleg A; Gartner, Elaina; Vladimirov, Vladimir; Crown, John; Steinberg, Joyce; Jie, Fei; Keating, Anne

    2015-01-01

    The objective of this study was to assess the efficacy and tolerability of YM155, a survivin suppressor, in combination with docetaxel, compared with docetaxel alone in patients with HER2-negative metastatic breast cancer. This phase II, multicenter, open-label, 2-arm study randomized patients (≥18 years) with histologically or cytologically confirmed stage IV HER2-negative metastatic breast cancer and ≥1 measurable lesion, to receive docetaxel alone or docetaxel plus YM155. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR), biomarker assessment, and analysis of circulating tumor cells. Patients were women diagnosed with HER2-negative breast cancer; most had received prior drug therapies. The median PFS was 8.4 months with YM155 plus docetaxel (n = 50) and 10.5 months with docetaxel alone (n = 51; HR 1.53; 95 % CI 0.83, 2.83; P = 0.176). No statistically significant differences were observed for secondary endpoints, although slightly greater OS (630 vs 601 days; P = 0.768), CBR (84.3 vs 82.0 %; P = 0.855), DOR, and TTR were observed with docetaxel alone compared with YM155 plus docetaxel, whereas ORR was similar (25.5 vs 26.0). The most common TEAEs observed with YM155 plus docetaxel compared with docetaxel alone were neutropenia (83.3 vs 84.3 %), alopecia (62.5 vs 52.9 %), fatigue (50 vs 41.2 %), and nausea (37.5 vs 41.2 %). Although YM155 is a novel drug that suppresses survivin, YM155 plus docetaxel exhibited no statistically significant differences in endpoints compared with docetaxel alone. The combination regimen was well tolerated. PMID:25547219

  13. Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells.

    PubMed

    Shetty, Praveenkumar; Bargale, Anil; Patil, Basavraj R; Mohan, Rajashekar; Dinesh, U S; Vishwanatha, Jamboor K; Gai, Pramod B; Patil, Vidya S; Amsavardani, T S

    2016-01-01

    Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N-linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value. PMID:26438086

  14. A phase II, multicenter, single-arm trial of eribulin as first-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer.

    PubMed

    Takashima, Tsutomu; Tokunaga, Shinya; Tei, Seika; Nishimura, Shigehiko; Kawajiri, Hidemi; Kashiwagi, Shinichiro; Yamagata, Shigehito; Noda, Satoru; Nishimori, Takeo; Mizuyama, Yoko; Sunami, Takeshi; Tezuka, Kenji; Ikeda, Katsumi; Ogawa, Yoshinari; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei

    2016-01-01

    The treatment goals for metastatic breast cancer (MBC) are prolonging survival and improving the quality of life. Eribulin, a non-taxane tubulin inhibitor, demonstrated improved survival in previous studies and also showed mild toxicity when used in late-line therapy for MBC. We conducted a phase II study to investigate the efficacy of eribulin mesylate as the first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative MBC. This was a phase II, open-label, single-arm, multicenter trial conducted in Japan. Patients with HER2-negative MBC received intravenous eribulin (1.4 mg/m(2) on days 1 and 8 of each 21-day cycle). The primary efficacy outcome was overall response rate (ORR). Secondary outcomes included time to treatment failure, progression-free survival (PFS), overall survival (OS), and safety. A total of 35 patients were enrolled and received a median of 8 (range 1-21) cycles of eribulin therapy. ORR and clinical benefit rate were 54.3 and 62.9 %, respectively. Median PFS was 5.8 months and median OS was 35.9 months. Grade 3 or 4 neutropenia was observed in 63 % of patients. The majority of non-hematological adverse events were mild in severity. The present trial demonstrated that eribulin has antitumor activity comparable with other key established cytotoxic agents with acceptable safety and tolerability. Thus, eribulin as first-line chemotherapy might be beneficial for patients with HER2-negative MBC. PMID:27026861

  15. Feasibility Study of EndoTAG-1, a Tumor Endothelial Targeting Agent, in Combination with Paclitaxel followed by FEC as Induction Therapy in HER2-Negative Breast Cancer

    PubMed Central

    Lemort, Marc; Wilke, Celine; Vanderbeeken, Marie-Catherine; D’Hondt, Veronique; De Azambuja, Evandro; Gombos, Andrea; Lebrun, Fabienne; Dal Lago, Lissandra; Bustin, Fanny; Maetens, Marion; Ameye, Lieveke; Veys, Isabelle; Michiels, Stefan; Paesmans, Marianne; Larsimont, Denis; Sotiriou, Christos; Nogaret, Jean-Marie; Piccart, Martine; Awada, Ahmad

    2016-01-01

    Background EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel. Methods HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated. Results Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04). Conclusions The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment

  16. Bevacizumab in combination with a taxane for the first-line treatment of HER2-negative metastatic breast cancer.

    PubMed

    Rodgers, M; Soares, M; Epstein, D; Yang, H; Fox, D; Eastwood, A

    2011-05-01

    This paper presents a summary of the evidence review group (ERG) report into the use of bevacizumab (Avastin®, Roche) in combination with a taxane for the treatment of untreated metastatic breast cancer (mBC). The main clinical effectiveness data were derived from a single, open-label randomised controlled trial (RCT) (E2100) that evaluated the addition of bevacizumab to weekly (q.w.) paclitaxel in patients with human epidermal growth factor receptor 2-negative mBC who had not previously received chemotherapy for advanced disease. This trial reported statistically significant increases in median progression-free survival (PFS) for the addition of bevacizumab (5.8-11.3 months). Median overall survival was not significantly different between the two groups; whether this is a true null finding or due to crossover between treatment arms cannot be established, as relevant data were not collected. The manufacturer reported that the addition of bevacizumab to paclitaxel q.w. therapy was associated with a significant improvement in quality of life, as measured by FACT-B (functional assessment of cancer therapy for breast cancer) scores. However, the ERG noted that these results were based on extreme imputed values, the removal of which led to non-significant differences in quality of life. The manufacturer conducted an indirect comparison. However, owing to methodological limitations and concerns about the validity and exchangeability of the included trials, the ERG did not consider the findings to be reliable. One additional relevant RCT [AVADO (Avastin and Docetaxel); BO17708] evaluating the addition of bevacizumab to docetaxel was excluded from the manufacturer's submission. This was summarised by the ERG. In terms of response rate and PFS, AVADO reported a markedly smaller benefit of adding bevacizumab to docetaxel than that reported for adding bevacizumab to q.w. paclitaxel in E2100. AVADO also reported no statistically significant effect of combination therapy

  17. Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

    PubMed

    Lobo, Christopher; Lopes, Gilberto; Baez, Odalys; Castrellon, Aurelio; Ferrell, Annapoorna; Higgins, Connie; Hurley, Erin; Hurley, Judith; Reis, Isildinha; Richman, Stephen; Seo, Pearl; Silva, Orlando; Slingerland, Joyce; Tukia, Keleni; Welsh, Catherine; Glück, Stefan

    2010-09-01

    In order to examine the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-P) in combination with bevacizumab (B) and gemcitabine (G) for the first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, open-label phase II trial, patients with HER2-negative MBC received gemcitabine 1500 mg/m(2), nab-paclitaxel 150 mg/m(2), and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary end point was progression free survival (PFS); secondary end points were overall response rate (ORR), complete (CR) and partial (PR) response rates, clinical benefit (ORR + stable disease), overall survival (OS), and safety. Thirty patients were enrolled. One patient was ineligible and was not included in analysis. Median PFS was 10.4 months (95% CI: 5.6-15.2 months). ORR was 75.9%, comprising eight (27.6%) CRs and 14 (48.3%) PRs; five patients had stable disease (SD) and two patients (6.9%) had progressive disease (PD) as their best response. The clinical benefit rate was 93.1% (27/29) in the overall group and 84.6% in the triple-negative cohort (11/13). The 18-month survival rate was 77.2% (95% CI: 51.1-90.5%). Eight (27.6%) patients experienced grade 3 or 4 toxicity: grade 4 neutropenic fever (n = 1) and grade 3 infection (n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-P, B, and G demonstrated a median PFS of 10.4 months and a 75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study. PMID:20585851

  18. Prospective Validation of Immunological Infiltrate for Prediction of Response to Neoadjuvant Chemotherapy in HER2-Negative Breast Cancer – A Substudy of the Neoadjuvant GeparQuinto Trial

    PubMed Central

    Issa-Nummer, Yasmin; Darb-Esfahani, Silvia; Loibl, Sibylle; Kunz, Georg; Nekljudova, Valentina; Schrader, Iris; Sinn, Bruno Valentin; Ulmer, Hans-Ullrich; Kronenwett, Ralf; Just, Marianne; Kühn, Thorsten; Diebold, Kurt; Untch, Michael; Holms, Frank; Blohmer, Jens-Uwe; Habeck, Jörg-Olaf; Dietel, Manfred; Overkamp, Friedrich; Krabisch, Petra; von Minckwitz, Gunter; Denkert, Carsten

    2013-01-01

    Introduction We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). The aim of this study was to prospectively validate the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT. Patients and Methods The immunological infiltrate was prospectively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study, a substudy of the neoadjuvant GeparQuinto study. Intratumoral lymphocytes (iTuLy), stromal lymphocytes (strLy) as well as lymphocyte-predominant breast cancer (LPBC) were evaluated by histopathological assessment. Pathological complete response (pCR) rates were analyzed and compared between the defined subgroups using the exact test of Fisher. Results Patients with lymphocyte-predominant breast cancer (LPBC) had a significantly increased pCR rate of 36.6%, compared to non-LPBC patients (14.3%, p<0.001). LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis (LPBC: OR 2.7, p = 0.003, strLy: OR 1.2, p = 0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p = 0.01) but not in multivariate logistic regression analysis (OR 1.2, p = 0.11). Conclusion Confirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies. PMID:24312450

  19. HER2 intratumoral heterogeneity analyses by concurrent HER2 gene and protein assessment for the prognosis of HER2 negative invasive breast cancer patients.

    PubMed

    Kurozumi, Sasagu; Padilla, Mary; Kurosumi, Masafumi; Matsumoto, Hiroshi; Inoue, Kenichi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari; Ranger-Moore, Jim; Allred, D Craig; Dennis, Eslie; Nitta, Hiroaki

    2016-07-01

    HER2 gene-protein assay (GPA) is a new method for the simultaneous evaluation of HER2 immunohistochemistry (IHC) and HER2 dual in situ hybridization (DISH) on single tissue sections of breast cancer. We investigated the presence of HER2 gene and protein discrepancy and HER2-heterogeneity using HER2-GPA. HER2 status was analyzed for the correlation between the presence of HER2-heterogeneity and patient prognosis. Consecutive 280 invasive breast cancer were examined. Statuses of HER2 protein and gene were evaluated in whole tumor sections of HER2 GPA slides. HER2 protein and gene combination patterns were classified to six phenotypic and genotypic types for each case, as well as at individual cell levels: (A) IHC and DISH positive; (B) IHC positive and DISH negative; (C) IHC equivocal and DISH positive; (D) IHC equivocal and DISH negative; (E) IHC negative and DISH positive; and (F) IHC and DISH negative. The presence of HER2-heterogeneity was determined by the existence of at least two of six types within one tumor. HER2-IHC positive patients had significantly worse survival than IHC negative patients and HER2-DISH positive patients had significantly worse survival than DISH negative patients. HER2 IHC negative and DISH positive patients had significantly worse recurrence-free survival than IHC and DISH negative patients. In the HER2 IHC and DISH negative group, the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Notably, among triple negative breast cancer (TNBC), the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Our study suggests that the presence of HER2-heterogeneity might be a prognostic factor in HER2 negative breast cancer patients, especially in TNBC. PMID:27318853

  20. Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study)

    PubMed Central

    Hasegawa, Yoshie; Tanino, Hirokazu; Horiguchi, Jun; Miura, Daishu; Ishikawa, Takashi; Hayashi, Mitsuhiro; Takao, Shintaro; Kim, Seung Jin; Yamagami, Kazuhiko; Miyashita, Masaru; Konishi, Muneharu; Shigeoka, Yasushi; Suzuki, Masato; Taguchi, Tetsuya; Kubota, Tomoyuki; Akazawa, Kouhei; Kohno, Norio

    2015-01-01

    Purpose Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT). Methods Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug. Results This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in

  1. Real-world adjuvant TAC or FEC-D for HER2-negative node-positive breast cancer in women less than 50 years of age

    PubMed Central

    Lupichuk, S.; Tilley, D.; Kostaras, X.; Joy, A.A.

    2016-01-01

    Purpose We compared the efficacy, toxicity, and use of granulocyte colony–stimulating factor (g-csf) with tac (docetaxel–doxorubicin–cyclophosphamide) and fec-d (5-fluorouracil–epirubicin–cyclophosphamide followed by docetaxel) in women less than 50 years of age. Methods The study included all women more than 18 years but less than 50 years of age with her2-negative, node-positive, stage ii or iii breast cancer diagnosed in Alberta between 2008 and 2012 who received tac (n = 198) or fec-d (n = 274). Results The patient groups were well-balanced, except that radiotherapy use was higher in the tac group (91.9% vs. 79.9%, p < 0.001). At a median follow-up of 49.6 months, disease-free survival was 91.4% for tac and 92.0% for fec-d (p = 0.76). Overall survival (os) was 96% with tac and 95.3% with fec-d (p = 0.86).The incidences of grades 3 and 4 toxicities were similar in the two groups (all p > 0.05). Overall, febrile neutropenia (fn) was reported in 11.6% of tac patients and 15.7% of fec-d patients (p = 0.26). However, use of g-csf was higher in the tac group than in the fec-d group (96.4% vs. 71.5%, p < 0.001). Hospitalization for fn was required in 10.5% of tac patients and 13.0% of fec-d patients (p = 0.41). In g-csf–supported and –unsupported patients receiving tac, fn occurred at rates of 11.1% and 33.3% respectively (p = 0.08); in patients receiving the fec portion of fec-d, those proportions were 2.9% and 8.1% respectively (p = 0.24); and in patients receiving docetaxel after fec, the proportions were 4.1% and 17.6% respectively (p < 0.001). Conclusions In women less than 50 years of age receiving adjuvant tac or fec-d, we observed no differences in efficacy or other nonhematologic toxicities. Based on the timing and rates of fn, use of prophylactic g-csf should be routine for the docetaxel-containing portion of treatment; however, prophylactic g-csf could potentially be avoided during the fec portion of fec-d treatment. PMID:27330344

  2. 18F-fluorodeoxyglucose (FDG) PET/CT after two cycles of neoadjuvant therapy may predict response in HER2-negative, but not in HER2-positive breast cancer

    PubMed Central

    Mo, Miao; Bao, Xiao; Zhang, Yingjian; Liu, Guangyu; Zhang, Jun; Geng, Daoying

    2015-01-01

    The aim of this prospective study was to assess the ability of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) scanning to predict pathological complete response (pCR) in breast cancer, and to investigate whether timing of the scan and trastuzumab treatment influence the accuracy of pCR prediction in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We treated 81 locally advanced breast cancer patients with four cycles of neoadjuvant chemotherapy (NAC). HER2-negative breast cancer patients received NAC alone, while HER2-positive breast cancer patients received NAC plus trastuzumab. 18FDG PET/CT scans were scheduled at baseline and after the second cycle of NAC. Axillary lymph node (ALN) dissection was performed after the last cycle of neoadjuvant therapy. Relative changes in standardized uptake values (SUV) between the two PET/CT scans (ΔSUV) in primary tumors and ALN metastases were calculated. There were 75 patients with 150 PET/CT scans in the final analysis, including 41 HER2-negative and 34 HER2-positive cases. In the HER2-negative group, the ΔSUV predicted overall and ALN pCR; the receiver operating characteristics-areas under curve (ROC-AUC) were 0.87 and 0.80 (P = 0.0014 and 0.031, respectively) and the negative predictive values were 94% and 89% respectively. However, in the HER2-positive group, ΔSUV could predict neither overall nor ALN pCR; the ROC-AUCs were only 0.56 and 0.53, with P = 0.53 and 0.84, respectively. Hence, the ΔSUV after two cycles of neoadjuvant therapy could predict pCR in HER2-negative patients treated with NAC alone, but not in HER2-positive patients treated with NAC plus trastuzumab. PMID:26336821

  3. FLT PET in Measuring Treatment Response in Patients With Newly Diagnosed Estrogen Receptor-Positive, HER2-Negative Stage I-III Breast Cancer

    ClinicalTrials.gov

    2016-06-02

    Estrogen Receptor Positive; HER2/Neu Negative; Male Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  4. Phase II Trial of Neoadjuvant Weekly Nanoparticle Albumin-Bound Paclitaxel, Carboplatin, and Biweekly Bevacizumab Therapy in Women With Clinical Stage II or III HER2-Negative Breast Cancer

    PubMed Central

    Mrózek, Ewa; Layman, Rachel; Ramaswamy, Bhuvaneswari; Lustberg, Maryam; Vecchione, Andrea; Knopp, Michael V.; Shapiro, Charles L.

    2014-01-01

    This phase II trial tested the rate of pathologic complete response (pCR) achieved by women with stage II–III human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (BC) treated with neo-adjuvant nanoparticle albumin-bound paclitaxel (nab-P), carboplatin and bevacizumab. The rate of pCR was 18%, all pCRs were observed in patients with triple negative BC. Background We hypothesized that adding bevacizumab to neoadjuvant chemotherapy (NCT) with nab-P and carboplatin would increase the rates of pCR in BC patients and that early changes in tumor vascularity imaged by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) would predict pCR. Methods Thirty-three women with clinical stage II or III HER2-negative BC received nab-P 100 mg/m2 and carboplatin area under the curve = 2 on days 1, 8, and 15 in combination with bevacizumab 10 mg/kg on days 1 and 15 administered every 28 days. Results Six patients (18%) achieved pCR, all pCRs occurred in triple-negative BC (TNBC) (pCR = 50% for TNBC). At the end of cycle 2, the changes in relative angiogenic volume were significantly different between responders and non-responders (P = .001). The major toxicity of this NCT was myelosuppression. Conclusion NCT with weekly nab-P, carboplatin, and biweekly bevacizumab resulted in a pCR rate that was neither superior to the historical data with anthracycline- or taxane-containing NCT nor to carboplatin and taxane combinations in patients with HER2-negative BC. In patients with TNBC, the observed pCR rate was 50%. The early changes in the relative angiogenic volume imaged by DCE-MRI could predict pCR. PMID:24703985

  5. 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

  6. 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

  7. A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies

    PubMed Central

    2011-01-01

    Introduction The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. Methods Blood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Student's t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data. Results The proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10). Conclusions Compared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset

  8. Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor–Positive, HER2-Negative Early Breast Cancer1

    PubMed Central

    Azim, Hamdy A.; Kassem, Loay; Treilleux, Isabelle; Wang, Qing; El Enein, Mona Abu; Anis, Shady E.; Bachelot, Thomas

    2016-01-01

    BACKGROUND: The PI3K/AKT/mTOR pathway alterations have been shown to play significant roles in the development, progression, and metastatic spread of breast cancer. Furthermore, they have been implicated in the process of drug resistance, especially endocrinal therapies. In this study, we aimed to define the correlation between the PI3K mutations and the expression of the phosphorylated forms of different downstream molecules in women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2–negative (luminal) early breast cancer treated at Cairo university hospitals. METHODS: Next-generation sequencing was used to detect mutations in the PIK3CA hotspots (in exons 9 and 20). Immunohistochemistry was performed on tissue microarray blocks prepared from samples of 35 Egyptian luminal breast cancer patients in the pathology department of Centre Léon Bérard (CLB). The intensity and the percentage of stained tumor cells were integrated to define high versus low biomarker expression. The cytoplasmic and nuclear stainings were graded separately. Patients were followed for a median of 4.7 years (2.1 to 6.9 years). Correlation was done between PI3K mutations and the immunohistochemistry expression of pAKT, LKB1, p4EBP1, and pS6 ribosomal protein (pS6RP) with the clinicopathologic features and disease free survival (DFS) of the patients. RESULTS: Median age at diagnosis was 51.3 years (range, 25 to 82 years). Tumors were larger than 20 mm in 79.2% of the cases, whereas 57.9% had axillary lymph node deposits. Only 12.3% of the patients had SBR grade I tumors, 50.8% had grade II, and 36.8% had grade III. ERs were negative in 6 patients (17%) after pathology review. Thirty-two cases were assessable for LKB1 and pAKT, 33 for p4EBP1 and pS6RP, and 24 for PI3K mutations. Nuclear LKB1, cytoplasmic LKB1, nuclear pAKT, cytoplasmic pAKT, nuclear p4EBP1, and cytoplasmic pS6RP expression was high in 65.6%, 62.5%, 62.5%, 68.8%, 42.4%, and 57.6%, respectively

  9. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life

    PubMed Central

    Palumbo, Raffaella; Sottotetti, Federico; Trifirò, Giuseppe; Piazza, Elena; Ferzi, Antonella; Gambaro, Anna; Spinapolice, Elena Giulia; Pozzi, Emma; Tagliaferri, Barbara; Teragni, Cristina; Bernardo, Antonio

    2015-01-01

    Background A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Patients and methods Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m2 as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. Results All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%–61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52–86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0–11.6 months, range 5–21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Conclusion Our results showed that single-agent nab-paclitaxel 260 mg/m2 every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen

  10. Determination of HER2 status using both serum HER2 levels and circulating tumor cells in patients with recurrent breast cancer whose primary tumor was HER2 negative or of unknown HER2 status

    PubMed Central

    Fehm, Tanja; Becker, Sven; Duerr-Stoerzer, Silke; Sotlar, Karl; Mueller, Volkmar; Wallwiener, Diethelm; Lane, Nancy; Solomayer, Erich; Uhr, Jonathan

    2007-01-01

    Introduction At the time when metastatic disease is identified, assessment of human epidermal growth factor receptor (HER)2 status might help to optimize treatment decisions if HER2 status was not determined at first diagnosis and if HER2 positivity has been acquired during disease progression. Within this context, determination of serum HER2 or evaluation of HER2 status in circulating tumor cells (CTCs) may be of clinical relevance because metastatic tissue may be difficult to obtain for analysis as a result of its localization. The aim of this study was therefore to determine the HER2 status in serum and corresponding CTCs in patients with metastatic breast cancer whose primary tumors were HER2 negative or of unknown HER2 status. Methods Blood samples were obtained from 77 metastatic breast cancer patients with negative (n = 44) or unknown (n = 33) HER2 status. Serum HER2 was determined using a commercial HER2/neu ELISA kit. CTCs were detected by slide-based assay using immunomagnetic enrichment and characterized by phenotyping and genotyping. Alternatively, a commercial kit, based on RT-PCR, was used to detect and characterize CTCs. Results Twenty out of 77 patients with metastatic disease had elevated serum levels of HER2. Blood samples could be analyzed for the presence of CTCs in 67 patients. Eight out of 21 patients with detectable CTCs exhibited HER2 amplification. Twenty-three out of 77 patients were HER2 positive using at least one method. Concordance between HER2 status of CTCs and serum HER2 was observed in 15 of 21 patients (71%). In six patients conflicting results were obtained. Three patients with elevated serum HER2 status had HER2-negative CTCs, whereas three patients with HER2-positive CTCs had normal serum HER2 levels. Conclusion A subgroup of patients with initially negative or unknown HER2 status can have elevated serum HER2 levels and/or HER2-positive CTCs at the time of development of metastatic disease. Although only a small number of

  11. Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9.

    PubMed

    Abraham, Jame; Robidoux, André; Tan, Antoinette R; Limentani, Steven; Sturtz, Keren; Shalaby, Ibrahim; Alcorn, Hope; Buyse, Marc E; Wolmark, Norman; Jacobs, Samuel A

    2015-07-01

    Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2-negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received ≥1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients. PMID:26126970

  12. Efficacy and safety of adding an agent to bevacizumab/taxane regimens for the first-line treatment of Her2-negative patients with locally recurrent or metastatic breast cancer: results from seven randomized controlled trials

    PubMed Central

    Liu, Xiaoqun; Liu, Xiangdong; Qiao, Tiankui; Chen, Wei; Yuan, Sujuan

    2016-01-01

    Background The combined therapy of bevacizumab (BEV) with taxane (paclitaxel or docetaxel) has shown an improvement on progression-free survival (PFS) and objective remission in Her2-negative patients with locally recurrent or metastatic breast cancer (LR/MBC). However, there was no benefit in overall survival (OS). The aim of this study was to evaluate the efficacy and safety of adding an agent to the BEV/taxane regimens for the treatment of Her2-negative patients with LR/MBC in a first-line setting. Materials and methods We searched PubMed, Web of Science, EMBASE, EBSCO, and the Cochrane Library databases for eligible trials. A meta-analysis was performed using Review Manager 5.0 freeware package. We calculated the hazard ratio (HR) for PFS and OS. The odds ratio (OR) was used to calculate objective response rate (ORR) and grade 3/4 drug-related adverse events. The heterogeneity of study outcomes was calculated by the χ2 test or I2 statistics. Results A total of 1,124 patients from seven randomized controlled trials were analyzed. Our meta-analysis showed that the ORR was significantly improved in the BEV/taxane-based triplet group when compared with the BEV/taxane-based doublet group (OR =1.31, 95% confidence interval [CI]: 1.03–1.67, P=0.03). A subset analysis showed that a similar result was achieved in the triplet group in which a cytotoxic agent was added (OR =1.46, 95% CI: 1.09–1.95, P=0.01). However, the PFS and OS had no statistically significant differences between the two groups (HR =0.87, 95% CI: 0.68–1.13, P=0.31; HR =0.98, 95% CI: 0.82–1.16, P=0.78, respectively). Regarding safety, thromboembolic events, fatigue, and diarrhea (all $grade 3) were more frequently observed in the BEV/taxane-based triplet group (OR =3.8, 95% CI: 1.86–7.79, P=0.0003; OR =1.55, 95% CI: 1.05–2.27, P=0.03; OR =2.1, 95% CI: 1.29–3.41, P=0.003, respectively). Other toxic effects had no statistically significant differences between the two groups. Conclusion Our

  13. Entinostat, Nivolumab, and Ipilimumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic HER2-Negative Breast Cancer

    ClinicalTrials.gov

    2016-09-09

    Breast Adenocarcinoma; HER2/Neu Negative; Invasive Breast Carcinoma; Recurrent Breast Carcinoma; Solid Neoplasm; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  14. Survival Improvement in Korean Breast Cancer Patients Due to Increases in Early-Stage Cancers and Hormone Receptor Positive/HER2 Negative Subtypes: A Nationwide Registry-Based Study

    PubMed Central

    You, Jee Man; Kim, Yun Gyoung; Moon, Hyeong-Gon; Nam, Seok Jin; Lee, Jong Won; Lim, Woosung; Lee, Mi-Ri; Noh, Dong-Young

    2015-01-01

    Purpose The aim of this study was to investigate whether the observed changes over time in the survival rates vary according to the intrinsic subtypes of breast cancer diagnosed. Methods Data from 46,320 breast cancer patients in the Korean Breast Cancer Registry who underwent surgery between 1999 and 2006 were reviewed. Among them, results from 25,887 patients with available data about the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were analyzed. Patients were classified into two cohorts according to the year in which they underwent surgery: 1999-2002 and 2003-2006. Results The patients treated in the latter time period showed significantly better overall survival (OS) compared with those in the former period when adjusted for follow-up duration. The proportion of hormone receptor+/HER2-subtype and stage I breast cancer were significantly higher in the latter period (47.4% vs. 54.6%, p<0.001; 31.0% vs. 39.6%, p<0.001, respectively). Improvement in OS between the former and latter periods was seen in all subtypes of breast cancer, including triple-negative cancers (all p-values <0.001 in univariate and multivariate analyses). Conclusion Improvement in survival in Korean breast cancer patients over the study years is being observed in all subtypes of breast cancer, implying that increases in both early-stage detection and the proportion of less aggressive cancers contribute to this improvement. PMID:25834605

  15. A phase 3 tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-Negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Sorafenib is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized phase 2b screening trial in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer demonstrated a significant improvement in progression-free survival (PFS) when sorafenib was added to capecitabine versus placebo (median 6.4 versus 4.1 months; hazard ratio = 0.58; P = 0.001). Most drug-related adverse events were Grade 1/2 in severity with the exception of Grade 3 hand-foot skin reaction/syndrome (44% versus 14%, respectively). These results suggest a role for the combination of sorafenib and capecitabine in breast cancer and supported a phase 3 confirmatory trial. Here we describe RESILIENCE - a multinational, double-blind, randomized, placebo-controlled, phase 3 trial - assessing the addition of sorafenib to first- or second-line capecitabine in advanced HER2-negative breast cancer. Methods/design Eligibility criteria include ≥18 years of age, ≤1 prior chemotherapy regimen for metastatic disease, and resistant to/failed taxane and anthracycline or no indication for further anthracycline. Prior treatment with a vascular endothelial growth factor inhibitor is not allowed. Patients with significant cardiovascular disease or active brain metastases are not eligible. Patients are stratified by hormone-receptor status, geographic region, and prior metastatic chemotherapy status and randomized (1:1) to capecitabine (1000 mg/m2 orally twice daily (BID), days 1 to 14 of 21) in combination with sorafenib (orally BID, days 1 to 21, total dose 600 mg/day) or matching placebo. Capecitabine and sorafenib/placebo doses can be escalated to 1250 mg/m2 BID and 400 mg BID, respectively, as tolerated, or reduced to manage toxicity. Dose re-escalation after a reduction is allowed for sorafenib/placebo but not for capecitabine. This dosing algorithm was designed to mitigate dermatologic and other toxicity, in addition to detailed guidelines

  16. Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

    PubMed

    Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

    2013-02-01

    Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928

  17. Is It Important to Adapt Neoadjuvant Chemotherapy to the Visible Clinical Response? An Open Randomized Phase II Study Comparing Response-Guided and Standard Treatments in HER2-Negative Operable Breast Cancer

    PubMed Central

    Mouret-Reynier, Marie-Ange; Savoye, Aude-Marie; Abrial, Catherine; Kwiatkowski, Fabrice; Garbar, Christian; DuBray-Longeras, Pascale; Eymard, Jean-Christophe; Lebouedec, Guillaume; Vanpraagh, Isabelle; Penault-Llorca, Frederique; Chollet, Philippe; Cure, Hervé

    2015-01-01

    Background. Neoadjuvant treatment provides a unique opportunity to evaluate individual tumor sensitivity. This study evaluated whether a response-guided strategy could improve clinical outcome compared with a standard treatment. Methods. Overall, 264 previously untreated stage II–III operable breast cancer patients were randomized to receive either standard treatment (arm A, n = 131), consisting of fluorouracil, epirubicin, and cyclophosphamide (FEC100: 500, 100, and 500 mg/m2, respectively, for 3 cycles) followed by docetaxel (100 mg/m2 for 3 cycles), or adapted treatment (arm B, n = 133), beginning with 2 cycles of FEC100 and switching to docetaxel if tumor size decreased by <30% after 2 cycles or <50% after 4 cycles of FEC100 (ultrasound assessments according to World Health Organization criteria). Otherwise, FEC100 was given for six cycles before surgery. Intent-to-treat analysis was performed. Results. Similar results were observed for clinical response (objective response was 54% vs 56%, p = .18), breast conservation surgery (BCS; 67% vs 68%, p = .97), and pathological complete response rate (Chevallier classification: 14% vs 11%, p = .68; Statloff classification: 16% vs 13%, p = .82) between arms A and B. Similar toxicities were observed, even with unbalanced numbers of FEC100 and docetaxel courses. Conclusion. Adapted and standard treatments had similar results in terms of tumor response, BCS rate, and tolerability. Further survival outcome data are expected. PMID:25637380

  18. Palbociclib as a first-line treatment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health economic analysis of the Swiss Group for Clinical Cancer Research (SAKK).

    PubMed

    Matter-Walstra, K; Ruhstaller, T; Klingbiel, D; Schwenkglenks, M; Dedes, K J

    2016-07-01

    Endocrine therapy continues to be the optimal systemic treatment for metastatic ER(+)HER2(-) breast cancer. The CDK4/6 inhibitor palbociclib combined with letrozole has recently been shown to significantly improve progression-free survival. Here we examined the cost-effectiveness of this regimen for the Swiss healthcare system. A Markov cohort simulation based on the PALOMA-1 trial (Finn et al. in Lancet Oncol 16:25-35, 2015) was used as the clinical course. Input parameters were based on summary trial data. Costs were assessed from the Swiss healthcare system perspective. Adding palbociclib to letrozole (PALLET) compared to letrozole monotherapy was estimated to cost an additional CHF342,440 and gain 1.14 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio (ICER) of CHF301,227/QALY gained. In univariate sensitivity analyses, no tested variation in key parameters resulted in an ICER below a willingness-to-pay threshold of CHF100,000/QALY. PALLET had a 0 % probability of being cost-effective in probabilistic sensitivity analyses. Lowering PALLET's price by 75 % resulted in an ICER of CHF73,995/QALY and a 73 % probability of being cost-effective. At current prices, PALLET would cost the Swiss healthcare system an additional CHF155 million/year. Palbociclib plus letrozole cannot be considered cost-effective for the first-line treatment of patients with metastatic breast cancer in the Swiss healthcare system. PMID:27277747

  19. Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor.

    PubMed

    Blackwell, Kimberly; Burris, Howard; Gomez, Patricia; Lynn Henry, N; Isakoff, Steven; Campana, Frank; Gao, Lei; Jiang, Jason; Macé, Sandrine; Tolaney, Sara M

    2015-11-01

    This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of pilaralisib (SAR245408), a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non-steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade ≥ 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer. PMID:26497877

  20. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial

    PubMed Central

    Harbeck, N.; Iyer, S.; Turner, N.; Cristofanilli, M.; Ro, J.; André, F.; Loi, S.; Verma, S.; Iwata, H.; Bhattacharyya, H.; Puyana Theall, K.; Bartlett, C. H.; Loibl, S.

    2016-01-01

    Background In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2− endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. Patients and methods Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1–4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0–100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. Results Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5–67.7 versus 63.0, 95% CI 60.6–65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (−3.3, 95% CI −5.1 to −1.5 versus 2.0, 95% CI −0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. Conclusion

  1. Breast tumour angiogenesis

    PubMed Central

    Fox, Stephen B; Generali, Daniele G; Harris, Adrian L

    2007-01-01

    The central importance of tumour neovascularization has been emphasized by clinical trials using antiangiogenic therapy in breast cancer. This review gives a background to breast tumour neovascularization in in situ and invasive breast cancer, outlines the mechanisms by which this is achieved and discusses the influence of the microenvironment, focusing on hypoxia. The regulation of angiogenesis and the antivascular agents that are used in an antiangiogenic dosing schedule, both novel and conventional, are also summarized. PMID:18190723

  2. The positive is inside the negative: HER2-negative tumors can express the HER2 intracellular domain and present a HER2-positive phenotype.

    PubMed

    Panis, Carolina; Pizzatti, Luciana; Corrêa, Stephany; Binato, Renata; Lemos, Gabriela Ferreira; Herrera, Ana Cristina da Silva do Amaral; Seixas, Teresa Fernandes; Cecchini, Rubens; Abdelhay, Eliana

    2015-02-01

    Overexpression of human epithelial growth factor receptor 2 (HER2) is a poor prognostic factor in breast cancer. HER2 is a transmembrane receptor comprising an extracellular domain (ECD), a single transmembrane domain, and an intracellular domain (ICD) with tyrosine-kinase activity. Receptor dimerization triggers pivotal effector pathways in cancer, such as phosphatidylinositol 3-kinase (PI3K) signaling. Currently, screening of HER2 in breast tumors for prognostic and therapeutic purposes involves immunohistochemical (IHC) phenotyping for the ECD, in which tumors with IHC scores below 2+ are reported as HER2-negative. We used a label-free liquid chromatography-mass spectrometry (LC-MS) proteomic approach to compare plasma samples from patients with HER2-positive breast tumors and patients with HER2-negative tumors. Patients with HER2-negative tumors expressed higher circulating levels of calpain-10 than patients with HER2-positive tumors. Calpains cleave HER2, releasing its ECD and transforming phenotypically positive tumors into phenotypically negative tumors. Therefore, we investigated the expression of the ICD in HER2-negative samples that overexpressed calpain-10. We found that 16% of HER2-negative tumors were positive for HER2-ICD, which was associated with circulating HER2-ECD. HER2 gene amplification was also observed in some HER2-negative tumors. Positive staining for the PI3K pathway was observed in the HER2-negative, ICD-positive tumors, similar to the HER2-positive cohort. Microarray analysis revealed that HER2-negative, ICD-positive samples clustered between HER2-positive tumors and triple-negative tumors. Survival analysis revealed that outcome in women with HER2-negative, ICD-positive tumors was better than in women bearing HER2-negative, ICD-negative (triple negative) tumors but was quite similar to HER2-positive tumors and worse than women with luminal A tumors. Moreover, in vitro analyses revealed that MDA-MB 231, a triple negative cell line

  3. Prognostic ability of EndoPredict compared to research-based versions of the PAM50 risk of recurrence (ROR) scores in node-positive, estrogen receptor-positive, and HER2-negative breast cancer. A GEICAM/9906 sub-study.

    PubMed

    Martin, Miguel; Brase, Jan C; Ruiz, Amparo; Prat, Aleix; Kronenwett, Ralf; Calvo, Lourdes; Petry, Christoph; Bernard, Philip S; Ruiz-Borrego, Manuel; Weber, Karsten E; Rodriguez, César A; Alvarez, Isabel M; Segui, Miguel A; Perou, Charles M; Casas, Maribel; Carrasco, Eva; Caballero, Rosalía; Rodriguez-Lescure, Alvaro

    2016-02-01

    There are several prognostic multigene-based tests for managing breast cancer (BC), but limited data comparing them in the same cohort. We compared the prognostic performance of the EndoPredict (EP) test (standardized for pathology laboratory) with the research-based PAM50 non-standardized qRT-PCR assay in node-positive estrogen receptor-positive (ER+) and HER2-negative (HER2-) BC patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial. EP and PAM50 risk of recurrence (ROR) scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/HER2- patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk-categories according to prespecified cutoffs. Distant metastasis-free survival (MFS) was analyzed by Kaplan-Meier. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year MFS: ROR-S 87 %; ROR-P 89 %; EP 93 %). There was no significant difference between tests. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88 %; ROR-PT 92 %; EPclin 100 %). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters. EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2- BC patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability. PMID:26909792

  4. The perivascular niche regulates breast tumour dormancy.

    PubMed

    Ghajar, Cyrus M; Peinado, Héctor; Mori, Hidetoshi; Matei, Irina R; Evason, Kimberley J; Brazier, Hélène; Almeida, Dena; Koller, Antonius; Hajjar, Katherine A; Stainier, Didier Y R; Chen, Emily I; Lyden, David; Bissell, Mina J

    2013-07-01

    In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth. PMID:23728425

  5. Giant malignant phyllodes tumour of breast.

    PubMed

    Krishnamoorthy, Ramakrishnan; Savasere, Thejas; Prabhuswamy, Vinod Kumar; Babu, Rajashekhara; Shivaswamy, Sadashivaiah

    2014-01-01

    The term phyllodes tumour includes lesions ranging from completely benign tumours to malignant sarcomas. Clinically phyllodes tumours are smooth, rounded, and usually painless multinodular lesions indistinguishable from fibroadenomas. Percentage of phyllodes tumour classified as malignant ranges from 23% to 50%. We report a case of second largest phyllodes tumour in a 35-year-old lady who presented with swelling of right breast since 6 months, initially small in size, that progressed gradually to present size. Examination revealed mass in the right breast measuring 36×32 cms with lobulated firm surface and weighing 10 kgs. Fine needle aspiration cytology was reported as borderline phyllodes; however core biopsy examination showed biphasic neoplasm with malignant stromal component. Simple mastectomy was done and specimen was sent for histopathological examination which confirmed the core biopsy report. Postoperatively the patient received chemotherapy and radiotherapy. The patient is on follow-up for a year and has not shown any evidence of metastasis or recurrence. PMID:25548696

  6. A composite malignant tumour of the elderly female breast

    PubMed Central

    Wayte, D. M.; Stewart, J. B.; McKenzie, C. G.

    1970-01-01

    A composite malignant tumour arising in the breast of an elderly woman is described. The cystic tumour containing areas of squamous metaplasia, bone formation, adenocarcinoma, and osteosarcoma was surrounded by the typical changes of mammary dysplasia (fibroadenosis). The classification and acceptance of such tumours is highly debatable. There is no one acceptable classification of breast sarcomas and hence the prognosis of such neoplasms, particularly those containing heterologous tissues, is poorly defined. Evidence is presented in support of such composite tumours as being definite entities which arise from the closely associated epithelial and mesenchymal components of the breast simultaneously. Images PMID:4320045

  7. Mixed tumour of salivary gland type of the male breast.

    PubMed

    Simha, M R; Doctor, V M; Udwadia, T E

    1992-03-01

    Benign breast tumours with a mixed cartilaginous and epithelial component are distinctly rare as evident from the literature. A case of Mixed Tumour of the breast presenting pre-operatively as a hard mass in a 65 year old male is reported. Histologically, it was composed of a mixture of benign cartilage, myoepithelial cells, tubules and a myxoid stroma in fat. A brief review of cartilage bearing lesions and mixed tumour in the mammary region is discussed. PMID:1328037

  8. Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery

    ClinicalTrials.gov

    2016-09-15

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  9. Breast spindle cell tumours: about eight cases

    PubMed Central

    Abd El All, Howayda S

    2006-01-01

    Background Breast spindle cell tumours (BSCTs), although rare, represent a heterogeneous group with different treatment modalities. This work was undertaken to evaluate the utility of fine needle aspiration cytology (FNAC), histopathology and immunohistochemistry (IHC) in differentiating BSCTs. Methods FNAC of eight breast masses diagnosed cytologically as BSCTs was followed by wide excision biopsy. IHC using a panel of antibodies against vimentin, pan-cytokeratin, s100, desmin, smooth muscle actin, CD34, and CD10 was evaluated to define their nature. Results FNAC defined the tumors as benign (n = 4), suspicious (n = 2) and malignant (n = 3), based on the cytopathological criteria of malignancy. Following wide excision biopsy, the tumors were reclassified into benign (n = 5) and malignant (n = 3). In the benign group, the diagnosis was raised histologically and confirmed by IHC for 3 cases (one spindle cell lipoma, one myofibroblastoma and one leiomyoma). For the remaining two cases, the diagnosis was set up after IHC (one fibromatosis and one spindle cell variant of adenomyoepithelioma). In the malignant group, a leiomyosarcoma was diagnosed histologically, while IHC was crucial to set up the diagnosis of one case of spindle cell carcinoma and one malignant myoepithelioma. Conclusion FNAC in BSCTs is an insufficient tool and should be followed by wide excision biopsy. The latter technique differentiate benign from malignant BSCTs and is able in 50% of the cases to set up the definite diagnosis. IHC is of value to define the nature of different benign lesions and is mandatory in the malignant ones for optimal treatment. Awareness of the different types of BSCTs prevents unnecessary extensive therapeutic regimes. PMID:16859566

  10. Breast tumour visualization using 3D quantitative ultrasound methods

    NASA Astrophysics Data System (ADS)

    Gangeh, Mehrdad J.; Raheem, Abdul; Tadayyon, Hadi; Liu, Simon; Hadizad, Farnoosh; Czarnota, Gregory J.

    2016-04-01

    Breast cancer is one of the most common cancer types accounting for 29% of all cancer cases. Early detection and treatment has a crucial impact on improving the survival of affected patients. Ultrasound (US) is non-ionizing, portable, inexpensive, and real-time imaging modality for screening and quantifying breast cancer. Due to these attractive attributes, the last decade has witnessed many studies on using quantitative ultrasound (QUS) methods in tissue characterization. However, these studies have mainly been limited to 2-D QUS methods using hand-held US (HHUS) scanners. With the availability of automated breast ultrasound (ABUS) technology, this study is the first to develop 3-D QUS methods for the ABUS visualization of breast tumours. Using an ABUS system, unlike the manual 2-D HHUS device, the whole patient's breast was scanned in an automated manner. The acquired frames were subsequently examined and a region of interest (ROI) was selected in each frame where tumour was identified. Standard 2-D QUS methods were used to compute spectral and backscatter coefficient (BSC) parametric maps on the selected ROIs. Next, the computed 2-D parameters were mapped to a Cartesian 3-D space, interpolated, and rendered to provide a transparent color-coded visualization of the entire breast tumour. Such 3-D visualization can potentially be used for further analysis of the breast tumours in terms of their size and extension. Moreover, the 3-D volumetric scans can be used for tissue characterization and the categorization of breast tumours as benign or malignant by quantifying the computed parametric maps over the whole tumour volume.

  11. A Study of Neoadjuvant Paclitaxel in Combination With Bavituximab in Early- Stage Triple- Negative Breast Cancer

    ClinicalTrials.gov

    2016-02-12

    Breast Cancer; Triple Negative Breast Neoplasms; Triple-Negative Breast Neoplasm; Triple-Negative Breast Cancer; Triple Negative Breast Cancer; ER-Negative PR-Negative HER2-Negative Breast Neoplasms; ER-Negative PR-Negative HER2-Negative Breast Cancer

  12. Carboplatin and Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IIB-IIIC Breast Cancer

    ClinicalTrials.gov

    2015-10-12

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  13. Neuroendocrine breast tumours: breast cancer or neuroendocrine cancer presenting in the breast?

    PubMed

    Adams, R W; Dyson, P; Barthelmes, L

    2014-04-01

    Neuroendocrine tumours (NET) of the breast are rare. Diagnosis depends on close scrutiny of core- or excisional-biopsy specimens for characteristic growth patterns (papillary, nesting or mixed), which should trigger immunohistochemical staining for neuroendocrine markers (in particular chromogranin and synaptophysin). The diagnosis is confirmed if a) >50% of the tissue specimen demonstrate neuroendocrine markers and b) in-situ ductal carcinoma is identified and/or imaging modalities exclude extra-mammary sites. Our literature search including the non-English literature identified 66 articles with data on 123 cases, including our own. Oestrogen receptors are not diagnostic for NET's of the breast as they are found in tumours of non-mammary origin, too. Half of reported cases of neuroendocrine tumours have axillary lymph node involvement. Breast-conserving surgery (wide local excision ± axillary clearance) is commonly performed for suitable tumours. Chemotherapy regimens utilised are commonly either platinum- (as for small-cell cancers) or anthracycline-based (as for primary breast cancers). Best management remains unknown. PMID:24342375

  14. Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis.

    PubMed

    Ören, Bilge; Urosevic, Jelena; Mertens, Christina; Mora, Javier; Guiu, Marc; Gomis, Roger R; Weigert, Andreas; Schmid, Tobias; Grein, Stephan; Brüne, Bernhard; Jung, Michaela

    2016-07-01

    Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV-PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27038000

  15. Thoracic Wall Reconstruction in Advanced Breast Tumours

    PubMed Central

    Daigeler, A.; Harati, K.; Goertz, O.; Hirsch, T.; Behr, B.; Lehnhardt, M.; Kolbenschlag, J.

    2014-01-01

    In advanced mammary tumours, extensive resections, sometimes involving sections of the thoracic wall, are often necessary. Plastic surgery reconstruction procedures offer sufficient opportunities to cover even large thoracic wall defects. Pedicled flaps from the torso but also free flap-plasties enable, through secure defect closure, the removal of large, ulcerated, painful or bleeding tumours with moderate donor site morbidity. The impact of thoracic wall resection on the respiratory mechanism can be easily compensated for and patientsʼ quality of life in the palliative stage of disease can often be improved. PMID:24976636

  16. Effects of childhood body size on breast cancer tumour characteristics

    PubMed Central

    2010-01-01

    Introduction Although a role of childhood body size in postmenopausal breast cancer risk has been established, less is known about its influence on tumour characteristics. Methods We studied the relationships between childhood body size and tumour characteristics in a Swedish population-based case-control study consisting of 2,818 breast cancer cases and 3,111 controls. Our classification of childhood body size was derived from a nine-level somatotype. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from fitting unconditional logistic regression models. Association between somatotype at age 7 and tumour characteristics were evaluated in a case-only analysis where P values for heterogeneity were obtained by performing one degree of freedom trend tests. Results A large somatotype at age 7 was found to be associated with decreased postmenopausal breast cancer risk. Although strongly associated with other risk factors such as age of menarche, adult body mass index and mammographic density, somatotype at age 7 remained a significant protective factor (odds ratio (OR) comparing large to lean somatotype at age 7 = 0.73, 95% confidence interval (CI) = 0.58-0.91, P trend = 0.004) after adjustment. The significant protective effect was observed within all subgroups defined by estrogen receptor (ER) and progesterone receptor (PR) status, with a stronger effect for ER-negative (0.40, 95% CI = 0.21-0.75, P trend = 0.002), than for ER-positive (0.80, 95% CI = 0.62-1.05, P trend = 0.062), tumours (P heterogeneity = 0.046). Somatotype at age 7 was not associated with tumour size, histology, grade or the presence or absence of metastatic nodes. Conclusions Greater body size at age 7 is associated with a decreased risk of postmenopausal breast cancer, and the associated protective effect is stronger for the ER-negative breast cancer subtype than for the ER-positive subtype. PMID:20398298

  17. 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

  18. Phyllodes tumours of the breast: a consensus review.

    PubMed

    Tan, Benjamin Y; Acs, Geza; Apple, Sophia K; Badve, Sunil; Bleiweiss, Ira J; Brogi, Edi; Calvo, José P; Dabbs, David J; Ellis, Ian O; Eusebi, Vincenzo; Farshid, Gelareh; Fox, Stephen B; Ichihara, Shu; Lakhani, Sunil R; Rakha, Emad A; Reis-Filho, Jorge S; Richardson, Andrea L; Sahin, Aysegul; Schmitt, Fernando C; Schnitt, Stuart J; Siziopikou, Kalliopi P; Soares, Fernando A; Tse, Gary M; Vincent-Salomon, Anne; Tan, Puay Hoon

    2016-01-01

    Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours. PMID:26768026

  19. 0927GCC: Entinostat and Anastrozole in Treating Postmenopausal Women With Triple-Negative Breast Cancer That Can Be Removed by Surgery

    ClinicalTrials.gov

    2016-03-01

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Triple-negative Breast Cancer

  20. Numerical modelling of biopotential field for detection of breast tumour.

    PubMed

    Ng, E Y K; Ng, W K; Sim, L S J; Rajendra Acharya, U

    2007-08-01

    Breast cancer is a disease characterised by the uncontrolled growth of abnormal cells. These cancer cells can travel through the body by way of blood or lymph nodes. Previous studies have indicated that, changes in the electrical properties of abnormal breast are more significant compared to the breast normal tissues. In the present study, a simple 2D models of breast (close to realistic), with and without artificially inserted malignant cancer were simulated, based upon electrical activity within the breast. We developed an inhomogeneous female breast model, closer to the actual, by considering a breast as a hemisphere with various layers of unequal thickness in supine condition. In order to determine the potential distribution developed due to a dipole source, isotropic homogeneous conductivity was assigned to each of these compartments and the volume conductor problem was solved using finite element method. Significant changes in the potential distribution were recoded in the malignant and normal breast regions. The surface potential decreases about 0.5%, for the small malignant region of surface area 13 mm(2) (spherical diameter=2mm). And it (surface potential) decreases about 16.4% for large malignant surface area of 615 mm(2) (spherical diameter=14 mm). Hence, the results show that, the sizes of tumours result in the reduction of surface potential and follows a fourth order polynomial equation. Thus, biofield analysis yields promising results in the detection of the breast cancer of various sizes. PMID:17145053

  1. Mucoadhesive Oral Wound Rinse in Preventing and Treating Stomatitis in Patients With ER- or PR-Positive Metastatic or Locally Recurrent Breast Cancer That Cannot be Removed by Surgery Receiving Everolimus

    ClinicalTrials.gov

    2016-03-04

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Oral Complications; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  2. Attenuating tumour angiogenesis: a preventive role of metformin against breast cancer.

    PubMed

    Gao, Shan; Jiang, Jingcheng; Li, Pan; Song, Huijuan; Wang, Weiwei; Li, Chen; Kong, Deling

    2015-01-01

    Metformin is one of the most widely prescribed antidiabetics for type 2 diabetes. A critical role of metformin against tumorigenesis has recently been implicated, although several studies also reported the lack of anticancer property of the antidiabetics. Given the controversies regarding the potential role of metformin against tumour progression, the effect of metformin against breast, cervical, and ovarian tumour cell lines was examined followed by in vivo assessment of metformin on tumour growth using xenograft breast cancer models. Significant inhibitory impact of metformin was observed in MCF-7, HeLa, and SKOV-3 cells, suggesting an antiproliferative property of metformin against breast, cervical, and ovarian tumour cells, respectively, with the breast tumour cells, MCF-7, being the most responsive. In vivo assessment was subsequently carried out, where mice with breast tumours were treated with metformin (20 mg/kg body weight) or sterile PBS solution for 15 consecutive days. No inhibition of breast tumour progression was detected. However, tumour necrosis was significantly increased in the metformin-treated group, accompanied by decreased capillary formation within the tumours. Thus, despite the lack of short-term benefit of metformin against tumour progression, a preventive role of metformin against breast cancer was implicated, which is at partially attributable to the attenuation of tumour angiogenesis. PMID:25883966

  3. Attenuating Tumour Angiogenesis: A Preventive Role of Metformin against Breast Cancer

    PubMed Central

    Gao, Shan; Jiang, Jingcheng; Li, Pan; Song, Huijuan; Wang, Weiwei; Li, Chen; Kong, Deling

    2015-01-01

    Metformin is one of the most widely prescribed antidiabetics for type 2 diabetes. A critical role of metformin against tumorigenesis has recently been implicated, although several studies also reported the lack of anticancer property of the antidiabetics. Given the controversies regarding the potential role of metformin against tumour progression, the effect of metformin against breast, cervical, and ovarian tumour cell lines was examined followed by in vivo assessment of metformin on tumour growth using xenograft breast cancer models. Significant inhibitory impact of metformin was observed in MCF-7, HeLa, and SKOV-3 cells, suggesting an antiproliferative property of metformin against breast, cervical, and ovarian tumour cells, respectively, with the breast tumour cells, MCF-7, being the most responsive. In vivo assessment was subsequently carried out, where mice with breast tumours were treated with metformin (20 mg/kg body weight) or sterile PBS solution for 15 consecutive days. No inhibition of breast tumour progression was detected. However, tumour necrosis was significantly increased in the metformin-treated group, accompanied by decreased capillary formation within the tumours. Thus, despite the lack of short-term benefit of metformin against tumour progression, a preventive role of metformin against breast cancer was implicated, which is at partially attributable to the attenuation of tumour angiogenesis. PMID:25883966

  4. The radiological features of phylloides tumour of the breast with clinico-pathological correlation.

    PubMed

    Page, J E; Williams, J E

    1991-07-01

    The mammograms of 13 patients with phylloides tumour of the breast are reviewed and the results correlated with clinical and histological features. Three patients had recurrent tumours. There is a strong association between phylloides tumour and fibroadenoma. Many of the tumours are radiologically indistinguishable from fibroadenomata and it is not possible to predict tumour behaviour on the basis of clinical and radiological features alone. PMID:1651822

  5. Subtypes of familial breast tumours revealed by expression and copy number profiling.

    PubMed

    Waddell, Nic; Arnold, Jeremy; Cocciardi, Sibylle; da Silva, Leonard; Marsh, Anna; Riley, Joan; Johnstone, Cameron N; Orloff, Mohammed; Assie, Guillaume; Eng, Charis; Reid, Lynne; Keith, Patricia; Yan, Max; Fox, Stephen; Devilee, Peter; Godwin, Andrew K; Hogervorst, Frans B L; Couch, Fergus; Grimmond, Sean; Flanagan, James M; Khanna, Kumkum; Simpson, Peter T; Lakhani, Sunil R; Chenevix-Trench, Georgia

    2010-10-01

    Extensive expression profiling studies have shown that sporadic breast cancer is composed of five clinically relevant molecular subtypes. However, although BRCA1-related tumours are known to be predominantly basal-like, there are few published data on other classes of familial breast tumours. We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2 breast tumours by gene expression profiling and found that 74% BRCA1 tumours were basal-like, 73% of BRCA2 tumours were luminal A or B, and 52% non-BRCA1/2 tumours were luminal A. Thirty-four tumours were also analysed by single nucleotide polymorphism-comparative genomic hybridization (SNP-CGH) arrays. Copy number data could predict whether a tumour was basal-like or luminal with high accuracy, but could not predict its mutation class. Basal-like BRCA1 and basal-like non-BRCA1 tumours were very similar, and contained the highest number of chromosome aberrations. We identified regions of frequent gain containing potential driver genes in the basal (8q and 12p) and luminal A tumours (1q and 17q). Regions of homozygous loss associated with decreased expression of potential tumour suppressor genes were also detected, including in basal tumours (5q and 9p), and basal and luminal tumours (10q). This study highlights the heterogeneity of familial tumours and the clinical consequences for treatment and prognosis. PMID:19960244

  6. The Er/Ki-67 Proportion in Breast Tumours - An Immunohistochemical Study

    PubMed Central

    Rai, M K

    2016-01-01

    Introduction Breast tumours are classified as benign, proliferative and invasive tumours. Estrogen hormone influences the proliferative activity and progression of the tumour. Estrogen Receptor (ER) status and proliferative index (Ki 67) are important histopathological factors in the development and prognosis of these tumours. Aim The present study was aimed to evaluate the variations in ER and Ki-67 expression in three broad categories of breast lesions namely benign breast disease, proliferative breast disease and malignant breast disease. Materials and Methods ER% and Ki-67% was evaluated on the histopathological tissues of 15 patients each of benign, proliferative and invasive breast tumours. The ER+/ Ki-67± ratio was calculated and the variation of expression between the three categories was analyzed using student’s t-test. Pearson’s coefficient of correlation was used to correlate ER and Ki-67 positivity within each category. Results The mean ER+/Ki-67+ in benign, proliferative and invasive tumours was 0.81, 0.87 and 1.42 respectively. A statistically significant difference in ER+/Ki-67+ proportions was observed between proliferative breast disease category and malignant breast disease category and also between benign breast disease category and malignant breast disease category (p<0.05). However, no significant difference was observed in benign breast disease category and proliferative breast disease category (p>0.05). A significant correlation was observed in proliferative breast disease and malignant breast disease categories. However, no significant correlation was observed in benign breast disease category Conclusion ER+/Ki-67+ ratio is an important determinant of the invasive breast cancer and can be used to differentiate invasive cancers from benign and proliferative breast tumours. PMID:27190810

  7. Diagnostic accuracy of MRI to evaluate tumour response and residual tumour size after neoadjuvant chemotherapy in breast cancer patients

    PubMed Central

    Acea, Benigno; Soler, Rafaela; Iglesias, Ángela; Santiago, Paz; Mosquera, Joaquín; Calvo, Lourdes; Seoane-Pillado, Teresa; García, Alejandra

    2016-01-01

    Background The aim, of the study was to estimate the accuracy of magnetic resonance imaging (MRI) in assessing residual disease in breast cancer patients receiving neoadjuvant chemotherapy (NAC) and to identify the clinico-pathological factors that affect the diagnostic accuracy of breast MRI to determine residual tumour size following NAC. Patients and methods 91 breast cancer patients undergoing NAC (92 breast lesions) were included in the study. Breast MRI was performed at baseline and after completion of NAC. Treatment response was evaluated by MRI and histopathological examination to investigate the ability of MRI to predict tumour response. Residual tumour size was measured on post-treatment MRI and compared with pathology in 89 lesions. Clinicopathological factors were analyzed to compare MRI-pathologic size differences. Results The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for diagnosing invasive residual disease by using MRI were 75.00%, 78.57%, 88.89%, 57.89%, and 76.09% respectively. The Pearson’s correlation coefficient (r) between tumour sizes determined by MRI and pathology was r = 0.648 (p < 0.001). The size discrepancy was significantly lower in cancers with initial MRI size ≤ 5 cm (p = 0.050), in cancers with high tumour grade (p < 0.001), and in patients with hormonal receptor-negative cancer (p = 0.033). Conclusions MRI is an accurate tool for evaluating tumour response after NAC. The accuracy of MRI in estimating residual tumour size varies with the baseline MRI tumour size, the tumour grade and the hormonal receptor status. PMID:27069452

  8. Carboplatin and Eribulin Mesylate in Triple Negative Breast Cancer Patients

    ClinicalTrials.gov

    2016-06-30

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  9. Tumour-adapted Reduction Mammoplasty – a New (Old) Breast Conserving Strategy: Review

    PubMed Central

    Eichbaum, M.; Dietrich, A.; Reinhard, J.; Steinwasser, R.; Eichbaum, C.

    2016-01-01

    Today over 70 % of patients treated for primary breast carcinoma in certified breast centres are managed with breast conserving surgery. The classical semicircular incision directly above the tumour, though in many cases easily carried out and associated with good cosmetic results, does have limitations. Unsatisfactory aesthetic results often occur when tumour location is unfavourable or when there is unfavourable tumour size relative to breast size. Distortion of the nipple, changes to breast shape and retraction of skin overlying surgical defects can occur. Tumour-adapted reduction mammoplasty/mastopexy or the “modified B technique” offer excellent chances of combining the oncological demands of breast surgery with satisfactory symmetrical cosmetic results. This article reviews a traditional, old operative technique that has been re-embraced in various new forms. PMID:26855438

  10. Mesenchymal tumours of the breast and their mimics: a review with approach to diagnosis.

    PubMed

    Cheah, Alison L; Billings, Steven D; Rowe, J Jordi

    2016-08-01

    Mesenchymal tumours of the breast comprise a broad spectrum of entities that frequently pose diagnostic challenges to surgical pathologists. Metaplastic carcinoma and phyllodes tumour are site-specific mimics that account for the majority of tumours in the breast with a sarcomatoid appearance. Although uncommon, mammary tumours with fibroblastic, adipocytic or vascular differentiation may be encountered, spanning the spectrum from benign to malignant. Tumours with histiocytoid morphology are potential traps due to bland cytomorphology and resemblance to reactive processes. This comprehensive review provides a diagnostic approach to specific challenging mesenchymal tumours of the breast and their mimics, with a discussion on the salient morphological, immunohistochemical and molecular features that allow accurate diagnosis and will help the pathologist avoid potential pitfalls. PMID:27318503

  11. Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Older Patients With Locally Advanced or Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-02-09

    Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  12. A Study Evaluating INIPARIB in Combination With Chemotherapy to Treat Triple Negative Breast Cancer Brain Metastasis

    ClinicalTrials.gov

    2016-02-17

    Estrogen Receptor Negative (ER-Negative) Breast Cancer; Progesterone Receptor Negative (PR-Negative) Breast Cancer; Human Epidermal Growth Factor Receptor 2 Negative (HER2-Negative) Breast Cancer; Brain Metastases

  13. Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models

    PubMed Central

    Bottos, Alessia; Gotthardt, Dagmar; Gill, Jason W.; Gattelli, Albana; Frei, Anna; Tzankov, Alexandar; Sexl, Veronika; Wodnar-Filipowicz, Aleksandra; Hynes, Nancy E.

    2016-01-01

    The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer. PMID:27406745

  14. Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models.

    PubMed

    Bottos, Alessia; Gotthardt, Dagmar; Gill, Jason W; Gattelli, Albana; Frei, Anna; Tzankov, Alexandar; Sexl, Veronika; Wodnar-Filipowicz, Aleksandra; Hynes, Nancy E

    2016-01-01

    The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer. PMID:27406745

  15. Breast-Conserving Surgery Followed by Radiation Therapy With MRI-Detected Stage I or Stage II Breast Cancer

    ClinicalTrials.gov

    2011-12-07

    Ductal Breast Carcinoma in Situ; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Male Breast Cancer; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Tubular Ductal Breast Carcinoma

  16. Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

    ClinicalTrials.gov

    2016-09-12

    Breast Tumor; Breast Cancer; Cancer of the Breast; Estrogen Receptor- Negative Breast Cancer; HER2- Negative Breast Cancer; Progesterone Receptor- Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer; Triple-negative Metastatic Breast Cancer; Metastatic Breast Cancer

  17. Paclitaxel and Cyclophosphamide With or Without Trastuzumab Before Surgery in Treating Patients With Previously Untreated Stage I-III Breast Cancer

    ClinicalTrials.gov

    2012-12-12

    Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  18. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis.

    PubMed

    Wang, Zhe; Xiong, Shanshan; Mao, Yubin; Chen, Mimi; Ma, Xiaohong; Zhou, Xueliang; Ma, Zhenling; Liu, Fan; Huang, Zhengjie; Luo, Qi; Ouyang, Gaoliang

    2016-08-01

    Periostin (POSTN) is a limiting factor in the metastatic colonization of disseminated tumour cells. However, the role of POSTN in regulating the immunosuppressive function of immature myeloid cells in tumour metastasis has not been documented. Here, we demonstrate that POSTN promotes the pulmonary accumulation of myeloid-derived suppressor cells (MDSCs) during the early stage of breast tumour metastasis. Postn deletion decreases neutrophil and monocytic cell populations in the bone marrow of mice and suppresses the accumulation of MDSCs to premetastatic sites. We also found that POSTN-deficient MDSCs display reduced activation of ERK, AKT and STAT3 and that POSTN deficiency decreases the immunosuppressive functions of MDSCs during tumour progression. Moreover, the pro-metastatic role of POSTN is largely limited to ER-negative breast cancer patients. Lysyl oxidase contributes to POSTN-promoted premetastatic niche formation and tumour metastasis. Our findings indicate that POSTN is essential for immunosuppressive premetastatic niche formation in the lungs during breast tumour metastasis and is a potential target for the prevention and treatment of breast tumour metastasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27193093

  19. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer

    PubMed Central

    Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M.; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W. Y.; Marass, Francesco; Gale, Davina; Ali, H. Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P.; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

    2015-01-01

    Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. PMID:26530965

  20. Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.

    PubMed

    Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W Y; Marass, Francesco; Gale, Davina; Ali, H Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

    2015-01-01

    Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. PMID:26530965

  1. Down-regulation of osteopontin attenuates breast tumour progression in vivo.

    PubMed

    Chakraborty, Goutam; Jain, Shalini; Patil, Tushar V; Kundu, Gopal C

    2008-12-01

    Development of breast tumour malignancies results in enhanced expression of various oncogenic molecules. Elevated expression of osteopontin (OPN) in higher grades of breast carcinoma correlates with enhanced expressions of several oncogenic molecules (urokinase-type plasminogen activator [uPA], matrix metalloproteinase-2/-9 [MMP-2 and -9]) and increased angiogenic potential of breast carcinoma. In this study, using in vitro and multiple in vivo models, we have demonstrated that silencing of OPN by its specific small interfering RNA (siRNA) down-regulates the expressions of oncogenic molecules such as uPA, MMP-2 and -9 resulting in inhibition of in vitro cell motility and in vivo tumourigenicity in mice. Moreover our results demonstrated that OPN-/- mice showed slower progression of tumour growth in breast cancer model as compared to wild-type mice. Furthermore, the data showed that injection of carcinogenic compound, pristane (2, 6,10,14-tetramethylpen-tadecane) induces breast tumour progression leading to enhanced expression of OPN and other oncogenic molecules in mammary fat pad of nude- and wild-type mice but not in OPN-/- mice. However, intratumoural injection of OPN siRNA to pristane-induced tumour significantly suppressed these effects. Our data revealed that knocking down of OPN effectively curb breast cancer progression and further suggested that developing of OPN-based therapeutics might be an emerging approach for the next generation of breast cancer management. PMID:18266970

  2. Veliparib, Cisplatin, and Vinorelbine Ditartrate in Treating Patients With Recurrent and/or Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-03-01

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Hereditary Breast/Ovarian Cancer - BRCA1; Hereditary Breast/Ovarian Cancer - BRCA2; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer

  3. Risk factors for second primary tumours in breast cancer survivors.

    PubMed

    Sánchez, Luis; Lana, Alberto; Hidalgo, Agustín; Rodríguez, Jose María; Del Valle, María Del Olivo; Cueto, Antonio; Folgueras, María Victoria; Belyakova, Elena; Comendador, Miguel Angel; López, María Luisa

    2008-10-01

    Breast cancer (BC) survivors have an increased risk of developing second primary cancer (SPC). The aim of this study was to detect and compare SPC predictors linked to the host, the first BC and its treatment. Two hundred and seventeen patients with a nonbreast SPC and 465 matched controls, nested in the cohort of BC patients diagnosed in a Spanish region between 1975 and 2003, were involved in a case-control study. The Tumour Registry database provided information about the host, BC and its treatment factors. Their contribution to the risk of developing SPC was measured by means of a conditional logistic regression. After controlling for differences between cases and controls at baseline, obesity [odds ratio (OR): 7.48; 95% confidence interval (CI): 1.25-44.88], smoking (OR: 3.16; 95% CI: 1.23-8.15), high blood pressure (OR: 1.68; 95% CI: 1.04-2.71) and having first-degree relatives suffering from cancer (OR: 1.69; 95% CI: 1.05-2.72) were the best SPC predictors. The risk of SPC increases by 1% per month of survival from BC (OR: 1.01; 95% CI: 1.007-1.012), while having metastases (OR: 0.23; 95% CI: 0.14-0.37) and being premenopausal at diagnosis of the BC (OR: 0.44; 95% CI: 0.247-0.792) diminish the risk, probably decreasing survival. The treatments were the regression model's worst predictors. Controlling modifiable factors linked to lifestyle such as obesity and smoking is essential to prevent SPC in survivors of BC. Health education to remove persistent risk factors should be included in the treatment protocol of BC patients, because they are important predictors of SPC. PMID:18714181

  4. Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience.

    PubMed

    Toh, Y F; Cheah, P L; Looi, L M; Teoh, K H; Tan, P H

    2016-04-01

    Taking cognizance of the purported variation of phyllodes tumours in Asians compared with Western populations, this study looked at phyllodes tumours of the breast diagnosed at the Department of Pathology, University of Malaya Medical Centre over an 8-year period with regards to patient profiles, tumour parameters, treatment offered and outcome. Sixty-four new cases of phyllodes tumour were diagnosed during the period, however only 30 (21 benign, 4 borderline and 5 malignant) finally qualified for entry into the study. These were followed-up for 4-102 months (average = 41.7 months). Thirteen cases (8 benign, 3 borderline, 2 malignant) were Chinese, 9 (all benign) Malay, 7 (4 benign, 1 borderline, 2 malignant) Indian and 1 (malignant) Indonesian. Prevalence of benign versus combined borderline and malignant phyllodes showed a marginally significant difference (p=0.049) between the Malays and Chinese. Patients' ages ranged from 21-70 years with a mean of 44.9 years with no significant difference in age between benign, borderline or malignant phyllodes tumours. Except for benign phyllodes tumours (mean size = 5.8 cm) being significantly smaller at presentation compared with borderline (mean size = 12.5 cm) and malignant (mean size = 15.8 cm) (p<0.05) tumours, history of previous pregnancy, breast feeding, hormonal contraception and tumour laterality did not differ between the three categories. Family history of breast cancer was noted in 2 cases of benign phyllodes. Local excision was performed in 17 benign, 2 borderline and 3 malignant tumours and mastectomy in 4 benign, 2 borderline and 2 malignant tumours. Surgical clearance was not properly recorded in 10 benign phyllodes tumours. Six benign and all 4 borderline and 5 malignant tumours had clearances of <10 mm. Two benign tumours recurred locally at 15 and 49 months after local excision, however information regarding surgical clearance was not available in both cases. One patient with a malignant tumour developed

  5. Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Cancer

    ClinicalTrials.gov

    2016-07-19

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer

  6. Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer.

    PubMed

    Banerji, Christopher R S; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E

    2015-03-01

    The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737

  7. Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer

    PubMed Central

    Banerji, Christopher R. S.; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E.

    2015-01-01

    The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample’s genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737

  8. Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

    ClinicalTrials.gov

    2016-01-12

    Estrogen Receptor-positive Breast Cancer; Gastrinoma; Glucagonoma; HER2-negative Breast Cancer; Insulinoma; Mucositis; Oral Complications; Pancreatic Polypeptide Tumor; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Islet Cell Carcinoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Renal Cell Cancer

  9. Potentialities of steady-state and transient thermography in breast tumour depth detection: A numerical study.

    PubMed

    Amri, Amina; Pulko, Susan Helen; Wilkinson, Anthony James

    2016-01-01

    Breast thermography still has inherent limitations that prevent it from being fully accepted as a breast screening modality in medicine. The main challenges of breast thermography are to reduce false positive results and to increase the sensitivity of a thermogram. Further, it is still difficult to obtain information about tumour parameters such as metabolic heat, tumour depth and diameter from a thermogram. However, infrared technology and image processing have advanced significantly and recent clinical studies have shown increased sensitivity of thermography in cancer diagnosis. The aim of this paper is to study numerically the possibilities of extracting information about the tumour depth from steady state thermography and transient thermography after cold stress with no need to use any specific inversion technique. Both methods are based on the numerical solution of Pennes bioheat equation for a simple three-dimensional breast model. The effectiveness of two approaches used for depth detection from steady state thermography is assessed. The effect of breast density on the steady state thermal contrast has also been studied. The use of a cold stress test and the recording of transient contrasts during rewarming were found to be potentially suitable for tumour depth detection during the rewarming process. Sensitivity to parameters such as cold stress temperature and cooling time is investigated using the numerical model and simulation results reveal two prominent depth-related characteristic times which do not strongly depend on the temperature of the cold stress or on the cooling period. PMID:26522612

  10. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells

    PubMed Central

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi

    2015-01-01

    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. PMID:25910782

  11. DT-diaphorase and cytochrome B5 reductase in human lung and breast tumours.

    PubMed Central

    Marín, A.; López de Cerain, A.; Hamilton, E.; Lewis, A. D.; Martinez-Peñuela, J. M.; Idoate, M. A.; Bello, J.

    1997-01-01

    The level of expression of enzymes that can activate or detoxify bioreductive agents within tumours has emerged as an important feature in the development of these anti-tumour compounds. The levels of two such reductase enzymes have been determined in 19 human non-small-cell lung tumours and 20 human breast tumours, together with the corresponding normal tissue. DT-diaphorase (DTD) enzyme levels (both expression and activity) were determined in these samples. Cytochrome b5 reductase (Cytb5R) activity was also assessed. With the exception of six patients, the levels of DTD activity were below 45 nmol min(-1) mg(-1) in the normal tissues assayed. DTD tumour activity was extremely variable, distinguishing two different groups of patients, one with DTD activity above 79 nmol min(-1) mg(-1) and the other with levels that were in the same range as found for the normal tissues. In 53% of the lung tumour samples, DTD activity was increased with respect to the normal tissue by a factor of 2.4-90.3 (range 79-965 nmol min[-1] mg[-1]). In 70% of the breast tumour samples, DTD activity was over 80 nmol min(-1) mg(-1) (range 83-267 nmol min[-1] mg[-1]). DTD expression measured by Western blot correlated well with the enzyme activity measured in both tumour and normal tissues. The levels of the other reductase enzyme, Cytb5R, were not as variable as those for DTD, being in the same range in both tumour and normal tissue or slightly higher in the normal tissues. The heterogeneous nature of DTD activity and expression reinforces the need to measure enzyme levels in individual patients before therapy with DTD-activated bioreductive drugs. Images Figure 1 Figure 2 PMID:9328153

  12. Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer

    ClinicalTrials.gov

    2016-03-08

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  13. Parametric study of the biopotential equation for breast tumour identification using ANOVA and Taguchi method.

    PubMed

    Ng, Eddie Y K; Ng, W Kee

    2006-03-01

    Extensive literatures have shown significant trend of progressive electrical changes according to the proliferative characteristics of breast epithelial cells. Physiologists also further postulated that malignant transformation resulted from sustained depolarization and a failure of the cell to repolarize after cell division, making the area where cancer develops relatively depolarized when compared to their non-dividing or resting counterparts. In this paper, we present a new approach, the Biofield Diagnostic System (BDS), which might have the potential to augment the process of diagnosing breast cancer. This technique was based on the efficacy of analysing skin surface electrical potentials for the differential diagnosis of breast abnormalities. We developed a female breast model, which was close to the actual, by considering the breast as a hemisphere in supine condition with various layers of unequal thickness. Isotropic homogeneous conductivity was assigned to each of these compartments and the volume conductor problem was solved using finite element method to determine the potential distribution developed due to a dipole source. Furthermore, four important parameters were identified and analysis of variance (ANOVA, Yates' method) was performed using design (n = number of parameters, 4). The effect and importance of these parameters were analysed. The Taguchi method was further used to optimise the parameters in order to ensure that the signal from the tumour is maximum as compared to the noise from other factors. The Taguchi method used proved that probes' source strength, tumour size and location of tumours have great effect on the surface potential field. For best results on the breast surface, while having the biggest possible tumour size, low amplitudes of current should be applied nearest to the breast surface. PMID:16929931

  14. Cytosolic thymidine kinase is a specific histopathologic tumour marker for breast carcinomas.

    PubMed

    He, Qimin; Mao, Yongrong; Wu, Jainping; Decker, Catrine; Merza, Malik; Wang, Naining; Eriksson, Staffan; Castro, Juan; Skog, Sven

    2004-10-01

    Thymidine kinase 1 (TK1), an enzyme involved in the synthesis of precursors for DNA, and thus proliferation dependent, has been suggested as a good tumour marker. We have recently developed poly/monoclonal antibodies against TK1, which proved useful for diagnostics in both serum and immunohistochemistry of cancer patients. The anti-TK1 monoclonal antibodies (mAbs) 1D11 and 1E3 were characterized by Western blot, immunoprecipitation and flow cytometry. TK1 mAbs and Ki-67 mAb were then used for immunohistochemistry staining of tumour sections from 54 patients with ductal infiltrated breast carcinoma. Results showed the relative number of patients with positively stained tumours for TK1 (mAb 1D11) and for Ki-67 (mAb MIB-1) were 47 and 41%, respectively, significantly related (p=0.007). Combination of TK1 mAbs 1D11 and 1E3 increased this number to 56%, due to detection of a significantly higher number of patients with grade 2 tumours. Patients with stage II and grade 2 tumours showed significantly higher TK1 staining when compared to stage I and grade 1. Ki-67 staining was significantly higher in stage III and grade 3. The tumours only stained for TK1 represented higher stages and grades, while tumours staining only for Ki-67 were of lower stages and grades. Combining TK1 and Ki-67 increased the number of patients with positively stained tumours to 69%. In conclusion, TK1 is a reliable marker for identification of patients with grade 2 tumours. The highest number of patients with positively stained tumours were obtained when both TK1 and Ki-67 markers were used. PMID:15375544

  15. Phylloides tumours of the breast: best practice for follow-up.

    PubMed

    Mylvaganam, Senthurun; Toro, Clare; Frank, Lucinda; Vestey, Sarah; Thrush, Steven

    2015-03-01

    Phylloides tumours are rare fibroepithelial breast tumours accounting for 1% of breast cancers. No UK guidance exists on the assessment, treatment and follow-up of these patients. To assess the diagnostic accuracy of the clinical core biopsy compared to the gold standard excision biopsy and determine the current follow-up practice and recurrence rate of phylloides tumours across two UK hospital trusts. Multicentre retrospective analysis of all cases of phylloides tumours over 6 years at Worcestershire Acute NHS Trust (WANHST) and Gloucestershire Hospitals NHS Trust (GHNHST). 94 Patients included. Mean age 48 years. Mean clinical and radiological size of lesions 31.7 and 35.4 mm, respectively, preoperative core biopsy sensitivity was 87% for WANHST and 74% for GHNHST with a positive predictive value of 90 and 100%, respectively. 29 Different follow-up regimes were observed from the practice of the 10 surgeons observed following diagnosis and resection of tumours. The follow-up length ranged from discharge following one post-operative clinic attendance to 5-year clinical and/or radiological follow-up. 4 Benign and 2 malignant recurrent phylloides tumours were seen. All benign recurrences were local and found independently of follow-up. The earliest benign phylloides recurrence was at 6 years and the latest at 10 years. There is no standard follow-up of benign or malignant phylloides tumours. This study suggests that in the benign group, the risk of recurrence is small. We advocate no routine follow-up of benign phylloides tumours. PMID:25575495

  16. RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation

    PubMed Central

    Leung, Hoi-Wing; Zhao, Si-Meng; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara Bik-San

    2015-01-01

    Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer. PMID:26592552

  17. Primary breast cancer tumours contain high amounts of IgA1 immunoglobulin: an immunohistochemical analysis of a possible carrier of the tumour-associated Tn antigen.

    PubMed

    Welinder, Charlotte; Baldetorp, Bo; Blixt, Ola; Grabau, Dorthe; Jansson, Bo

    2013-01-01

    The Tn antigen (GalNAc alpha-O-Ser/Thr) as defined by the binding of the lectin, helix pomatia agglutinin (HPA) or anti-Tn monoclonal antibodies, is known to be exposed in a majority of cancers, and it has also been shown to correlate positively with the metastatic capacity in breast carcinoma. The short O-glycan that forms the antigen is carried by a number of different proteins. One potential carrier of the Tn antigen is immunoglobulin A1 (IgA1), which we surprisingly found in tumour cells of the invasive parts of primary breast carcinoma. Conventional immunohistochemical analysis of paraffin-embedded sections from primary breast cancers showed IgA1 to be present in the cytoplasm and plasma membrane of 35 out of 36 individual primary tumours. The immunohistochemical staining of HPA and anti-Tn antibody (GOD3-2C4) did to some extent overlap with the presence of IgA1 in the tumours, but differences were seen in the percentage of stained cells and in the staining pattern in the different breast cancers analysed. Anti-Tn antibody and HPA were also shown to specifically bind to a number of possible constellations of the Tn antigen in the hinge region of IgA1. Both reagents could also detect the presence of Tn positive IgA in serum. On average 51% of the tumour cells in the individual breast cancer tumour sections showed staining for IgA1. The overall amount of staining in the invasive part of the tumour with the anti Tn antibody was 67%, and 93% with HPA. The intra-expression or uptake of IgA1 in breast cancer makes it a new potential carrier of the tumour associated and immunogenic Tn antigen. PMID:23637900

  18. Modelling Circulating Tumour Cells for Personalised Survival Prediction in Metastatic Breast Cancer

    PubMed Central

    2015-01-01

    Ductal carcinoma is one of the most common cancers among women, and the main cause of death is the formation of metastases. The development of metastases is caused by cancer cells that migrate from the primary tumour site (the mammary duct) through the blood vessels and extravasating they initiate metastasis. Here, we propose a multi-compartment model which mimics the dynamics of tumoural cells in the mammary duct, in the circulatory system and in the bone. Through a branching process model, we describe the relation between the survival times and the four markers mainly involved in metastatic breast cancer (EPCAM, CD47, CD44 and MET). In particular, the model takes into account the gene expression profile of circulating tumour cells to predict personalised survival probability. We also include the administration of drugs as bisphosphonates, which reduce the formation of circulating tumour cells and their survival in the blood vessels, in order to analyse the dynamic changes induced by the therapy. We analyse the effects of circulating tumour cells on the progression of the disease providing a quantitative measure of the cell driver mutations needed for invading the bone tissue. Our model allows to design intervention scenarios that alter the patient-specific survival probability by modifying the populations of circulating tumour cells and it could be extended to other cancer metastasis dynamics. PMID:25978366

  19. Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies

    PubMed Central

    Schmidt, Marjanka K.; Broeks, Annegien; van Leeuwen, Flora E.; Wesseling, Jelle; Cheang, Maggie C.; Gelmon, Karen; Nielsen, Torsten O.; Blomqvist, Carl; Heikkilä, Päivi; Heikkinen, Tuomas; Nevanlinna, Heli; Akslen, Lars A.; Bégin, Louis R.; Foulkes, William D.; Couch, Fergus J.; Wang, Xianshu; Cafourek, Vicky; Olson, Janet E.; Baglietto, Laura; Giles, Graham G.; Severi, Gianluca; McLean, Catriona A.; Southey, Melissa C.; Rakha, Emad; Green, Andrew R.; Ellis, Ian O.; Sherman, Mark E.; Lissowska, Jolanta; Anderson, William F.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Provenzano, Elena; Dawson, Sarah-Jane; Dunning, Alison M.; Humphreys, Manjeet; Easton, Douglas F.; García-Closas, Montserrat; Caldas, Carlos; Pharoah, Paul D.; Huntsman, David

    2010-01-01

    Background Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. Methods and Findings We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. Conclusions The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical

  20. Early prognosis of metastasis risk in inflammatory breast cancer by texture analysis of tumour microscopic images.

    PubMed

    Kolarevic, Daniela; Tomasevic, Zorica; Dzodic, Radan; Kanjer, Ksenija; Vukosavljevic, Dragica Nikolic; Radulovic, Marko

    2015-10-01

    Inflammatory breast cancer (IBC) is a rare and aggressive type of locally advanced breast cancer. The purpose of this study was to determine the value of microscopic tumour histomorphology texture for prognosis of local and systemic recurrence at the time of initial IBC diagnosis. This retrospective study included a group of 52 patients selected on the basis of non-metastatic IBC diagnosis, stage IIIB. Gray-Level-Co-Occurrence-Matrix (GLCM) texture analysis was performed on digital images of primary tumour tissue sections stained with haematoxylin/eosin. Obtained values were categorized by use of both data- and outcome-based methods. All five acquired GLCM texture features significantly associated with metastasis outcome. By accuracies of 69-81% and AUCs of 0.71-0.81, prognostic performance of GLCM parameters exceeded that of standard major IBC clinical prognosticators such as tumour grade and response to induction chemotherapy. Furthermore, a composite score consisting of tumour grade, contrast and correlation as independent features resulted in further enhancement of prognostic performance by accuracy of 89%, discrimination efficiency by AUC of 0.93 and an outstanding hazard ratio of 71.6 (95%CI, 41.7-148.4). Internal validation was successfully performed by bootstrap and split-sample cross-validation, suggesting that the model is generalizable. This study indicates for the first time the potential use of primary breast tumour histology texture as a highly accurate, simple and cost-effective prognostic indicator of metastasis risk in IBC. Clinical relevance of the obtained results rests on the role of prognosis in decisions on induction chemotherapy and the resulting impact on quality of life and survival. PMID:26286863

  1. Pseudoangiomatous stromal hyperplasia (PASH) tumour at the surgical scar site in a patient of carcinoma breast.

    PubMed

    Abrari, Andleeb

    2011-01-01

    A patient on follow-up post surgery for carcinoma breast, presented with a nodule under the surgical scar. The sinister eventuality of recurrent carcinoma was clinically considered first. The lesion was biopsied and the histopathology was diagnostic of pseudoangiomatous stromal hyperplasia tumour. The nodule was excised and the patient's clinical denouement has been uneventful in the 4 months which have elapsed after this event. PMID:22688488

  2. Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma.

    PubMed Central

    Leek, R. D.; Landers, R.; Fox, S. B.; Ng, F.; Harris, A. L.; Lewis, C. E.

    1998-01-01

    Angiogenesis is an essential requirement for tumour growth and metastasis and is regulated by a complex network of factors produced by both stromal cells and neoplastic cells within solid tumours. The cytokine tumour necrosis factor alpha (TNF-alpha) and the enzyme thymidine phosphorylase (TP) are two factors known to promote tumour angiogenesis. We have demonstrated recently that high numbers of tumour-associated macrophages (TAMs) are significantly associated with increased tumour angiogenesis and poor prognosis in invasive carcinoma of the breast. We have also shown that TAMs are a major source of TNF-alpha in invasive breast carcinomas, and that macrophage-like stromal cells as well as tumour cells synthesize TP in such tumours. However, little is known of the factors that regulate the production or activity of these factors in the tumour microenvironment. As TNF-alpha has been shown to up-regulate TP expression in tumour cells in vitro we performed an immunohistochemical study to investigate the possibility that TNF-alpha may be involved in the regulation of TP expression by malignant breast epithelial cells in vivo. To do this, we used a cocktail of non-neutralizing monoclonal anti-TNF-alpha antibodies to visualize both TNF-alpha-expressing macrophages and TNF-alpha bound to its receptors on tumour cells and endothelial cells in a series of 93 invasive carcinomas of the breast. A semiquantitative grading system was then used to compare these staining patterns with that for TP in the same biopsies. TNF-alpha immunoreactivity was also compared with various important tumour variables known to relate to outcome in this disease (microvessel density, node status, grade, stage, receptor status and macrophage infiltration), as well as relapse-free and overall survival data for these patients. Our data show significant positive correlations between TNF-alpha bound to its receptors on tumour cells and: (1) TP protein production by tumour cells, and (2) axillary lymph

  3. Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model.

    PubMed

    Stannard, Kimberley A; Collins, Patrick M; Ito, Koichi; Sullivan, Emily M; Scott, Stacy A; Gabutero, Elwyn; Darren Grice, I; Low, Pauline; Nilsson, Ulf J; Leffler, Hakon; Blanchard, Helen; Ralph, Stephen J

    2010-12-28

    High level galectin-1 expression results in cancer cell evasion of the immune response, increased tumour survival and aggressive metastases. Using a galectin-1 polyclonal antibody, high levels of galectin-1 protein were shown to be expressed by breast cancer cells established from FVB/N MMTV-c-neu mice as well as by the B16F10 melanoma cell line. In mixed lymphocyte cultures using tumour cells as antigenic stimulators, addition of recombinant galectin-1 dose-dependently inhibited lymphocyte production. Disaccharides were identified that inhibited galectin-1 function and increased growth and activation of CD8(+) CTL's killing cancer cells. X-ray crystallographic structures of human galectin-1 in complex with inhibitory disaccharides revealed their mode of binding. Combining galectin-blocking carbohydrates as adjuvants with vaccine immunotherapy in vivo to promote immune responses significantly decreased tumour progression and improved the outcomes for tumour challenged mice. This is the first report showing that suitably selected galectin-1 blocking disaccharides will act as adjuvants promoting vaccine stimulated immune responses against tumours in vivo. PMID:20826047

  4. Expression of membrane transporters and metabolic enzymes involved in estrone-3-sulphate disposition in human breast tumour tissues.

    PubMed

    Banerjee, Nilasha; Miller, Naomi; Allen, Christine; Bendayan, Reina

    2014-06-01

    Two-thirds of newly diagnosed hormone-dependent (HR?) breast cancers are detected in post-menopausal patients where estrone-3-sulphate (E3S) is the predominant source for tumour estradiol. Understanding intra-tumoral fate of E3S would facilitate in the identification of novel molecular targets for HR? post-menopausal breast cancer patients. Hence this study investigates the clinical expression of (i) organic anion-transporting polypeptides (OATPs), (ii) multidrug resistance protein (MRP-1), breast cancer resistance proteins (BCRP), and (iii) sulphatase (STS), 17β-hydroxysteroid dehydrogenase (17β-HSD-1), involved in E3S uptake, efflux and metabolism, respectively. Fluorescent and brightfield images of stained tumour sections (n = 40) were acquired at 4× and 20× magnification, respectively. Marker densities were measured as the total area of positive signal divided by the surface area of the tumour section analysed and was reported as % area (ImageJ software). Tumour, stroma and non-tumour tissue areas were also quantified (Inform software), and the ratio of optical intensity per histologic area was reported as % area/tumour, % area/stroma and % area/non-tumour. Functional role of OATPs and STS was further investigated in HR? (MCF-7, T47-D, ZR-75) and HR-(MDA-MB-231) cells by transport studies conducted in the presence or absence of specific inhibitors. Amongst all the transporters and enzymes, OATPs and STS have significantly (p < 0.0001) higher expression in HR? tumour sections with highest target signals obtained from the tumour regions of the tissues. Specific OATP-mediated E3S uptake and STS-mediated metabolism were also observed in all HR? breast cancer cells. These observations suggest the potential of OATPs as novel molecular targets for HR? breast cancers. PMID:24831777

  5. Challenges of treating incidental synchronous bilateral breast cancer with differing tumour biology.

    PubMed

    Esclovon, Jonathan Walter; Ponder, Melissa; Aydin, Nail; Misra, Subhasis

    2016-01-01

    A 59-year-old woman with right breast mass was diagnosed with invasive ductal carcinoma (IDC). Workup consisted of bilateral diagnostic mammogram and ultrasound (US); both showed a right breast mass with normal left breast. Core biopsy showed IDC with estrogen receptor negative (ER-)/progesterone receptor negative (PR-) and HER2/neu positive receptor status. The patient underwent carboplatin-based chemotherapy with Herceptin. The mass completely resolved. The patient desired to proceed with bilateral total mastectomy with right sentinel lymph node biopsy (SLNB). Pathology showed complete resolution of the right-sided breast mass without malignancy in right SLN. Incidentally, IDC was found in the left breast specimen, which was ER+/PR+ and HER 2/neu negative. Tumour board consensus was to obtain a left axilla US with MRI in 6 months if the US was unremarkable. Biologically different synchronous bilateral breast cancer poses a difficult clinical challenge for management due to differing responses to treatment. Use of MRI may be a diagnostic option in women who choose contralateral prophylactic mastectomy. PMID:27539136

  6. The human tumour cloning assay in the management of breast cancer patients.

    PubMed Central

    Dittrich, C.; Jakesz, R.; Wrba, F.; Havelec, L.; Haas, O.; Spona, J.; Holzner, H.; Kolb, R.; Moser, K.

    1985-01-01

    A tumour cloning system was used to cultivate breast cancer specimens. Fifty-six percent of 87 samples were adequate for evaluation, showing clonal growth in about one third (35%). Effusions yielded significantly better growth than solid specimens, the median colony numbers being 64 and 18 respectively. An attempt was made to examine whether there was any association between parameters accepted as prognostic factors for breast cancer and clonal growth in vitro. No correlation was found between preoperative tumour burden, histopathologic grading, menopausal status or overall survival and clonal growth in vitro, whereas we observed an inverse trend between progesterone receptor content of the tumours and their growth potential (P less than 0.01). In those few cases where in vitro and in vivo data could be compared, a high accuracy of the predicted sensitivities was found with respect to chemotherapy, but not in relation to hormonal treatment. A statistically significant higher overall chemosensitivity was associated with the absence of oestrogen receptors (P less than 0.01). PMID:4027163

  7. Tailored chemotherapy based on tumour gene expression analysis: breast cancer patients' misinterpretations and positive attitudes.

    PubMed

    Pellegrini, I; Rapti, M; Extra, J-M; Petri-Cal, A; Apostolidis, T; Ferrero, J-M; Bachelot, T; Viens, P; Julian-Reynier, C; Bertucci, F

    2012-03-01

    The aim of this study was to document how breast cancer patients perceive their prognosis and a tailored treatment based on tumour gene expression analysis, and to identify the features of this approach that may impact its clinical application. In-depth interviews were conducted at three French cancer centres with 37 women (35-69 years of age) with node-positive breast cancer undergoing an adjuvant chemotherapy regimen defined on the basis of the genomic signature predicting the outcome after chemotherapy. Several concerns were identified. First, some misconceptions about these methods were identified due to semantic confusions between the terms 'genomic' and 'genetic', which generated anxiety and uncertainty about the future. Second, the 'not done' and 'not interpretable' signatures were misinterpreted by the women and associated with highly negative connotations. However, the use of tumour genomic analysis to adapt the treatment to each patient received most of the patients' approval because it was perceived as an approach facilitating personalised medicine. In conclusion, improving the quality of provider/patient communications should enable patients to play a more active part in the decision making about their treatment. This will ensure that those who agree to have tumour gene analysis have realistic expectations and sound deductions about the final result disclosure process. PMID:22070677

  8. FDG PET and tumour markers in the diagnosis of recurrent and metastatic breast cancer.

    PubMed

    Siggelkow, Wulf; Rath, Werner; Buell, Udalrich; Zimny, Michael

    2004-06-01

    Breast cancer continues to be one of the most common cancers in North America and Western Europe. Positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG PET) represents a non-invasive functional imaging modality that is based on metabolic characteristics of malignant tumours. In breast cancer, FDG PET is more accurate than conventional methods for staging of distant metastases or local recurrences and enables early assessment of treatment response in patients undergoing primary chemotherapy. Recent data indicate a rationale for the use of FDG PET in cases of asymptomatically elevated tumour marker levels in the presence of uncertain results of conventional imaging. Despite the fact that PET cannot rule out microscopic disease, it does have particular value in providing, in a single examination, a reliable assessment of the true extent of the disease. This technique is complementary to morphological imaging for primary diagnosis, staging and re-staging. It may become the method of choice for the assessment of asymptomatic patients with elevated tumour marker levels. This method, however, cannot replace invasive procedures if microscopic disease is of clinical relevance. PMID:15146295

  9. Influence of electrical and thermal properties on RF ablation of breast cancer: is the tumour preferentially heated?

    PubMed Central

    Ekstrand, Vilhelm; Wiksell, Hans; Schultz, Inkeri; Sandstedt, Bengt; Rotstein, Samuel; Eriksson, Anders

    2005-01-01

    Background Techniques based on radio frequency (RF) energy have many applications in medicine, in particular tumour ablation. Today, mammography screening detects many breast cancers at an early stage, facilitating treatment by minimally invasive techniques such as radio frequency ablation (RFA). The breast cancer is mostly surrounded by fat, which during RFA-treatment could result in preferential heating of the tumour due to the substantial differences in electrical parameters. The object of this study was to investigate if this preferential heating existed during experimental in vitro protocols and during computer simulations. Methods Excised breast material from four patients with morphologically diagnosed breast cancers were treated with our newly developed RFA equipment. Subsequently, two finite element method (FEM) models were developed; one with only fat and one with fat and an incorporated breast cancer of varying size. The FEM models were solved using temperature dependent electrical conductivity versus constant conductivity, and transient versus steady-state analyses. Results Our experimental study performed on excised breast tissue showed a preferential heating of the tumour, even if associated with long tumour strands. The fat between these tumour strands was surprisingly unaffected. Furthermore, the computer simulations demonstrated that the difference in electrical and thermal parameters between fat and tumour tissue can cause preferential heating of the tumour. The specific absorption rate (SAR) distribution changed significantly when a tumour was present in fatty tissue. The degree of preferential heating depended on tissue properties, tumour shape, and placement relative to the electrode. Temperature dependent electrical conductivity increased the thermal lesion volume, but did not change the preferential heating. Transient solutions decreased the thermal lesion volume but increased the preferential heating of the tumour. Conclusion Both the

  10. Aberrant Promoter Methylation of the Tumour Suppressor RASSF10 and Its Growth Inhibitory Function in Breast Cancer

    PubMed Central

    Richter, Antje M.; Walesch, Sara K.; Dammann, Reinhard H.

    2016-01-01

    Breast cancer is the most common cancer in women, with 1.7 million new cases each year. As early diagnosis and prognosis are crucial factors in cancer treatment, we investigated potential DNA methylation biomarkers of the tumour suppressor family Ras-association domain family (RASSF). Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby promotes cancer development and progression. In this study we analysed the tumour suppressors RASSF1A and RASSF10. Our study shows that RASSF10 is expressed in normal breast but inactivated by methylation in breast cancer. We observed a significant inactivating promoter methylation of RASSF10 in primary breast tumours. RASSF10 is inactivated in 63% of primary breast cancer samples but only 4% of normal control breast tissue is methylated (p < 0.005). RASSF1A also shows high promoter methylation levels in breast cancer of 56% vs. 8% of normal tissue (p < 0.005). Interestingly more than 80% of breast cancer samples harboured a hypermethylation of RASSF10 and/or RASSF1A promoter. Matching samples exhibited a strong tumour specific promoter methylation of RASSF10 in comparison to the normal control breast tissue. Demethylation treatment of breast cancer cell lines MCF7 and T47D reversed RASSF10 promoter hypermethylation and re-established RASSF10 expression. In addition, we could show the growth inhibitory potential of RASSF10 in breast cancer cell lines MCF7 and T47D upon exogenous expression of RASSF10 by colony formation. We could further show, that RASSF10 induced apoptotic changes in MCF7 and T47D cells, which was verified by a significant increase in the apoptotic sub G1 fraction by 50% using flow cytometry for MCF7 cells. In summary, our study shows the breast tumour specific inactivation of RASSF10 and RASSF1A due to DNA methylation of their CpG island promoters. Furthermore RASSF10 was characterised by the ability to block growth of breast cancer cell lines by apoptosis induction. PMID

  11. Pharmacoeconomics of bisphosphonates for skeletal-related event prevention in metastatic non-breast solid tumours.

    PubMed

    Carter, John A; Joshi, Avani D; Kaura, Satyin; Botteman, Marc F

    2012-05-01

    Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost-effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in $US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE

  12. Addition of vasopressin synthetic analogue [V(4)Q(5)]dDAVP to standard chemotherapy enhances tumour growth inhibition and impairs metastatic spread in aggressive breast tumour models.

    PubMed

    Garona, Juan; Pifano, Marina; Pastrian, Maria B; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

    2016-08-01

    [V(4)Q(5)]dDAVP is a novel 2nd generation vasopressin analogue with robust antitumour activity against metastatic breast cancer. We recently reported that, by acting on vasopressin V2r membrane receptor present in tumour cells and microvascular endothelium, [V(4)Q(5)]dDAVP inhibits angiogenesis and metastatic progression of the disease without overt toxicity. Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer, its use is limited by low selectivity and associated adverse effects. In this regard, we evaluated potential combinational benefits by adding [V(4)Q(5)]dDAVP to standard-of-care chemotherapy. In vitro, combination of [V(4)Q(5)]dDAVP with sub-IC50 concentrations of paclitaxel or carmustine resulted in a cooperative inhibition of breast cancer cell growth in comparison to single-agent therapy. In vivo antitumour efficacy of [V(4)Q(5)]dDAVP addition to chemotherapy was first evaluated using the triple-negative MDA-MB-231 breast cancer xenograft model. Tumour-bearing mice were treated with i.v. injections of [V(4)Q(5)]dDAVP (0.3 μg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.). After 6 weeks of treatment, combination regimen resulted in greater tumour growth inhibition compared to monotherapy. [V(4)Q(5)]dDAVP addition was also associated with reduction of local aggressiveness, and impairment of tumour invasion and infiltration of the skin. Benefits of combined therapy were confirmed in the hormone-independent and metastatic F3II breast cancer model by combining [V(4)Q(5)]dDAVP with carmustine (25 mg/kg i.p.). Interestingly, [V(4)Q(5)]dDAVP plus cytotoxic agents severely impaired colony forming ability of tumour cells and inhibited breast cancer metastasis to lung. The present study shows that [V(4)Q(5)]dDAVP may complement conventional chemotherapy by modulating metastatic progression and early stages of microtumour establishment, and thus supports further preclinical testing of

  13. Novel genetic aberrations in breast phyllodes tumours: comparison between prognostically distinct groups.

    PubMed

    Tan, Wai Jin; Lai, Johnathan C; Thike, Aye Aye; Lim, Jeffrey Chun Tatt; Tan, Sie Yong; Koh, Valerie Cui Yun; Lim, Tse Hui; Bay, Boon Huat; Tan, Min-Han; Tan, Puay Hoon

    2014-06-01

    Phyllodes tumours of the breast are uncommon fibroepithelial neoplasms which pose management challenges due to difficulties in accurate prediction of clinical behaviour, as histological assessment has its limitations. Molecular studies have improved the understanding of these rare tumours but such findings are scant. We aimed to investigate genetic aberrations in phyllodes tumours stratified according to clinical behaviour, to identify potential genes contributing to disease progression. Twenty phyllodes tumours were separated into prognostically distinct categories depending on whether they had recurred/metastasized within the follow-up period. DNA extracted from FFPE materials was subjected to Affymetrix OncoScan™ FFPE Express molecular inversion probe microarray platform for analysis of copy number changes and mutational status. Results were cross validated with Sanger sequencing, FISH and immunohistochemistry. A higher number of chromosomal aberrations were observed in cases which recurred/metastasized, with median events of 19 compared to 3.5 in cases which did not recur/metastasize. High-level amplification and homozygous deletions were detected exclusively in the former group. Regions of high-level amplification included MDM4 (1q32.1), RAF1 (3p25), EGFR (7p12) and PDZD2 (5p13.3). EGFR amplification was confirmed on FISH and accompanied by intense EGFR immunostaining. Regions of homozygous deletion included CDKN2A (9p21) and MACROD2 (20p12.1). Homozygous deletion of 9p21 which involved CDKN2A was accompanied by loss of protein expression. No mutations were identified in all samples. These findings provide insights into identifying target genes and pathways exploited by phyllodes tumours, which would aid future development of individualised therapy. PMID:24831776

  14. Neoadjuvant endocrine treatment in early breast cancer: An overlooked alternative?

    PubMed

    van Dam, P A; van Dam, V C N; Altintas, S; Papadimitriou, K; Rolfo, C; Trinh, X B

    2016-03-01

    During the last decade neoadjuvant endocrine therapy (NET) has moved from being reserved for elderly and frail non-chemotherapy candidates to a primary systemic modality in selected patients with hormone sensitive breast cancer. Neoadjuvant hormonal treatment in patients with hormone receptor positive, HER-2 negative early breast cancer is proven to be an effective and safe option; it is associated with a higher rate of breast conserving surgery (BCS), may reduce the need for adjuvant chemotherapy and enables a delay of surgery for medical or practical reasons. Clinical responses range from 13% to 100% with at least 3 months of NET. Methods of assessing response should include MRI of the breast, particularly in lobular tumours. In studies comparing tamoxifen with aromatase inhibitors (AI), AI proved to be superior in terms of tumour response and rates of BCS. Change in Ki67 is accepted as a validated endpoint for comparing endocrine neoadjuvant agents. Levels of Ki67 during treatment are more closely related to long-term prognosis than pretreatment Ki67. Neoadjuvant endocrine therapy provides a unique opportunity for studies of endocrine responsiveness and the development of new experimental drugs combined with systemic hormonal treatment. PMID:26776766

  15. Multifractal analysis of tumour microscopic images in the prediction of breast cancer chemotherapy response.

    PubMed

    Vasiljevic, Jelena; Pribic, Jelena; Kanjer, Ksenija; Jonakowski, Wojtek; Sopta, Jelena; Nikolic-Vukosavljevic, Dragica; Radulovic, Marko

    2015-10-01

    Due to the individual heterogeneity, highly accurate predictors of chemotherapy response in invasive breast cancer are needed for effective chemotherapeutic management. However, predictive molecular determinants for conventional chemotherapy are only emerging and still incorporate a high degree of predictive variability. Based on such pressing need for predictive performance improvement, we explored the value of pre-therapy tumour histology image analysis to predict chemotherapy response. Fractal analysis was applied to hematoxylin/eosin stained archival tissue of diagnostic biopsies derived from 106 patients diagnosed with invasive breast cancer. The tissue was obtained prior to neoadjuvant anthracycline-based chemotherapy and patients were subsequently divided into three groups according to their actual chemotherapy response: partial pathological response (pPR), pathological complete response (pCR) and progressive/stable disease (PD/SD). It was shown that multifractal analysis of breast tumour tissue prior to chemotherapy indeed has the capacity to distinguish between histological images of the different chemotherapy responder groups with accuracies of 91.4% for pPR, 82.9% for pCR and 82.1% for PD/SD. F(α)max was identified as the most important predictive parameter. It represents the maximum of multifractal spectrum f(α), where α is the Hölder's exponent. This is the first study investigating the predictive value of multifractal analysis as a simple and cost-effective tool to predict the chemotherapy response. Improvements in chemotherapy prediction provide clinical benefit by enabling more optimal chemotherapy decisions, thus directly affecting the quality of life and survival. PMID:26303582

  16. Gene expression-based classifications of fibroadenomas and phyllodes tumours of the breast.

    PubMed

    Vidal, Maria; Peg, Vicente; Galván, Patricia; Tres, Alejandro; Cortés, Javier; Ramón y Cajal, Santiago; Rubio, Isabel T; Prat, Aleix

    2015-06-01

    Fibroepithelial tumors (FTs) of the breast are a heterogeneous group of lesions ranging from fibroadenomas (FAD) to phyllodes tumors (PT) (benign, borderline, malignant). Further understanding of their molecular features and classification might be of clinical value. In this study, we analysed the expression of 105 breast cancer-related genes, including the 50 genes of the PAM50 intrinsic subtype predictor and 12 genes of the Claudin-low subtype predictor, in a panel of 75 FTs (34 FADs, 5 juvenile FADs, 20 benign PTs, 5 borderline PTs and 11 malignant PTs) with clinical follow-up. In addition, we compared the expression profiles of FTs with those of 14 normal breast tissues and 49 primary invasive ductal carcinomas (IDCs). Our results revealed that the levels of expression of all breast cancer-related genes can discriminate the various groups of FTs, together with normal breast tissues and IDCs (False Discovery Rate < 5%). Among FTs, the levels expression of proliferation-related genes (e.g. CCNB1 and MKI67) and mesenchymal/epithelial-related (e.g. CLDN3 and EPCAM) genes were found to be most discriminative. As expected, FADs showed the highest and lowest expression of epithelial- and proliferation-related genes, respectively, whereas malignant PTs showed the opposite expression pattern. Interestingly, the overall profile of benign PTs was found more similar to FADs and normal breast tissues than the rest of tumours, including juvenile FADs. Within the dataset of IDCs and normal breast tissues, the vast majority of FADs, juvenile FADs, benign PTs and borderline PTs were identified as Normal-like by intrinsic breast cancer subtyping, whereas 7 (63.6%) and 3 (27.3%) malignant PTs were identified as Claudin-low and Basal-like, respectively. Finally, we observed that the previously described PAM50 risk of relapse prognostic score better predicted outcome in FTs than the morphological classification, even within PTs-only. Our results suggest that classification of FTs

  17. Tumour morphology of early-onset breast cancers predicts breast cancer risk for first-degree relatives: the Australian Breast Cancer Family Registry

    PubMed Central

    2012-01-01

    Introduction We hypothesised that breast cancer risk for relatives of women with early-onset breast cancer could be predicted by tumour morphological features. Methods We studied female first-degree relatives of a population-based sample of 452 index cases with a first primary invasive breast cancer diagnosed before the age of 40 years. For the index cases, a standardised tumour morphology review had been conducted for all; estrogen (ER) and progesterone receptor (PR) status was available for 401 (89%), and 77 (17%) had a high-risk mutation in a breast cancer susceptibility gene or methylation of the BRCA1 promoter region in peripheral blood DNA. We calculated standardised incidence ratios (SIR) by comparing the number of mothers and sisters with breast cancer with the number expected based on Australian incidence rates specific for age and year of birth. Results Using Cox proportional hazards modelling, absence of extensive sclerosis, extensive intraductal carcinoma, absence of acinar and glandular growth patterns, and the presence of trabecular and lobular growth patterns were independent predictors with between a 1.8- and 3.1-fold increased risk for relatives (all P <0.02). Excluding index cases with known genetic predisposition or BRCA1 promoter methylation, absence of extensive sclerosis, circumscribed growth, extensive intraductal carcinoma and lobular growth pattern were independent predictors with between a 2.0- and 3.3-fold increased risk for relatives (all P <0.02). Relatives of the 128 (34%) index cases with none of these four features were at population risk (SIR = 1.03, 95% CI = 0.57 to 1.85) while relatives of the 37 (10%) index cases with two or more features were at high risk (SIR = 5.18, 95% CI = 3.22 to 8.33). Conclusions This wide variation in risks for relatives based on tumour characteristics could be of clinical value, help discover new breast cancer susceptibility genes and be an advance on the current clinical practice of using ER and PR as

  18. An Approach to Breast Cancer Immunotherapy: The Apoptotic Activity of Recombinant Anti-Interleukin-6 Monoclonal Antibodies in Intact Tumour Microenvironment of Breast Carcinoma.

    PubMed

    Abou-Shousha, S; Moaaz, M; Sheta, M; Motawea, M A

    2016-06-01

    Current work is one of our comprehensive preclinical studies, a new approach to breast cancer (BC) immunotherapy through induction of tumour cell apoptosis. Tumour growth is not just a result of uncontrolled cell proliferation but also of reduced apoptosis. High levels of interleukin-6 (IL-6) are associated with metastatic BC and correlated with poor survival as it promotes growth of tumour-initiating cells during early tumorigenesis protecting these cells from apoptosis. Therefore, this study aims at investigating the potential of anti-IL-6 monoclonal antibodies to suppress IL-6 proliferative/anti-apoptotic activities in intact tumour microenvironment of BC. Fresh sterile tumour and normal breast tissue specimens were taken from 50 female Egyptian patients with BC undergoing radical mastectomy. A unique tissue culture system designed to provide cells of each intact tumour/normal tissue sample with its proper microenvironment either supplemented or not with anti-IL-6 monoclonal antibodies. To evaluate the apoptotic activity of anti-IL-6 as a novel candidate for BC treatment strategy, we compared its effects with those obtained using tumour necrosis-related apoptosis-inducing ligand TRAIL as an established apoptotic agent. Our results revealed that levels of either anti-IL-6- or TRAIL-induced apoptosis in the tumour or normal tissue cultures were significantly higher than those in their corresponding untreated ones (P < 0.001). No statistically significant differences have been found between apoptosis levels induced by anti-IL-6 monoclonal antibodies and those induced by TRAIL. Recombinant anti-IL-6 monoclonal antibodies could represent a novel effective element of immunotherapeutic treatment strategy for BC. The selectivity and anti-apoptotic potential of anti-IL-6 is highly hopeful in IL-6- abundant BC tumour microenvironment. PMID:26971879

  19. Fc receptor-bearing peripheral blood mononuclear cells in breast cancer patients: a possible marker of tumour burden and prognosis.

    PubMed Central

    Bray, J; McPherson, T A

    1981-01-01

    Indirect immunofluorescence was used to identify and quantitate peripheral blood mononuclear (PBM) cells possessing high avidity Fc receptors in 105 patients upon referral to the breast cancer clinic at the Cross Cancer Institute. The cell detected was shown to be a non-adherent PBM, probably belonging to the T or null cell population. The mean percentage +/- 2 standard deviations of PBM-positive cells in 75 patients with no disease or benign breast disease was 5.3 +/- ;6.7, and this was significantly (P less than 0.001) less than the percentage found for 31 patients with breast cancer. The percentage of PBM-positive cells correlated directly with tumour burden in patient with small (less than or equal to 5 cm) tumours without regional node or extranodal metastases (5/13 had greater than or equal to 12% positive PBM) and in those with small tumours plus regional node metastases, but without extranodal metastases (8/10 had greater than or equal to 12% positive PBM). This correlation was less, however, in patients with large tumours (greater than 5 cm), and in those with extranodal metastases (4/8 had greater than or equal to 12% positive PBM), and in patients tested postoperatively (1/13 had greater than or equal to 12% positive PBM) even though 6!13 had regional node metastases at the time of surgery. Thus, this relatively simple assay, which can be done on peripheral blood samples, may turn out to be useful in patients with breast cancer as a prognostic marker insofar as it may be an indirect indicator of tumour burden preoperatively. If so, it may lead to a more aggressive postoperative adjuvant therapy approach to the subpopulation of node-negative PBM-positive breast cancer patients than is currently used for node-negative patients. PMID:7035033

  20. miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours

    PubMed Central

    Biagioni, Francesca; Bossel Ben-Moshe, Noa; Fontemaggi, Giulia; Canu, Valeria; Mori, Federica; Antoniani, Barbara; Di Benedetto, Anna; Santoro, Raffaela; Germoni, Sabrina; De Angelis, Fernanda; Cambria, Anna; Avraham, Roi; Grasso, Giuseppe; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Yarden, Yosef; Domany, Eytan; Blandino, Giovanni

    2012-01-01

    Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA-10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5 kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression. This also suggests that restoration of microRNA-10b* expression might have therapeutic promise. PMID:23125021

  1. miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours.

    PubMed

    Biagioni, Francesca; Bossel Ben-Moshe, Noa; Fontemaggi, Giulia; Canu, Valeria; Mori, Federica; Antoniani, Barbara; Di Benedetto, Anna; Santoro, Raffaela; Germoni, Sabrina; De Angelis, Fernanda; Cambria, Anna; Avraham, Roi; Grasso, Giuseppe; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Yarden, Yosef; Domany, Eytan; Blandino, Giovanni

    2012-11-01

    Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA-10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5 kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression. This also suggests that restoration of microRNA-10b* expression might have therapeutic promise. PMID:23125021

  2. The effect of low dose carbidopa/levodopa on prolactin and growth hormone concentrations in patients with breast cancer and in benign breast tumours.

    PubMed Central

    Jones, M K; Ramsay, I D; Jenner, P G

    1978-01-01

    1 Low doses of carbidopa/levodopa (12.5 mg 1-alpha-methyl-dopahydrazine, 125 mg levodopa) were administered orally to 29 patients with tumours of the breast (16 with breast cancer, 13 with benign breast disease). 2 Plasma dopa response curves were similar in all the patients studied. 3 Prolactin and growth hormone showed similar responses to carbidopa/levodopa irrespective of age or diagnosis. 4 Prolactin showed an unusual reponse in four patients which has not previously been recorded. PMID:656281

  3. Breast sarcomas and malignant phyllodes tumours: comparison of clinicopathological features, treatment strategies, prognostic factors and outcomes.

    PubMed

    Lim, Sue Zann; Selvarajan, Sathiyamoorthy; Thike, Aye Aye; Nasir, Nur Diyana Binte Md; Tan, Benita Kiat Tee; Ong, Kong Wee; Tan, Puay Hoon

    2016-09-01

    We aimed to compare the clinicopathological features, treatment strategies and clinical outcomes of breast sarcomas (BS) and malignant phyllodes tumours (MPT), and determine their prognostic factors. Cases of BS and MPT diagnosed at the Department of Pathology, Singapore General Hospital from January 1991 to December 2014 were derived from department files. Clinicopathological features, treatment strategies and survivals of patients with BS and MPT were compared. Prognostic indicators for BS and MPT were identified. BS and MPT were comparable in all except one of their clinicopathological features. A significantly higher proportion of BS patients had a history of previous breast carcinoma and thus radiation to the chest as compared to the MPT group (17.6 vs 0 %, P = 0.018). There was no significant difference in survival outcomes between BS and MPT. The 5-year disease-free survivals (DFS) for BS and MPT were 59.1 and 57.4 % respectively (P = 0.816), while the 5-year overall survivals (OS) for BS and MPT were 86.5 and 78.5 % respectively (P = 0.792). Combining both groups of tumours, univariate analysis showed that DFS was significantly affected by multifocality (P = 0.019), histological subtype (P = 0.014), presence of malignant heterologous elements (P < 0.001) and margin status (P = 0.023). Margin status was the only parameter which had a significant impact on OS (P = 0.040). Multivariate analysis confirmed the above findings. BS and MPT are rare entities with remarkable heterogeneity. They share similar clinicopathological features and outcomes, provoking thoughts on their biological relationship and clinical significance of pathologic distinction. PMID:27541020

  4. Deep tissue volume imaging of birefringence through fibre-optic needle probes for the delineation of breast tumour

    NASA Astrophysics Data System (ADS)

    Villiger, Martin; Lorenser, Dirk; McLaughlin, Robert A.; Quirk, Bryden C.; Kirk, Rodney W.; Bouma, Brett E.; Sampson, David D.

    2016-07-01

    Identifying tumour margins during breast-conserving surgeries is a persistent challenge. We have previously developed miniature needle probes that could enable intraoperative volume imaging with optical coherence tomography. In many situations, however, scattering contrast alone is insufficient to clearly identify and delineate malignant regions. Additional polarization-sensitive measurements provide the means to assess birefringence, which is elevated in oriented collagen fibres and may offer an intrinsic biomarker to differentiate tumour from benign tissue. Here, we performed polarization-sensitive optical coherence tomography through miniature imaging needles and developed an algorithm to efficiently reconstruct images of the depth-resolved tissue birefringence free of artefacts. First ex vivo imaging of breast tumour samples revealed excellent contrast between lowly birefringent malignant regions, and stromal tissue, which is rich in oriented collagen and exhibits higher birefringence, as confirmed with co-located histology. The ability to clearly differentiate between tumour and uninvolved stroma based on intrinsic contrast could prove decisive for the intraoperative assessment of tumour margins.

  5. Deep tissue volume imaging of birefringence through fibre-optic needle probes for the delineation of breast tumour.

    PubMed

    Villiger, Martin; Lorenser, Dirk; McLaughlin, Robert A; Quirk, Bryden C; Kirk, Rodney W; Bouma, Brett E; Sampson, David D

    2016-01-01

    Identifying tumour margins during breast-conserving surgeries is a persistent challenge. We have previously developed miniature needle probes that could enable intraoperative volume imaging with optical coherence tomography. In many situations, however, scattering contrast alone is insufficient to clearly identify and delineate malignant regions. Additional polarization-sensitive measurements provide the means to assess birefringence, which is elevated in oriented collagen fibres and may offer an intrinsic biomarker to differentiate tumour from benign tissue. Here, we performed polarization-sensitive optical coherence tomography through miniature imaging needles and developed an algorithm to efficiently reconstruct images of the depth-resolved tissue birefringence free of artefacts. First ex vivo imaging of breast tumour samples revealed excellent contrast between lowly birefringent malignant regions, and stromal tissue, which is rich in oriented collagen and exhibits higher birefringence, as confirmed with co-located histology. The ability to clearly differentiate between tumour and uninvolved stroma based on intrinsic contrast could prove decisive for the intraoperative assessment of tumour margins. PMID:27364229

  6. Deep tissue volume imaging of birefringence through fibre-optic needle probes for the delineation of breast tumour

    PubMed Central

    Villiger, Martin; Lorenser, Dirk; McLaughlin, Robert A.; Quirk, Bryden C.; Kirk, Rodney W.; Bouma, Brett E.; Sampson, David D.

    2016-01-01

    Identifying tumour margins during breast-conserving surgeries is a persistent challenge. We have previously developed miniature needle probes that could enable intraoperative volume imaging with optical coherence tomography. In many situations, however, scattering contrast alone is insufficient to clearly identify and delineate malignant regions. Additional polarization-sensitive measurements provide the means to assess birefringence, which is elevated in oriented collagen fibres and may offer an intrinsic biomarker to differentiate tumour from benign tissue. Here, we performed polarization-sensitive optical coherence tomography through miniature imaging needles and developed an algorithm to efficiently reconstruct images of the depth-resolved tissue birefringence free of artefacts. First ex vivo imaging of breast tumour samples revealed excellent contrast between lowly birefringent malignant regions, and stromal tissue, which is rich in oriented collagen and exhibits higher birefringence, as confirmed with co-located histology. The ability to clearly differentiate between tumour and uninvolved stroma based on intrinsic contrast could prove decisive for the intraoperative assessment of tumour margins. PMID:27364229

  7. The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis

    PubMed Central

    Cleator, Susan J; Powles, Trevor J; Dexter, Tim; Fulford, Laura; Mackay, Alan; Smith, Ian E; Valgeirsson, Haukur; Ashworth, Alan; Dowsett, Mitch

    2006-01-01

    Introduction The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy. Materials and methods Core biopsies were taken from primary breast tumours of 43 patients prior to AC, and subsequent clinical response was recorded. Post-chemotherapy (day 21) samples were available for 16 of these samples. Frozen sections of each core were used to estimate the proportion of invasive cancer and other tissue components at three levels. Transcriptional profiling was performed using a cDNA array containing 4,600 elements. Results Twenty-three (53%) patients demonstrated a 'good' and 20 (47%) a 'poor' clinical response. The percentage invasive tumour in core biopsies collected from these patients varied markedly. Despite this, agglomerative clustering of sample expression profiles showed that almost all biopsies from the same tumour aggregated as nearest neighbours. SAM (significance analysis of microarrays) regression analysis identified 144 genes which distinguished high- and low-percentage invasive tumour biopsies at a false discovery rate of not more than 5%. The misclassification error of prediction of clinical response using microarray data from pre-treatment biopsies (on leave-one-out cross-validation) was 28%. When prediction was performed on subsets of samples which were more homogeneous in their proportions of malignant and stromal cells, the misclassification error was considerably lower (8%–13%, p < 0.05 on permutation). Conclusion The non-tumour content of breast cancer samples has a significant effect on gene expression profiles. Consideration of this factor improves accuracy of response prediction by expression array profiling. Future gene expression array prediction studies should be planned taking this into account. PMID:16790077

  8. Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer.

    PubMed

    Hornsveld, M; Tenhagen, M; van de Ven, R A; Smits, A M M; van Triest, M H; van Amersfoort, M; Kloet, D E A; Dansen, T B; Burgering, B M; Derksen, P W B

    2016-09-01

    Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer. PMID:27035620

  9. Triple-negative breast cancers are increased in black women regardless of age or body mass index

    PubMed Central

    Stead, Lesley A; Lash, Timothy L; Sobieraj, Jerome E; Chi, Dorcas D; Westrup, Jennifer L; Charlot, Marjory; Blanchard, Rita A; Lee, John C; King, Thomas C; Rosenberg, Carol L

    2009-01-01

    Introduction We investigated clinical and pathologic features of breast cancers (BC) in an unselected series of patients diagnosed in a tertiary care hospital serving a diverse population. We focused on triple-negative (Tneg) tumours (oestrogen receptor (ER), progesterone receptor (PR) and HER2 negative), which are associated with poor prognosis. Methods We identified female patients with invasive BC diagnosed between 1998 and 2006, with data available on tumor grade, stage, ER, PR and HER2 status, and patient age, body mass index (BMI) and self-identified racial/ethnic group. We determined associations between patient and tumour characteristics using contingency tables and multivariate logistic regression. Results 415 cases were identified. Patients were racially and ethnically diverse (born in 44 countries, 36% white, 43% black, 10% Hispanic and 11% other). 47% were obese (BMI > 30 kg/m2). 72% of tumours were ER+ and/or PR+, 20% were Tneg and 13% were HER2+. The odds of having a Tneg tumour were 3-fold higher (95% CI 1.6, 5.5; p = 0.0001) in black compared with white women. Tneg tumours were equally common in black women diagnosed before and after age 50 (31% vs 29%; p = NS), and who were obese and non-obese (29% vs 31%; p = NS). Considering all patients, as BMI increased, the proportion of Tneg tumours decreased (p = 0.08). Conclusions Black women of diverse background have 3-fold more Tneg tumours than non-black women, regardless of age and BMI. Other factors must determine tumour subtype. The higher prevalence of Tneg tumours in black women in all age and weight categories likely contributes to black women's unfavorable breast cancer prognosis. PMID:19320967

  10. Prognostic significance of epithelial-mesenchymal transition proteins Twist and Foxc2 in phyllodes tumours of the breast.

    PubMed

    Lim, Jeffrey Chun Tatt; Koh, Valerie Cui Yun; Tan, Jane Sie Yong; Tan, Wai Jin; Thike, Aye Aye; Tan, Puay Hoon

    2015-02-01

    Epithelial-mesenchymal transition (EMT), an important process during embryonic development, is reportedly exploited during tumour progression. Deregulation of EMT-related molecules has been shown in many malignancies, including breast carcinoma. We aim to investigate the clinical relevance and prognostic significance of EMT proteins, Twist and Foxc2, in breast phyllodes tumours (PTs). The study cohort comprised 271 PTs diagnosed from 2003 to 2010. Of these, 188 (69.4 %) were benign, 60 (22.1 %) borderline, and 23 (8.5 %) malignant. Immunohistochemistry for Twist and Foxc2 was performed on tissue microarray sections. Percentage of tumour cells stained was evaluated and correlated with clinicopathological parameters and clinical outcome. Twist and Foxc2 stromal nuclear expression was associated with tumour grade (P = 0.038 and 0.012). Foxc2 stromal nuclear expression was positively correlated with epithelial expression (P < 0.001), tumour relapse, and metastasis (P = 0.037). Furthermore, stromal nuclear immunoreactivity of Twist and Foxc2 was interrelated (P < 0.001). Tumours expressing Foxc2 and those co-expressing both Twist and Foxc2 revealed a shorter time to recurrence (P < 0.001 and 0.001) and death (P = 0.044 and 0.015). Twist and Foxc2 stromal expression in PTs was significantly correlated with tumour grade and worse histological features. In addition, expression of Foxc2 and co-expression of Twist and Foxc2 in the stroma of PTs contributed to poorer prognosis. Clinical relevance of EMT-related molecules may be worthy of further investigation in PTs. PMID:25677742

  11. Value of tissue harmonic imaging (THI) and contrast harmonic imaging (CHI) in detection and characterisation of breast tumours

    PubMed Central

    Jung, E. M.; Jungius, K.-P.; Ertan, K.

    2006-01-01

    The purpose of this study was to investigate the extent to which tissue harmonic imaging (THI), speckle reduction imaging (SRI), spatial compounding (SC) and contrast can improve detection and differentiation of breast tumours. We examined 38 patients (14 benign, 24 malignant tumours) with different combinations of THI, SRI and SC. The effect on delineation, margin, tissue differentiation and posttumoral phenomena was evaluated with a three-point score. Additionally, 1oo not palpable tumours (diameters: 4–15 mm) were examined by contrast harmonic imaging (CHI) with power Doppler. After bolus injection (0.5 ml Optison), vascularisation and enhancement were observed for 20 min. The best combination for detection of margin, infiltration, echo pattern and posterior lesion boundary was the combination of SRI level 2 with SC low. THI was helpful for lesions OF more than 1 cm depth. In native Power Doppler, vessels were found in 54 of 100 lesions. Within 5 min after contrast medium (CM) injection, marginal and penetrating vessels increased in benign and malignant tumours and central vessels mostly in carcinomas (p<0.05). A diffuse CM accumulation was observed up to 20 min after injection in malignant tumours only (p<0.05). THI, SRI and SC improved delineation and tissue differentiation. Second-generation contrast agent allowed detection of tumour vascularisation with prolonged enhancement. PMID:16823568

  12. Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values.

    PubMed

    Cserni, Gábor; Vörös, András; Liepniece-Karele, Inta; Bianchi, Simonetta; Vezzosi, Vania; Grabau, Dorthe; Sapino, Anna; Castellano, Isabella; Regitnig, Peter; Foschini, Maria Pia; Zolota, Vassiliki; Varga, Zsuzsanna; Figueiredo, Paulo; Decker, Thomas; Focke, Cornelia; Kulka, Janina; Kaya, Handan; Reiner-Concin, Angelika; Amendoeira, Isabel; Callagy, Grace; Caffrey, Emer; Wesseling, Jelle; Wells, Clive

    2014-06-01

    The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5. PMID:24613255

  13. Prostate tumour overexpressed-1 promotes tumourigenicity in human breast cancer via activation of Wnt/β-catenin signalling.

    PubMed

    Cui, Yanmei; Ma, Weifeng; Lei, Fangyong; Li, Qingyuan; Su, Yanhong; Lin, Xi; Lin, Chuyong; Zhang, Xin; Ye, Liping; Wu, Shu; Li, Jun; Yuan, Zhongyu; Song, Libing

    2016-07-01

    Breast cancer is the most common malignancy in females. The presence of cancer stem cells (CSCs) is the main cause of local and distant tumour recurrence and is associated with poor outcome in breast cancer. However, the molecular mechanisms underlying the maintenance of CSCs remain largely unknown. This study demonstrates that prostate tumour overexpressed-1 (PTOV1) enhances the CSC population and augments the tumourigenicity of breast cancer cells both in vitro and in vivo. Moreover, PTOV1 suppresses transcription of Dickkopf-1 (DKK1) by recruiting histone deacetylases and subsequently reducing DKK1 promoter histone acetylation, followed by activation of Wnt/β-catenin signalling. Restoration of DKK1 expression in PTOV1-overexpressing cells counteracts the effects of PTOV1 on Wnt/β-catenin activation and the CSC population. Collectively, these results suggest that PTOV1 positively regulates the Wnt/β-catenin signalling pathway and enhances tumourigenicity in breast cancer; this novel mechanism may represent a therapeutic target for breast cancer. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27060981

  14. Early detection of metastatic disease in asymptomatic breast cancer patients with whole-body imaging and defined tumour marker increase

    PubMed Central

    Di Gioia, D; Stieber, P; Schmidt, G P; Nagel, D; Heinemann, V; Baur-Melnyk, A

    2015-01-01

    Background: Follow-up care in breast cancer is still an issue of debate. Diagnostic methods are more sensitive, and more effective therapeutic options are now available. The risk of recurrence is not only influenced by tumour stage but also by the different molecular subtypes. This study was performed to evaluate the use of whole-body imaging combined with tumour marker monitoring for the early detection of asymptomatic metastatic breast cancer (MBC). Methods: This analysis was performed as part of a follow-up study evaluating 813 patients with a median follow-up of 63 months. After primary therapy, all patients underwent tumour marker monitoring for CEA, CA 15-3 and CA 125 at 6-week intervals within an intensified diagnostic aftercare algorithm. A reproducible previously defined increase was considered as a strong indicator of MBC. From 2007 to 2010, 44 patients with tumour marker increase underwent whole-body magnetic resonance imaging and/or an FDG-PET/CT scan. Histological clarification and/or imaging follow-up were done. Results: Metastases were detected in 65.9% (29/44) of patients, 13.6% (6/44) had secondary malignancies besides breast cancer and 20.5% (9/44) had no detectable malignancy. Limited disease was found in 24.1% (7/29) of patients. Median progression-free survival of MBC was 9.2 months and median overall survival was 41.1 months. The 3- and 5-year survival rates were 64.2% and 40.0%, respectively. Conclusions: A reproducible tumour marker increase followed by whole-body imaging is highly effective for early detection. By consequence, patients might benefit from earlier detection and improved therapeutic options with a prolonged survival. PMID:25647014

  15. Gene expression profiling of formalin-fixed, paraffin-embedded familial breast tumours using the whole genome-DASL assay.

    PubMed

    Waddell, Nic; Cocciardi, Sibylle; Johnson, Julie; Healey, Sue; Marsh, Anna; Riley, Joan; da Silva, Leonard; Vargas, Ana Cristina; Reid, Lynne; Simpson, Peter T; Lakhani, Sunil R; Chenevix-Trench, Georgia

    2010-08-01

    Tissue sample acquisition is a limiting step in many studies. There are many thousands of formalin-fixed, paraffin-embedded archival blocks collected around the world, but in contrast relatively few fresh frozen samples in tumour banks. Once samples are fixed in formalin, the RNA is degraded and traditional methods for gene expression profiling are not suitable. In this study, we have evaluated the ability of the whole genome DASL (cDNA-mediated Annealing, Selection, extension, and Ligation) assay from Illumina to perform transcriptomic analysis of archived breast tumour tissue in formalin-fixed, paraffin-embedded (FFPE) blocks. We profiled 76 familial breast tumours from cases carrying a BRCA1, BRCA2 or ATM mutation, or from non-BRCA1/2 families. We found that replicate samples correlated well with each other (r(2) = 0.9-0.98). In 12/15 cases, the matched formalin-fixed and frozen samples predicted the same tumour molecular subtypes with confidence. These results demonstrate that the whole genome DASL assay is a valuable tool to profile degraded RNA from archival FFPE material. This assay will enable transcriptomic analysis of a large number of archival samples that are stored in pathology archives around the globe and consequently will have the potential to improve our understanding and characterization of many diseases. PMID:20593485

  16. Tumour-Associated Autoantibodies as Diagnostic Biomarkers for Breast Cancer: A Systematic Review and Meta-Analysis.

    PubMed

    Xia, J; Shi, J; Wang, P; Song, C; Wang, K; Zhang, J; Ye, H

    2016-06-01

    Tumour-associated autoantibodies may be promising biomarkers that could facilitate breast cancer (BC) diagnosis and improve patient outcomes. This review aims to identify the tumour-associated autoantibodies with the greatest diagnostic potential. Systematic searches were conducted using PubMed and Web of Science. The most studied tumour-associated autoantibody was included in a meta-analysis, and its clinical value was determined using Fagan's nomogram. The analysis included 84 studies regarding tumour-associated autoantibodies with the diagnostic value. Anti-p53 antibody was the most frequently studied autoantibody, followed by autoantibodies against MUC1, HER2 and cyclin B1. Although individual tumour-associated autoantibodies showed low diagnostic sensitivity, combinations of autoantibodies offered relatively high sensitivity. Enzyme-linked immunosorbent assay (ELISA) was the most common detection method, and nucleic acid programmable protein microarrays appeared preferable to common protein microarrays. As the most commonly studied autoantibody, anti-p53 antibody was included in a meta-analysis. When it had been detected using ELISA and cut-off values were defined as the mean +2 or 3 standard deviations, the summary area under the receiver operating characteristic curve for the presence of BC was 0.78. Fagan's nomogram showed post-test probabilities of 32% and 6% for positive and negative results, respectively. Mammography might be supplemented by the use of tumour-associated autoantibodies as biomarkers for BC diagnosis in younger women with increased risks of BC. Even though several studies have investigated the diagnostic use of tumour-associated autoantibodies as biomarkers for BC detection, a high-quality prospective study is needed to validate their diagnostic value in practice. PMID:26991924

  17. Imaging tumour heterogeneity of the consequences of a PKCα–substrate interaction in breast cancer patients

    PubMed Central

    Weitsman, Gregory; Lawler, Katherine; Kelleher, Muireann T.; Barrett, James E.; Barber, Paul R.; Shamil, Eamon; Festy, Frederic; Patel, Gargi; Fruhwirth, Gilbert O.; Huang, Lufei; Tullis, Iain D.C.; Woodman, Natalie; Ofo, Enyinnaya; Ameer-Beg, Simon M.; Irshad, Sheeba; Condeelis, John; Gillett, Cheryl E.; Ellis, Paul A.; Vojnovic, Borivoj; Coolen, Anthony C.C.; Ng, Tony

    2014-01-01

    Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early compared with late metastatic risk prediction. In pre-clinical studies, we and others have shown that various protein–protein interactions, pertaining to the actin microfilament-associated proteins, ezrin and cofilin, mediate breast cancer cell migration, a prerequisite for cancer metastasis. Moreover, as a direct substrate for protein kinase Cα, ezrin has been shown to be a determinant of cancer metastasis for a variety of tumour types, besides breast cancer; and has been described as a pivotal regulator of metastasis by linking the plasma membrane to the actin cytoskeleton. In the present article, we demonstrate that our tissue imaging-derived parameters that pertain to or are a consequence of the PKC–ezrin interaction can be used for breast cancer prognostication, with inter-cohort reproducibility. The application of fluorescence lifetime imaging microscopy (FLIM) in formalin-fixed paraffin-embedded patient samples to probe protein proximity within the typically <10 nm range to address the oncological challenge of tumour heterogeneity, is discussed. PMID:25399560

  18. Chemotherapy for Metastatic Breast Cancer – An Anachronism in the Era of Personalised and Targeted Oncological Therapy?

    PubMed Central

    Schneeweiss, A.; Ruckhäberle, E.; Huober, J.

    2015-01-01

    Based on the findings of modern molecular biology, breast cancer is nowadays considered to be a heterogeneous disease. This leads to the objective of an individualised, more patient-oriented therapy. A series of target molecules for this purpose has already been identified. The principle of targeted oncological therapy was realised decades ago with the introduction of endocrine therapy for patients with hormone receptor-positive tumours. The modern therapy for HER2-positive tumours is a further example for the translation of targeted therapy into clinical routine. For patients with HER2-negative metastatic breast cancer, to date two targeted drugs, bevacizumab and everolimus, are available for routine clinical use. Many other substances are still undergoing clinical development. However, validated predictive markers to aid in therapeutic decision-making and therapy control are still lacking. Chemotherapy constitutes an effective palliative therapy with proven efficacy for the patients. In this process strategies have also been realised for a targeted therapy against tumour cells with the help of chemotherapeutic agents such as, for example, the intracellular activation of the prodrug capecitabine or the active albumin-mediated transport of nab-paclitaxel which leads to higher peri- and intratumoural enrichments. The continuing unchanged relevance of chemotherapy is often underestimated in the current discussions and will be comprehensively evaluated in this review. PMID:26166838

  19. RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

    ClinicalTrials.gov

    2015-01-22

    Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Unspecified Adult Solid Tumor, Protocol Specific

  20. Platelet sensitivity to prostacyclin in normal subjects, and in patients with benign and malignant tumours of the breast.

    PubMed Central

    Benedetto, C.; Zonca, M.; Tavella, A. M.; Petitti, E.; Massobrio, M.; Nigam, S.; Slater, T. F.

    1985-01-01

    Platelet sensitivity to prostacyclin (PG12) was determined in normal male and female subjects, and in patients with benign and malignant tumours of the breast. The IC50 overall mean values for PG12 on ADP-induced platelet aggregation were similar for normal men and women, being 0.97 +/- 0.05 ng ml-1 and 0.83 +/- 0.07 ng ml-1 respectively. However, there were significant differences in the IC50 values for women in the 1st (0.81 +/- 0.06 ng ml-1) vs. 2nd (1.37 +/- 0.13 ng ml-1) phase of the menstrual cycle; post-menopausal women gave similar values to normal males and to pre-menopausal women in the 1st phase of the cycle. No significant differences were found between normal subjects and patients with benign or malignant tumours of the breast when account was taken of the status of the patient in relation to the phase of the menstrual cycle and the menopause. The importance of the hormonal status in evaluating changes in platelet sensitivity in patients with breast cancer is strongly emphasised. PMID:3881119

  1. Molecular characterisation of formalin-fixed paraffin-embedded (FFPE) breast tumour specimens using a custom 512-gene breast cancer bead array-based platform

    PubMed Central

    Abramovitz, M; Barwick, B G; Willis, S; Young, B; Catzavelos, C; Li, Z; Kodani, M; Tang, W; Bouzyk, M; Moreno, C S; Leyland-Jones, B

    2011-01-01

    Background: Formalin-fixed, paraffin-embedded (FFPE) tumour tissue represents an immense but mainly untapped resource with respect to molecular profiling. The DASL (cDNA-mediated Annealing, Selection, extension, and Ligation) assay is a recently described, RT–PCR-based, highly multiplexed high-throughput gene expression platform developed by Illumina specifically for fragmented RNA typically obtained from FFPE specimens, which enables expression profiling. In order to extend the utility of the DASL assay for breast cancer, we have custom designed and validated a 512-gene human breast cancer panel. Methods: The RNA from FFPE breast tumour specimens were analysed using the DASL assay. Breast cancer subtype was defined from pathology immunohistochemical (IHC) staining. Differentially expressed genes between the IHC-defined subtypes were assessed by prediction analysis of microarrays (PAM) and then used in the analysis of two published data sets with clinical outcome data. Results: Gene expression signatures on our custom breast cancer panel were very reproducible between replicates (average Pearson's R2=0.962) and the 152 genes common to both the standard cancer DASL panel (Illumina) and our breast cancer DASL panel were similarly expressed for samples run on both panels (average R2=0.877). Moreover, expression of ESR1, PGR and ERBB2 corresponded well with their respective pathology-defined IHC status. A 30-gene set indicative of IHC-defined breast cancer subtypes was found to segregate samples based on their subtype in our data sets and published data sets. Furthermore, several of these genes were significantly associated with overall survival (OS) and relapse-free survival (RFS) in these previously published data sets, indicating that they are biomarkers of the different breast cancer subtypes and the prognostic outcomes associated with these subtypes. Conclusion: We have demonstrated the ability to expression profile degraded RNA transcripts derived from FFPE

  2. Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy

    NASA Astrophysics Data System (ADS)

    Kong, Kenny; Zaabar, Fazliyana; Rakha, Emad; Ellis, Ian; Koloydenko, Alexey; Notingher, Ioan

    2014-10-01

    Breast-conserving surgery (BCS) is increasingly employed for the treatment of early stage breast cancer. One of the key challenges in BCS is to ensure complete removal of the tumour while conserving as much healthy tissue as possible. In this study we have investigated the potential of Raman micro-spectroscopy (RMS) for automated intra-operative evaluation of tumour excision. First, a multivariate classification model based on Raman spectra of normal and malignant breast tissue samples was built and achieved diagnosis of mammary ductal carcinoma (DC) with 95.6% sensitivity and 96.2% specificity (5-fold cross-validation). The tumour regions were discriminated from the healthy tissue structures based on increased concentration of nucleic acids and reduced concentration of collagen and fat. The multivariate classification model was then applied to sections from fresh tissue of new patients to produce diagnosis images for DC. The diagnosis images obtained by raster scanning RMS were in agreement with the conventional histopathology diagnosis but were limited to long data acquisition times (typically 10 000 spectra mm-2, which is equivalent to ~5 h mm-2). Selective-sampling based on integrated auto-fluorescence imaging and Raman spectroscopy was used to reduce the number of Raman spectra to ~20 spectra mm-2, which is equivalent to an acquisition time of ~15 min for 5 × 5 mm2 tissue samples. This study suggests that selective-sampling Raman microscopy has the potential to provide a rapid and objective intra-operative method to detect mammary carcinoma in tissue and assess resection margins.

  3. Thrombospondin-1 expression in breast cancer: prognostic significance and association with p53 alterations, tumour angiogenesis and extracellular matrix components.

    PubMed

    Ioachim, E; Damala, K; Tsanou, E; Briasoulis, E; Papadiotis, E; Mitselou, A; Charhanti, A; Doukas, M; Lampri, L; Arvanitis, D L

    2012-02-01

    Thrombospondin (TSP-1) is a 450-kd adhesive glycoprotein that was initially discovered in platelets and subsequently in a variety of cell types. Several reports suggest that TSP-1 possesses tumour suppressor function, through its ability to inhibit tumour neovascularization. In this study we investigated tissue sections from 124 breast carcinomas for the immuno-histochemical expression of TSP-1 protein and its relationship to several clinicopathological parameters. The possible relationship to hormone receptors content, p53 protein, proliferation associated indices, angiogenesis, VEGF expression and extracellular matrix components (tenascin, fibronectin, laminin, collagen type IV and syndecan-1) was also estimated. TSP-1 was detected in the perivascular tissue, at the epithelial-stromal junction, in the stroma and in the tumour cells. High tumour cell TSP-1 expression was observed in 9.7%, moderate in 17.7%, mild in 10.5%, while 62.1% of the cases were negative for TSP-1 expression. The survival analysis showed an increased risk of recurrence associated with low TSP-1 tumour cell expression. High stromal TSP-1 expression was observed in 3.2% of the cases, moderate in 3.3%, mild in 27.4%, while 63.6% of the cases showed absence of TSP-1 expression. This expression was higher in invasive lobular type of breast cancer and inversely correlated with the lymph node involvement and the estrogen receptor content. Stromal TSP-1 expression was also positively correlated with extracellular matrix components expression, tenascin, fibronectin, collagen type IV, laminin, and syndecan-1. The relationship of TSP-1 expression with tumor angiogenesis, growth fraction and p53 protein expression was not significant. Our data suggest that TSP-1 expression seems to be associated with favorable biological behavior and may have clinical value in terms of predicting the risk of recurrence. In addition, TSP-1 might not be a direct anti-angiogenic factor, although it seems to be implicated

  4. Phylloides tumours of the breast. A clinicopathologic study of 19 cases.

    PubMed

    Popescu, I; Serbănescu, M; Ivăşchescu, C

    1991-01-01

    During a period of 29 years (1960-1989), 19 patients with benign (15 cases) or malignant (4 cases) phylloides tumours were seen at the Surgical Clinic of Fundeni Hospital. Fourteen patients were followed up for a period of 2 to 21 years (mean 9.3 years). Two patients with benign tumours developed malignant recurrences. The malignant potential could not be predicted by histologic criteria. Although 4 patients had malignant tumours and other 2 developed malignant recurrences later, no distant metastases and no death in the 14 patients available for follow up were observed. We believe that in large or malignant tumours simple mastectomy is the surgical treatment of choice, in most benign phylloides tumours a conservative approach (quadrantectomy or lumpectomy) may be considered of the patients can be adaquately followed up. PMID:1647600

  5. Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer.

    PubMed

    Cresti, Nicola; Lee, Joanne; Rourke, Emma; Televantou, Despina; Jamieson, David; Verrill, Mark; Boddy, Alan V

    2016-03-01

    Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5' nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease. PMID:26773371

  6. Localization of a breast cancer tumour-suppressor gene to a 3-cM interval within chromosomal region 16q22.

    PubMed

    Iida, A; Isobe, R; Yoshimoto, M; Kasumi, F; Nakamura, Y; Emi, M

    1997-01-01

    Allelic losses on chromosome 16q in tumour cells are frequent in a variety of malignancies, suggesting the presence of one or more tumour-suppressor genes in the region. Among 210 sporadic breast cancers we examined using 15 microsatellite markers on the long arm of chromosome 16, heterozygosity for at least one locus was lost in 141 (67%). Detailed deletion mapping revealed two distinct commonly deleted regions. One region was defined as a 3-cM interval flanked by markers D16S512 and D16S515 at 16q22; the second consisted of a 9.5-cM interval flanked by markers D16S498 and D16S303 at q24.3. Allelic loss on 16q was observed frequently in small tumours, tumours without lymph node metastasis and tumours of the non-invasive histological type as well as in tumours of more advanced phenotype, suggesting that inactivation of one of at least two tumour-suppressor genes on 16q plays a role in early stage breast carcinogenesis. PMID:9010036

  7. Impact of tumour bed boost integration on acute and late toxicity in patients with breast cancer: A systematic review.

    PubMed

    Hamilton, Daniel George; Bale, Rebecca; Jones, Claire; Fitzgerald, Emma; Khor, Richard; Knight, Kellie; Wasiak, Jason

    2016-06-01

    The purpose of this systematic review was to summarise the evidence from studies investigating the integration of tumour bed boosts into whole breast irradiation for patients with Stage 0-III breast cancer, with a focus on its impact on acute and late toxicities. A comprehensive systematic electronic search through the Ovid MEDLINE, EMBASE and PubMed databases from January 2000 to January 2015 was conducted. Studies were considered eligible if they investigated the efficacy of hypo- or normofractionated whole breast irradiation with the inclusion of a daily concurrent boost. The primary outcomes of interest were the degree of observed acute and late toxicity following radiotherapy treatment. Methodological quality assessment was performed on all included studies using either the Newcastle-Ottawa Scale or a previously published investigator-derived quality instrument. The search identified 35 articles, of which 17 satisfied our eligibility criteria. Thirteen and eleven studies reported on acute and late toxicities respectively. Grade 3 acute skin toxicity ranged from 1 to 7% whilst moderate to severe fibrosis and telangiectasia were both limited to 9%. Reported toxicity profiles were comparable to historical data at similar time-points. Studies investigating the delivery of concurrent boosts with whole breast radiotherapy courses report safe short to medium-term toxicity profiles and cosmesis rates. Whilst the quality of evidence and length of follow-up supporting these findings is low, sufficient evidence has been generated to consider concurrent boost techniques as an alternative to conventional sequential techniques. PMID:27113229

  8. The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling

    PubMed Central

    Moreira Sousa, Cristovão; McGuire, John Russel; Thion, Morgane Sonia; Gentien, David; de la Grange, Pierre; Tezenas du Montcel, Sophie; Vincent-Salomon, Anne; Durr, Alexandra; Humbert, Sandrine

    2013-01-01

    In Huntington disease (HD), polyglutamine expansion in the huntingtin protein causes specific neuronal death. The consequences of the presence of mutant huntingtin in other tissues are less well understood. Here we propose that mutant huntingtin influences breast cancer progression. Indeed, we show that mammary tumours appear earlier in mouse breast cancer models expressing mutant huntingtin as compared to control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern that reflects enhanced aggressiveness with the overexpression of genes favouring invasion and metastasis. In agreement, mutant huntingtin accelerates epithelial to mesenchymal transition and enhances cell motility and invasion. Also, lung metastasis is higher in HD conditions than in control mice. Finally, we report that in HD, the dynamin dependent endocytosis of the ErbB2/HER2 receptor tyrosine kinase is reduced. This leads to its accumulation and to subsequent increases in cell motility and proliferation. Our study may thus have important implications for both cancer and HD. PMID:23300147

  9. Predictive diagnosis of the risk of breast cancer recurrence after surgery by single-particle quantum dot imaging

    PubMed Central

    Gonda, Kohsuke; Miyashita, Minoru; Higuchi, Hideo; Tada, Hiroshi; Watanabe, Tomonobu M.; Watanabe, Mika; Ishida, Takanori; Ohuchi, Noriaki

    2015-01-01

    In breast cancer, the prognosis of human epidermal growth factor receptor 2 (HER2)-positive patients (20–25%) has been dramatically improved by the clinical application of the anti-HER2 antibody drugs trastuzumab and pertuzumab. However, the clinical outcomes of HER2-negative cases with a poor prognosis have not improved, and novel therapeutic antibody drugs or diagnostic molecular markers of prognosis are urgently needed. Here, we targeted protease-activated receptor 1 (PAR1) as a new biomarker for HER2-negative patients. The developed anti-PAR1 antibody inhibited PAR1 activation by matrix metalloprotease 1 and thereby prevented cancer-cell migration and invasion. To estimate PAR1 expression levels in HER2-negative patient tissues using the antibody, user-friendly immunohistochemistry with fluorescence nanoparticles or quantum dots (QDs) was developed. Previously, immunohistochemistry with QDs was affected by tissue autofluorescence, making quantitative measurement extremely difficult. We significantly improved the quantitative sensitivity of immunohistochemistry with QDs by using an autofluorescence-subtracted image and single-QD imaging. The immunohistochemistry showed that PAR1 expression was strongly correlated with relapse-free survival time in HER2-negative breast cancer patients. Therefore, the developed anti-PAR1 antibody is a strong candidate for use as an anticancer drug and a prognostic biomarker for HER2-negative patients. PMID:26392299

  10. Characterization of the human activator protein-2gamma (AP-2gamma) gene: control of expression by Sp1/Sp3 in breast tumour cells.

    PubMed Central

    Hasleton, Mark D; Ibbitt, J Claire; Hurst, Helen C

    2003-01-01

    The activator protein-2 (AP-2) family of DNA-binding transcription factors are developmentally regulated and also play a role in human neoplasia. In particular, the AP-2gamma protein has been shown to be overexpressed in a high percentage of breast tumours. In the present study, we report the complete sequence determination of the human TFAP2C gene encoding the AP-2gamma transcription factor plus the mapping of the transcription start site used in breast tumour-derived cells. The 5'-end of the gene lies within a CpG island and transcription is initiated at a single site within a classical initiator motif. We have gone on to investigate why some breast tumour-derived cell lines readily express AP-2gamma, whereas others do not, and show that the proximal promoter (+191 to -312) is differentially active in the two cell phenotypes. DNase footprinting led to the identification of three Sp1/Sp3-binding sites within this region, two of which are absolutely required both for promoter function and cell-type-specific activity. By Western blotting a panel of expressing and non-expressing breast tumour lines we show that the latter have higher levels of Sp3. Furthermore, increasing Sp3 levels in AP-2gamma-expressing cells led to the repression of AP-2gamma promoter activity, particularly when Sp3 inhibitory function was maximized through sumoylation. We propose that differences in the level and activity of Sp3 between breast tumour lines can determine the expression level of their AP-2gamma gene. PMID:12733991

  11. The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene.

    PubMed

    Chua, Y L; Ito, Y; Pole, J C M; Newman, S; Chin, S-F; Stein, R C; Ellis, I O; Caldas, C; O'Hare, M J; Murrell, A; Edwards, P A W

    2009-11-19

    Neuregulin-1 (NRG1) is both a candidate oncogene and a candidate tumour suppressor gene. It not only encodes the heregulins and other mitogenic ligands for the ERBB family, but also causes apoptosis in NRG1-expressing cells. We found that most breast cancer cell lines had reduced or undetectable expression of NRG1. This included cell lines that had translocation breaks in the gene. Similarly, expression in cancers was generally comparable to or less than that in various normal breast samples. Many non-expressing cell lines had extensive methylation of the CpG island at the principal transcription start site at exon 2 of NRG1. Expression was reactivated by demethylation. Many tumours also showed methylation, whereas normal mammary epithelial fragments had none. Lower NRG1 expression correlated with higher methylation. Small interfering RNA (siRNA)-mediated depletion of NRG1 increased net proliferation in a normal breast cell line and a breast cancer cell line that expressed NRG1. The short arm of chromosome 8 is frequently lost in epithelial cancers, and NRG1 is the most centromeric gene that is always affected. NRG1 may therefore be the major tumour suppressor gene postulated to be on 8p: it is in the correct location, is antiproliferative and is silenced in many breast cancers. PMID:19802002

  12. Use of Finite Difference Time Domain Simulations and Debye Theory for Modelling the Terahertz Reflection Response of Normal and Tumour Breast Tissue

    PubMed Central

    Fitzgerald, Anthony J.; Pickwell-MacPherson, Emma; Wallace, Vincent P.

    2014-01-01

    The aim of this work was to evaluate the capabilities of Debye theory combined with Finite Difference Time Domain (FDTD) methods to simulate the terahertz (THz) response of breast tissues. Being able to accurately model breast tissues in the THz regime would facilitate the understanding of image contrast parameters used in THz imaging of breast cancer. As a test case, the model was first validated using liquid water and simulated reflection pulses were compared to experimental measured pulses with very good agreement (p = 1.00). The responses of normal and cancerous breast tissues were simulated with Debye properties and the correlation with measured data was still high for tumour (p = 0.98) and less so for normal breast (p = 0.82). Sections of the time domain pulses showed clear differences that were also evident in the comparison of pulse parameter values. These deviations may arise from the presence of adipose and other inhomogeneities in the breast tissue that are not accounted for when using the Debye model. In conclusion, the study demonstrates the power of the model for simulating THz reflection imaging; however, for biological tissues extra Debye terms or a more detailed theory may be required to link THz image contrast to physiological composition and structural changes of breast tissue associated with differences between normal and tumour tissues. PMID:25010734

  13. Wide-field optical coherence elastography for intraoperative assessment of tumour margins in breast cancer (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Allen, Wes M.; Chin, Lixin; Sampson, David D.; Kennedy, Brendan F.

    2016-03-01

    Incomplete excision of tumour margins is a major issue in breast-conserving surgery. Currently 20 - 60% of cases require a second surgical procedure required as a result of cancer recurrence. A number of techniques have been proposed to assess margin status, including frozen section analysis and imprint cytology. However, the recurrence rate after using these techniques remains very high. Over the last several years, our group has been developing optical coherence elastography (OCE) as a tool for the intraoperative assessment of tumour margins in breast cancer. We have reported a feasibility study on 65 ex vivo samples from patients undergoing mastectomy or wide local excision demonstrates the potential of OCE in differentiating benign from malignant tissue. In this study, malignant tissue was readily distinguished from surrounding relative tissue by a distinctive heterogeneous pattern in micro-elastograms. To date the largest field of view for a micro-elastogram is 20 x 20mm, however, lumpectomy samples are typically ~50 x 50 x 30mm. For OCE to progress as a useful clinical tool, elastograms must be acquired over larger areas to allow a greater portion of the surface area of lumpectomies to be assessed. Here, we propose a wide-field OCE scanner that utilizes a piezoelectric transducer with an internal diameter of 65mm. In this approach partially overlapped elastograms are stitched together forming a mosaic with overall dimensions of 50 x 50mm in a total acquisition time of 15 - 30 minutes. We present results using this approach on both tissue-mimicking phantoms and tissue, and discuss prospects for shorter acquisitions times.

  14. Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer

    PubMed Central

    Jung, Hae Hyun; Choi, Yoon-La; Ahn, TaeJin; Park, Kyunghee; Lee, Aeri; Do, In-Gu; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Woong-Yang; Im, Young-Hyuck

    2015-01-01

    In women with metastatic breast cancer (MBC), introduction of the anti-HER2 (human epidermal growth factor receptor-2) directed therapies including trastuzumab, pertuzumab, lapatinib, and/or trastuzumab-DM1 has markedly improved overall survival. However, not all cases of HER2-positive breast tumours derive similar benefit from HER2-directed therapy, and a significant number of patients experience disease progression because of primary or acquired resistance to anti-HER2-directed therapies. We integrated genomic and clinicopathological analyses in a cohort of patients with refractory breast cancer to anti-HER2 therapies to identify the molecular basis for clinical heterogeneity. To study the molecular basis underlying refractory MBC, we obtained 36 MBC tumours tissues and used next-generation sequencing to investigate the mutational and transcriptional profiles of 83 genes. We focused on HER2 mutational sites and HER2 pathways to identify the roles of HER2 mutations and the HER2 pathway in the refractoriness to anti-HER2 therapies. Analysis using massively parallel sequencing platform, CancerSCAN™, revealed that HER2 mutations were found in six of 36 patients (16.7%). One patient was ER (estrogen receptor)-positive and HER2-negative and the other five HER2 mutated patients were HER2-positive and HR (hormone receptor)-negative. Most importantly, four of these five patients did not show any durable clinical response to HER2-directed therapies. The HER2 pathway score obtained through transcriptional analyses identified that Growth Receptor Biding protein 2 (GRB2) was the most significantly down regulated gene in the HER2 mutated samples. Detection of HER2 mutations using higher deep DNA sequencing may identify a predictive biomarker of resistance to HER2-directed therapy. Functional validation is warranted. PMID:26397225

  15. Even With Very Small Breast Tumors, Studies Find HER2 Status Matters | Division of Cancer Prevention

    Cancer.gov

    Two retrospective studies have found that women with HER2-positive breast tumors (that is, tumors that produce too much of the HER2 protein) that are 1 centimeter or smaller had a higher risk of their disease returning within 5 years than women with similarly small HER2-negative tumors. |

  16. Refining Post-Surgical Therapy for Women with Lymph Node-Positive Breast Cancer

    Cancer.gov

    In this trial, women with HER2-negative, HR-positive breast cancer and 1-3 positive lymph nodes with recurrence scores of 25 or lower will be randomized to undergo adjuvant chemotherapy before starting endocrine therapy or to begin endocrine therapy.

  17. Importance of P450 reductase activity in determining sensitivity of breast tumour cells to the bioreductive drug, tirapazamine (SR 4233).

    PubMed Central

    Patterson, A. V.; Barham, H. M.; Chinje, E. C.; Adams, G. E.; Harris, A. L.; Stratford, I. J.

    1995-01-01

    P450 reductase (NADPH:cytochrome P450 reductase, EC 1.6.2.4) is known to be important in the reductive activation of the benzotriazene-di-N-oxide tirapazamine (SR 4233). Using a panel of six human breast adenocarcinoma cell lines we have examined the relationship between P450 reductase activity and sensitivity to tirapazamine. The toxicity of tirapazamine was found to correlate strongly with P450 reductase activity following an acute (3 h) exposure under hypoxic conditions, the drug being most toxic in the cell lines with the highest P450 reductase activity. A similar correlation was also observed following a chronic (96 h) exposure to the drug in air but not following acute (3 h) exposure in air. We have also determined the ability of lysates prepared from the cell lines to metabolise tirapazamine to its two-electron reduced product, SR 4317, under hypoxic conditions using NADPH as an electron donor. The rate of SR 4317 formation was found to correlate both with P450 reductase activity and with sensitivity to tirapazamine, the highest rates of SR 4317 formation being associated with the highest levels of P450 reductase activity and the greatest sensitivity to the drug. These findings indicate a major role for P450 reductase in determining the hypoxic toxicity of tirapazamine in breast tumour cell lines. Images Figure 4 PMID:7577460

  18. Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms

    PubMed Central

    Hancox, Rachael A; Allen, Michael D; Holliday, Deborah L; Edwards, Dylan R; Pennington, Caroline J; Guttery, David S; Shaw, Jacqueline A; Walker, Rosemary A; Pringle, J Howard; Jones, J Louise

    2009-01-01

    Introduction The stromal microenvironment has a profound influence on tumour cell behaviour. In tumours, the extracellular matrix (ECM) composition differs from normal tissue and allows novel interactions to influence tumour cell function. The ECM protein tenascin-C (TNC) is frequently up-regulated in breast cancer and we have previously identified two novel isoforms – one containing exon 16 (TNC-16) and one containing exons 14 plus 16 (TNC-14/16). Methods The present study has analysed the functional significance of this altered TNC isoform profile in breast cancer. TNC-16 and TNC-14/16 splice variants were generated using PCR-ligation and over-expressed in breast cancer cells (MCF-7, T47D, MDA-MD-231, MDA-MB-468, GI101) and human fibroblasts. The effects of these variants on tumour cell invasion and proliferation were measured and compared with the effects of the large (TNC-L) and fully spliced small (TNC-S) isoforms. Results TNC-16 and TNC-14/16 significantly enhanced tumour cell proliferation (P < 0.05) and invasion, both directly (P < 0.01) and as a response to transfected fibroblast expression (P < 0.05) with this effect being dependent on tumour cell interaction with TNC, because TNC-blocking antibodies abrogated these responses. An analysis of 19 matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases 1 to 4 (TIMP 1 to 4) revealed that TNC up-regulated expression of MMP-13 and TIMP-3 two to four fold relative to vector, and invasion was reduced in the presence of MMP inhibitor GM6001. However, this effect was not isoform-specific but was elicited equally by all TNC isoforms. Conclusions These results demonstrate a dual requirement for TNC and MMP in enhancing breast cancer cell invasion, and identify a significant role for the tumour-associated TNC-16 and TNC-14/16 in promoting tumour invasion, although these isoform-specific effects appear to be mediated through MMP-independent mechanisms. PMID:19405959

  19. Minimal residual disease in breast cancer: an overview of circulating and disseminated tumour cells.

    PubMed

    Tachtsidis, A; McInnes, L M; Jacobsen, N; Thompson, E W; Saunders, C M

    2016-08-01

    Within the field of cancer research, focus on the study of minimal residual disease (MRD) in the context of carcinoma has grown exponentially over the past several years. MRD encompasses circulating tumour cells (CTCs)-cancer cells on the move via the circulatory or lymphatic system, disseminated tumour cells (DTCs)-cancer cells which have escaped into a distant site (most studies have focused on bone marrow), and resistant cancer cells surviving therapy-be they local or distant, all of which may ultimately give rise to local relapse or overt metastasis. Initial studies simply recorded the presence and number of CTCs and DTCs; however recent advances are allowing assessment of the relationship between their persistence, patient prognosis and the biological properties of MRD, leading to a better understanding of the metastatic process. Technological developments for the isolation and analysis of circulating and disseminated tumour cells continue to emerge, creating new opportunities to monitor disease progression and perhaps alter disease outcome. This review outlines our knowledge to date on both measurement and categorisation of MRD in the form of CTCs and DTCs with respect to how this relates to cancer outcomes, and the hurdles and future of research into both CTCs and DTCs. PMID:27189371

  20. A Clinicopathological Study of Benign Phyllodes Tumour of Breast with Emphasis on Unusual Features

    PubMed Central

    Naik, Reena

    2016-01-01

    Introduction Benign Phyllodes Tumours (PTs) are rare fibroepithelial neoplasms that resemble fibroadenoma. But unlike fibroadenoma, benign PT can recur and both stromal & epithelial components can progress to malignancy. Contrary to earlier belief that benign PT is a stromal neoplasm and possibly arises from fibroadenoma, more recent molecular studies have suggested that both stroma and epithelium can become neoplastic. Sometimes, benign PT can occur synchronously with fibroadenoma. Here histomorphologic analysis of eleven cases of benign PT are presented including some unusual features. Materials and Methods Eleven cases of benign PT diagnosed between Dec 2014 and Jan 2016 in the Department of Pathology were studied. The demographic and clinicopathological features were analysed. Results The most common age group affected was 20-30 years (range: 13-45). Clinical features included pain, lump and bleeding from nipple. The tumour size varied from 2.5-18 cm in diameter. H&E stained sections showed secondary changes (haemorrhage, myxoid, change, cystic degeneration), epithelial hyperplasia (8), squamous & columnar metaplasia (1), benign tubular adenoma like areas (1), Ductal Carcinoma In Situ (DCIS) (1), Invasive Ductal Carcinoma (IDC) (1), Pseudoangiomatous Stromal Hyperplasia (PASH) (1), histologic infarction (2), tumour necrosis (1) and synchronous fibroadenoma (1). Unusual histologic features included atypical ductal hyperplasia, DCIS, IDC, synchronous fibroadenoma and tubular adenoma like areas arising within benign PT. Conclusion This study shows a spectrum of hyperplastic, metaplastic, dysplastic, benign, in-situ-malignancy and even invasive ductal malignancy occurring in benign PT. Therefore adequate and extensive sampling is recommended for accurate diagnosis.

  1. Giant nodular pseudoangiomatous stromal hyperplasia (PASH) of the breast presenting as a rapidly growing tumour.

    PubMed

    Mezzabotta, Maurizio; Riccardi, Silvia; Bonvini, Simona; Declich, Paolo; Tavani, Enrico; Morandi, Eugenio

    2009-01-01

    Pseudoangiomatous stromal hyperplasia (PASH) is often a microscopic incidental finding in breast biopsies performed for benign or malignant diseases. In rare cases, it presents as a localised breast mass. Since Vuitch et al first described this condition in 1986, only 109 cases of PASH presenting as a palpable or mammographically detectable mass have been documented. PASH is characterised by a dense, collagenous proliferation of mammary stroma, forming inter-anastomosing capillary-like spaces. It is important to distinguish this benign lesion from a low-grade angiosarcoma. Here we describe the clinical, radiological and histological features of a very unusual case of PASH that presented as a rapidly growing breast lesion in a 37-year old woman. PMID:19694241

  2. Fractal analysis for assessing tumour grade in microscopic images of breast tissue

    NASA Astrophysics Data System (ADS)

    Tambasco, Mauro; Costello, Meghan; Newcomb, Chris; Magliocco, Anthony M.

    2007-03-01

    In 2006, breast cancer is expected to continue as the leading form of cancer diagnosed in women, and the second leading cause of cancer mortality in this group. A method that has proven useful for guiding the choice of treatment strategy is the assessment of histological tumor grade. The grading is based upon the mitosis count, nuclear pleomorphism, and tubular formation, and is known to be subject to inter-observer variability. Since cancer grade is one of the most significant predictors of prognosis, errors in grading can affect patient management and outcome. Hence, there is a need to develop a breast cancer-grading tool that is minimally operator dependent to reduce variability associated with the current grading system, and thereby reduce uncertainty that may impact patient outcome. In this work, we explored the potential of a computer-based approach using fractal analysis as a quantitative measure of cancer grade for breast specimens. More specifically, we developed and optimized computational tools to compute the fractal dimension of low- versus high-grade breast sections and found them to be significantly different, 1.3+/-0.10 versus 1.49+/-0.10, respectively (Kolmogorov-Smirnov test, p<0.001). These results indicate that fractal dimension (a measure of morphologic complexity) may be a useful tool for demarcating low- versus high-grade cancer specimens, and has potential as an objective measure of breast cancer grade. Such prognostic value could provide more sensitive and specific information that would reduce inter-observer variability by aiding the pathologist in grading cancers.

  3. The sodium channel β1 subunit mediates outgrowth of neurite-like processes on breast cancer cells and promotes tumour growth and metastasis

    PubMed Central

    Nelson, Michaela; Millican-Slater, Rebecca; Forrest, Lorna C; Brackenbury, William J

    2014-01-01

    Voltage-gated Na+ channels (VGSCs) are heteromeric proteins composed of pore-forming α subunits and smaller β subunits. The β subunits are multifunctional channel modulators and are members of the immunoglobulin superfamily of cell adhesion molecules (CAMs). β1, encoded by SCN1B, is best characterized in the central nervous system (CNS), where it plays a critical role in regulating electrical excitability, neurite outgrowth and migration during development. β1 is also expressed in breast cancer (BCa) cell lines, where it regulates adhesion and migration in vitro. In the present study, we found that SCN1B mRNA/β1 protein were up-regulated in BCa specimens, compared with normal breast tissue. β1 upregulation substantially increased tumour growth and metastasis in a xenograft model of BCa. β1 over-expression also increased vascularization and reduced apoptosis in the primary tumours, and β1 over-expressing tumour cells had an elongate morphology. In vitro, β1 potentiated outgrowth of processes from BCa cells co-cultured with fibroblasts, via trans-homophilic adhesion. β1-mediated process outgrowth in BCa cells required the presence and activity of fyn kinase, and Na+ current, thus replicating the mechanism by which β1 regulates neurite outgrowth in CNS neurons. We conclude that when present in breast tumours, β1 enhances pathological growth and cellular dissemination. This study is the first demonstration of a functional role for β1 in tumour growth and metastasis in vivo. We propose that β1 warrants further study as a potential biomarker and targeting β1-mediated adhesion interactions may have value as a novel anti-cancer therapy. PMID:24729314

  4. Biochemical signatures of in vitro radiation response in human lung, breast and prostate tumour cells observed with Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Matthews, Q.; Jirasek, A.; Lum, J. J.; Brolo, A. G.

    2011-11-01

    This work applies noninvasive single-cell Raman spectroscopy (RS) and principal component analysis (PCA) to analyze and correlate radiation-induced biochemical changes in a panel of human tumour cell lines that vary by tissue of origin, p53 status and intrinsic radiosensitivity. Six human tumour cell lines, derived from prostate (DU145, PC3 and LNCaP), breast (MDA-MB-231 and MCF7) and lung (H460), were irradiated in vitro with single fractions (15, 30 or 50 Gy) of 6 MV photons. Remaining live cells were harvested for RS analysis at 0, 24, 48 and 72 h post-irradiation, along with unirradiated controls. Single-cell Raman spectra were acquired from 20 cells per sample utilizing a 785 nm excitation laser. All spectra (200 per cell line) were individually post-processed using established methods and the total data set for each cell line was analyzed with PCA using standard algorithms. One radiation-induced PCA component was detected for each cell line by identification of statistically significant changes in the PCA score distributions for irradiated samples, as compared to unirradiated samples, in the first 24-72 h post-irradiation. These RS response signatures arise from radiation-induced changes in cellular concentrations of aromatic amino acids, conformational protein structures and certain nucleic acid and lipid functional groups. Correlation analysis between the radiation-induced PCA components separates the cell lines into three distinct RS response categories: R1 (H460 and MCF7), R2 (MDA-MB-231 and PC3) and R3 (DU145 and LNCaP). These RS categories partially segregate according to radiosensitivity, as the R1 and R2 cell lines are radioresistant (SF2 > 0.6) and the R3 cell lines are radiosensitive (SF2 < 0.5). The R1 and R2 cell lines further segregate according to p53 gene status, corroborated by cell cycle analysis post-irradiation. Potential radiation-induced biochemical response mechanisms underlying our RS observations are proposed, such as (1) the regulated

  5. Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells

    PubMed Central

    Kamel, Marwa; Shouman, Samia; El-Merzebany, Mahmoud; Kilic, Gokhan; Veenstra, Timothy; Saeed, Muhammad; Wagih, Mohamed; Diaz-Arrastia, Concepcion; Patel, Deepa; Salama, Salama

    2012-01-01

    Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-β estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer. PMID:22866165

  6. Predictive value of c-erbB-2, p53, cathepsin-D and histology of the primary tumour in metastatic breast cancer.

    PubMed Central

    Niskanen, E.; Blomqvist, C.; Franssila, K.; Hietanen, P.; Wasenius, V. M.

    1997-01-01

    The value of various prognostic factors in breast cancer patients has been determined in a number of studies. Few reports have been published on the dependence of treatment outcome on histological and immunohistochemical characteristics in the primary tumour in patients with metastatic disease. We studied the incidence and prognostic value of histological and molecular abnormalities in the primary tumour of patients who had developed metastatic breast cancer. Eligible patients received a fluorouracil, epirubicin and cyclophosphamide (FEC) regimen either once a week or once every 4 weeks. Adequate specimens for various analyses were available from 127 patients. Median follow-up time of the patients ranged from 15 to 101 months. In this study, the histological grade of the malignancy best predicted response to chemotherapy (P < 0.0005). Most of the responses were observed in patients with grade 1 tumours; in this group, time to progression was delayed. C-erb B-2 gene amplification and oncoprotein expression had no predictive value. Neither p53 nor cathepsin-D predicted treatment outcome after chemotherapy. None of the factors had an effect on overall survival. Among breast cancer patients who received anthracycline-containing chemotherapy, response to treatment correlated with histological grade. In patients with histological grade 1 breast cancer, the time to progression was longest. However, overall survival was not affected by histological grade nor the other parameters tested. In addition to histological grade, other prognostic factors that are not included in this study need to be identified to determine which patients with metastatic breast cancer would benefit from cytotoxic treatment. PMID:9328152

  7. Real-time RT-PCR systems for CTC detection from blood samples of breast cancer and gynaecological tumour patients (Review).

    PubMed

    Andergassen, Ulrich; Kölbl, Alexandra C; Mahner, Sven; Jeschke, Udo

    2016-04-01

    Cells, which detach from a primary epithelial tumour and migrate through lymphatic vessels and blood stream are called 'circulating tumour cells'. These cells are considered to be the main root of remote metastasis and are correlated to a worse prognosis concerning progression-free and overall survival of the patients. Therefore, the detection of the minimal residual disease is of great importance regarding therapeutic decisions. Many different detection strategies are already available, but only one method, the CellSearch® system, reached FDA approval. The present review focusses on the detection of circulating tumour cells by means of real-time PCR, a highly sensitive method based on differences in gene expression between normal and malignant cells. Strategies for an enrichment of tumour cells are mentioned, as well as a large panel of potential marker genes. Drawbacks and advantages of the technique are elucidated, whereas, the greatest advantage might be, that by selection of appropriate marker genes, also tumour cells, which have already undergone epithelial to mesenchymal transition can be detected. Finally, the application of real-time PCR in different gynaecological malignancies is described, with breast cancer being the most studied cancer entity. PMID:26848098

  8. A peptide corresponding to the neuropilin-1-binding site on VEGF165 induces apoptosis of neuropilin-1-expressing breast tumour cells

    PubMed Central

    Barr, M P; Byrne, A M; Duffy, A M; Condron, C M; Devocelle, M; Harriott, P; Bouchier-Hayes, D J; Harmey, J H

    2005-01-01

    There is increasing evidence that vascular endothelial growth factor (VEGF) has autocrine as well as paracrine functions in tumour biology. Vascular endothelial growth factor-mediated cell survival signalling occurs via the classical tyrosine kinase receptors Flt-1, KDR/Flk-1 and the more novel neuropilin (NP) receptors, NP-1 and NP-2. A 24-mer peptide, which binds to neuropilin-1, induced apoptosis of murine and human breast carcinoma cells, whereas a peptide directed against KDR had no effect. Both anti-NP1 and anti-KDR peptides induced endothelial cell apoptosis. Confocal microscopy using 5-(6)-carboxyfluorescein-labelled peptides showed that anti-NP1 bound to both tumour and endothelial cells, whereas anti-KDR bound endothelial cells only. This study demonstrates that NP-1 plays an essential role in autocrine antiapoptotic signalling by VEGF in tumour cells and that NP1-blockade induces tumour cell and endothelial cell apoptosis. Specific peptides can therefore be used to target both autocrine (tumour cells) and paracrine (endothelial cells) signalling by VEGF. PMID:15655556

  9. Clofarabine, a novel adenosine analogue, reactivates DNA methylation-silenced tumour suppressor genes and inhibits cell growth in breast cancer cells.

    PubMed

    Lubecka-Pietruszewska, Katarzyna; Kaufman-Szymczyk, Agnieszka; Stefanska, Barbara; Cebula-Obrzut, Barbara; Smolewski, Piotr; Fabianowska-Majewska, Krystyna

    2014-01-15

    Clofarabine (2-chloro-2'-fluoro-2'-deoxyarabinosyladenine, ClF) is a second-generation 2'-deoxyadenosine analogue that is structurally related to cladribine (2-chloro-2'-deoxyadenosine, 2CdA) and fludarabine (9-beta-d-arabinosyl-2-fluoroadenine, F-ara-A). It demonstrates potent antitumour activity at much lower doses than parent compounds with high therapeutic efficacy in paediatric blood cancers. Our previous studies in breast cancer cells indicate that 2CdA and F-ara-A are involved in epigenetic regulation of gene transcription. We therefore investigated whether ClF influences methylation and expression of selected tumour suppressor genes, such as adenomatous polyposis coli (APC), phosphatase and tensin homologue (PTEN), and retinoic acid receptor beta 2 (RARbeta2), as well as expression of p53, p21 and DNA methyltransferase 1 (DNMT1) in MCF-7 and MDA-MB-231 breast cancer cell lines with different invasive potential. Promoter methylation and gene expression were estimated using methylation-sensitive restriction analysis (MSRA) and real-time PCR, respectively. ClF demonstrated potent growth inhibitory activity in MCF-7 and MDA-MB-231 cells after 96h treatment with IC50 determined as equal to 640nM and 50nM, respectively. In both breast cancer cell lines, ClF led to hypomethylation and up-regulation of APC, PTEN and RARbeta2 as well as increase in p21 expression. Only in non-invasive MCF-7 cells, these changes were associated with down-regulation of DNMT1. Our results provide first evidence of ClF implications in epigenetic regulation of transcriptional activity of selected tumour suppressor genes in breast cancer. It seems to be a new important element of ClF anticancer activity and may indicate its potential efficacy in epigenetic therapy of solid tumours, especially at early stages of carcinogenesis. PMID:24296317

  10. Hyperuricemia in 2 Patients Receiving Palbociclib for Breast Cancer.

    PubMed

    Bromberg, David J; Valenzuela, Mauricio; Nanjappa, Sowmya; Pabbathi, Smitha

    2016-01-01

    The authors reviewed retrospective cases of 2 women - one aged 78 years and the other aged 86 years - with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer treated with combination palbociclib/letrozole who presented with hyperuricemia. In both cases, the patients experienced hyperuricemia and neutropenia that required palbociclib to be temporarily discontinued and its dose to be subsequently reduced. Although study data have demonstrated that combination palbociclib/letrozole is safe and effective as a first-line treatment option for patients with advanced ER-positive, HER2-negative breast cancer, the efficacy and safety of cyclin-dependent kinase inhibitors, including their adverse events, still remains an active area of research. The authors postulate that hyperuricemia may be a potential adverse event of palbociclib not yet reported in randomized control studies or in clinical practice. PMID:27009458

  11. The novel desmopressin analogue [V4Q5]dDAVP inhibits angiogenesis, tumour growth and metastases in vasopressin type 2 receptor-expressing breast cancer models

    PubMed Central

    GARONA, JUAN; PIFANO, MARINA; ORLANDO, ULISES D.; PASTRIAN, MARIA B.; IANNUCCI, NANCY B.; ORTEGA, HUGO H.; PODESTA, ERNESTO J.; GOMEZ, DANIEL E.; RIPOLL, GISELLE V.; ALONSO, DANIEL F.

    2015-01-01

    Desmopressin (dDAVP) is a safe haemostatic agent with previously reported antitumour activity. It acts as a selective agonist for the V2 vasopressin membrane receptor (V2r) present on tumour cells and microvasculature. The purpose of this study was to evaluate the novel peptide derivative [V4Q5]dDAVP in V2r-expressing preclinical mouse models of breast cancer. We assessed antitumour effects of [V4Q5]dDAVP using human MCF-7 and MDA-MB-231 breast carcinoma cells, as well as the highly metastatic mouse F3II cell line. Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. In order to study the effect of intravenously administered [V4Q5]dDAVP on tumour growth and angiogenesis, breast cancer xenografts were generated in athymic mice. F3II cells were injected into syngeneic mice to evaluate the effect of [V4Q5]dDAVP on spontaneous and experimental metastatic spread. In vitro cytostatic effects of [V4Q5]dDAVP against breast cancer cells were greater than those of dDAVP, and associated with V2r-activated signal transduction and partial cell cycle arrest. In MDA-MB-231 xenografts, [V4Q5]dDAVP (0.3 μg/kg, thrice a week) reduced tumour growth and angiogenesis. Treatment of F3II mammary tumour-bearing immunocompetent mice resulted in complete inhibition of metastatic progression. [V4Q5]dDAVP also displayed greater antimetastatic efficacy than dDAVP on experimental lung colonisation by F3II cells. The novel analogue was well tolerated in preliminary acute toxicology studies, at doses ≥300-fold above that required for anti-angiogenic/antimetastatic effects. Our data establish the preclinical activity of [V4Q5]dDAVP in aggressive breast cancer, providing the rationale for further clinical trials. PMID:25846632

  12. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer

    PubMed Central

    van Geldermalsen, M; Wang, Q; Nagarajah, R; Marshall, A D; Thoeng, A; Gao, D; Ritchie, W; Feng, Y; Bailey, C G; Deng, N; Harvey, K; Beith, J M; Selinger, C I; O'Toole, S A; Rasko, J E J; Holst, J

    2016-01-01

    Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but

  13. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer.

    PubMed

    van Geldermalsen, M; Wang, Q; Nagarajah, R; Marshall, A D; Thoeng, A; Gao, D; Ritchie, W; Feng, Y; Bailey, C G; Deng, N; Harvey, K; Beith, J M; Selinger, C I; O'Toole, S A; Rasko, J E J; Holst, J

    2016-06-16

    Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but

  14. Human breast cancer bone metastasis in vitro and in vivo: a novel 3D model system for studies of tumour cell-bone cell interactions.

    PubMed

    Holen, I; Nutter, F; Wilkinson, J M; Evans, C A; Avgoustou, P; Ottewell, Penelope D

    2015-10-01

    Bone is established as the preferred site of breast cancer metastasis. However, the precise mechanisms responsible for this preference remain unidentified. In order to improve outcome for patients with advanced breast cancer and skeletal involvement, we need to better understand how this process is initiated and regulated. As bone metastasis cannot be easily studied in patients, researchers have to date mainly relied on in vivo xenograft models. A major limitation of these is that they do not contain a human bone microenvironment, increasingly considered to be an important component of metastases. In order to address this shortcoming, we have developed a novel humanised bone model, where 1 × 10(5) luciferase-expressing MDA-MB-231 or T47D human breast tumour cells are seeded on viable human subchaodral bone discs in vitro. These discs contain functional osteoclasts 2-weeks after in vitro culture and positive staining for calcine 1-week after culture demonstrating active bone resorption/formation. In vitro inoculation of MDA-MB-231 or T47D cells colonised human bone cores and remained viable for <4 weeks, however, use of matrigel to enhance adhesion or a moving platform to increase diffusion of nutrients provided no additional advantage. Following colonisation by the tumour cells, bone discs pre-seeded with MDA-MB-231 cells were implanted subcutaneously into NOD SCID mice, and tumour growth monitored using in vivo imaging for up to 6 weeks. Tumour growth progressed in human bone discs in 80 % of the animals mimicking the later stages of human bone metastasis. Immunohistochemical and PCR analysis revealed that growing MDA-MB-231 cells in human bone resulted in these cells acquiring a molecular phenotype previously associated with breast cancer bone metastases. MDA-MB-231 cells grown in human bone discs showed increased expression of IL-1B, HRAS and MMP9 and decreased expression of S100A4, whereas, DKK2 and FN1 were unaltered compared with the same cells grown in

  15. Visualisation of calcifications and thin collagen strands in human breast tumour specimens by the diffraction-enhanced imaging technique: a comparison with conventional mammography and histology.

    PubMed

    Keyriläinen, Jani; Fernández, Manuel; Fiedler, Stefan; Bravin, Alberto; Karjalainen-Lindsberg, Marja-Liisa; Virkkunen, Pekka; Elo, Eva-Maria; Tenhunen, Mikko; Suortti, Pekka; Thomlinson, William

    2005-02-01

    Six excised human breast tissue specimens carrying benign and malignant tumours were examined with the diffraction-enhanced imaging technique. Diffraction-enhanced images were compared with diagnostic screen-film mammograms and the correlation with histological information of the specimens was established. The enhanced visibility of calcifications, some of which were smaller than 0.15 mm in diameter, is reported in detail. Fine details of the structures such as strands of collagen and contours between glandular and adipose tissue, which are barely visible at the contrast detection limit in the conventional absorption-based mammograms, are clearly visible in the diffraction-enhanced images. Microscopic study of the stained histopathological sections unequivocally confirms the correlation of the radiographic findings with the morphologic changes in specimens. An increased soft tissue contrast and a combination of information obtained with disparate diffraction-enhanced images provide better visibility of mammographically indistinguishable features. This kind of additional structural information of the breast tissue is required to improve assessment accuracy and earlier detection of the breast lesions. These advances in image quality make the method a very promising candidate for mammography. PMID:15664286

  16. GSTPi-positive tumour microenvironment-associated fibroblasts are significantly associated with GSTPi-negative cancer cells in paired cases of primary invasive breast cancer and axillary lymph node metastases

    PubMed Central

    Chaiwun, B; Sukhamwang, N; Trakultivakorn, H; Saha, B; Young, L; Tsao-Wei, D; Naritoku, W Y; Groshen, S; Taylor, C R; Imam, S A

    2011-01-01

    Background: Glutathione S-transferase Pi (GSTPi) expression is one of the factors, which is known to be associated with development of resistance to chemotherapeutics in cancer patients, including those with breast cancer. Yet, its expression has been reported to be undetectable in cancer cells in high percent of patients with primary breast cancer. However, GSTPi expression in stromal cells in breast tumour microenvironment, namely cancer-associated fibroblast (CAF), which is recognised to have major roles in cancer progression, remains poorly reported. Methods: The aim of the study was to determine the expression of GSTPi; vimetin, a fibroblast-associated cytoskeleton protein; and α-smooth muscle actin (α-SMA), a known marker of CAF in breast cancer tissue, by immunohistochemical staining method in consecutive histologic sections of formalin-fixed and paraffin-embedded tissue biopsy specimens from a cohort of 39 paired cases of patients with invasive breast cancer and the corresponding axillary lymph nodes metastases. Results: Ductal and acinar luminal epithelial cells, myoepithelial cells and surrounding fibroblasts exhibited a homogeneous cytoplasmic reactivity with anti-GSTPi antibody in 11 of 11 cases of benign breast tissue biopsies. The vimentin-positive fibroblasts were unreactive with anti-α-SMA antibody. Loss of GSTPi expression was observed in breast cancer cells, at both the primary and metastatic sites, in 31 of 39 paired cases, as compared with benign breast epithelial cells (Fisher's exact test P<0.001). A significant association was observed between GSTPi-positive, vimentin-positive and α-SMA-positive fibroblast in tumour microenvironment at both sites. Conclusion: This is an original report of demonstration of a significance association between tumour microenvironment-associated GSTPi-positive CAF (vimentin/α-SMA-positive) and the GSTPi-negative cancer cells in paired cases of primary invasive breast cancer and the corresponding axillary

  17. Prolonged Response to Trastuzumab in a Patient With HER2-Nonamplified Breast Cancer With Elevated HER2 Dimerization Harboring an ERBB2 S310F Mutation.

    PubMed

    Chumsri, Saranya; Weidler, Jodi; Ali, Siraj; Balasubramanian, Sohail; Wallweber, Gerald; DeFazio-Eli, Lisa; Chenna, Ahmed; Huang, Weidong; DeRidder, Angela; Goicocheal, Lindsay; Perez, Edith A

    2015-09-01

    In the current genomic era, increasing evidence demonstrates that approximately 2% of HER2-negative breast cancers, by current standard testings, harbor activating mutations of ERBB2. However, whether patients with HER2-negative breast cancer with activating mutations of ERBB2 also experience response to anti-HER2 therapies remains unclear. This case report describes a patient with HER2-nonamplified heavily pretreated breast cancer who experienced prolonged response to trastuzumab in combination with pertuzumab and fulvestrant. Further molecular analysis demonstrated that her tumors had an elevated HER2 dimerization that corresponded to ERBB2 S310F mutation. Located in the extracellular domain of the HER2 protein, this mutation was reported to promote noncovalent dimerization that results in the activation of the downstream signaling pathways. This case highlights the fact that HER2-targeted therapy may be valuable in patients harboring an ERBB2 S310F mutation. PMID:26358791

  18. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    PubMed Central

    2011-01-01

    Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models

  19. Tyrosine kinase inhibitors (TKIs) in human and pet tumours with special reference to breast cancer: a comparative review.

    PubMed

    Ranieri, Girolamo; Pantaleo, Marianna; Piccinno, Mariagrazia; Roncetti, Maria; Mutinati, Maddalena; Marech, Ilaria; Patruno, Rosa; Rizzo, Annalisa; Sciorsci, Raffaele Luigi

    2013-11-01

    Tyrosine kinase receptors (TKRs) play a key role in tumour cell proliferation and survival since they are involved in endothelial cell activation leading to tumour neoangiogenesis. In particular, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-KitR), and colony-stimulating factor 1 (CSF-1) are overexpressed or constitutively activated in human and pet malignancies. A variety of small molecule inhibitors targeting specific tyrosine kinases (known as tyrosine kinase inhibitors or TKIs) have recently been approved, or are under investigation, for the treatment of human cancer. TKI application in animal cancer is however relatively recent. This review aims to illustrate the major aspects of tyrosine kinase dysfunctions, with special regard to human and animal cancer of the mammary gland, providing an update on the background of the anti-angiogenic and anti-neoplastic properties of TKIs in human and veterinary cancer. PMID:23768779

  20. Inhibition of Wnt signalling and breast tumour growth by the multi-purpose drug suramin through suppression of heterotrimeric G proteins and Wnt endocytosis.

    PubMed

    Koval, Alexey; Ahmed, Kamal; Katanaev, Vladimir L

    2016-02-15

    Overactivation of the Wnt signalling pathway underlies oncogenic transformation and proliferation in many cancers, including the triple-negative breast cancer (TNBC), the deadliest form of tumour in the breast, taking about a quarter of a million lives annually worldwide. No clinically approved targeted therapies attacking Wnt signalling currently exist. Repositioning of approved drugs is a promising approach in drug discovery. In the present study we show that a multi-purpose drug suramin inhibits Wnt signalling and proliferation of TNBC cells in vitro and in mouse models, inhibiting a component in the upper levels of the pathway. Through a set of investigations we identify heterotrimeric G proteins and regulation of Wnt endocytosis as the likely target of suramin in this pathway. G protein-dependent endocytosis of plasma membrane-located components of the Wnt pathway was previously shown to be important for amplification of the signal in this cascade. Our data identify endocytic regulation within Wnt signalling as a promising target for anti-Wnt and anti-cancer drug discovery. Suramin, as the first example of such drug or its analogues might pave the way for the appearance of first-in-class targeted therapies against TNBC and other Wnt-dependent cancers. PMID:26604320

  1. Tumour-associated eosinophilia: a review.

    PubMed Central

    Lowe, D; Jorizzo, J; Hutt, M S

    1981-01-01

    In a recent study of cervical carcinoma, 13 cases with a marked eosinophil infiltrate around the tumour were found. The histological appearance of the tumours was distinctive and suggested a specific response, similar to the lymphocyte infiltration in medullary carcinoma of the breast and seminoma. A review of published reports shows that tumour-associated tissue eosinophilia (TATE) and tumour-associated blood eosinophilia (TABE) may be seen in tumours of different histological types from different anatomical sites, and may occur together or separately. Tumours with TATE alone appear to have a better prognosis that those without, while TABE is associated with tumor spread and a poor prognosis. Images PMID:7035499

  2. Dissecting the Role of Curcumin in Tumour Growth and Angiogenesis in Mouse Model of Human Breast Cancer

    PubMed Central

    Bimonte, Sabrina; Barbieri, Antonio; Palma, Giuseppe; Luciano, Antonio; D'Aiuto, Massimiliano; Arra, Claudio; Izzo, Francesco

    2015-01-01

    Breast cancer is considered the most common cancer for women worldwide and it is now the second leading cause of cancer-related deaths among females in the world. Since breast cancer is highly resistant to chemotherapy, alternative anticancer strategies have been developed. In particular, many studies have demonstrated that curcumin, a derivative of turmeric, can be used as natural agent in treatment of some types of cancer by playing antiproliferative and antioxidant effects. In our study, we assessed the antitumor activities of curcumin in ER-negative human breast cancer cell line resistant to chemotherapy, MDA.MB231 by in vitro and in vivo experiments. In vitro data allowed us to demonstrate that curcumin played a role in regulation of proliferation and apoptosis in MDA.MB231 cells. In vivo, by generation of mouse model of breast cancer, we showed that treatment of curcumin inhibited tumor growth and angiogenesis. Specifically, we showed that curcumin is able to deregulate the expression of cyclin D1, PECAM-1, and p65, which are regulated by NF-κB. Our data demonstrated that curcumin could be used as an adjuvant agent to chemotherapy in treatment of triple negative breast cancer. PMID:25879038

  3. Association between breast cancer and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) gene 1595C/T SNP in a Pakistani population

    PubMed Central

    Rehman, Saima F.; Mansoor, Qaisar; Nazir, Nusrat; Kausar, Rukhsana; Jabeen, Nyla; Ismail, Muhammad

    2015-01-01

    Aim of the Study TRAIL-mediated signalling has emerged as an extensively studied biological mechanism reported to differentially induce apoptosis in cancer cells. However, overwhelmingly increasing experimentally verified data is shedding light on resistance against TRAIL-induced apoptosis in cancer cells. Moreover, genetic and epigenetic mutations also exert effects on the functionality of TRAIL and its receptors. In this study we investigated the association between breast cancer and polymorphisms in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in a Pakistani Population. Material and methods Genotyping for TRAIL gene 1595 C/T polymorphism was done for 363 breast cancer patients and 193 age- and sex-matched healthy controls. DNA was extracted using standard organic methods. PCR-RFLP analysis was done for C/T polymorphism at position 1595 in exon 5 of the TRAIL gene using site-specific primers and restriction enzyme. The results were statistically evaluated by SPSS14. Results In this study, CC homozygotes were 46.3% in patients and 49.7% in controls, p = 0.729 with OR value 0.8705 (95% CI: 0.6137–1.2348). CT was statistically insignificant, p = 0.837 with OR value 0.9242 (95% CI: 0.6494–1.3154). However, the minor allele or risk allele genotype TT had a higher percentage among breast cancer patients (12.1%) than in the control group (6.7%). Since there was a statistically insignificant difference (p = 0.212, OR value 1.9098 with 95% CI 1.0019 to 3.6406) of TT genotype between the two groups, the contrastingly higher percentage of TT genotype in breast cancer patients seems to be a risk factor for the disease. Moreover, the frequency of minor allele T was also found to be higher in the patients (0.329) than in the controls (0.285). Conclusions The TRAIL gene 1595 C/T SNP has a contradictory role in cancer development in different populations. In our population group although the percentage of homozygous risk allele TT was higher in patients

  4. 8-Oxo-7,8-dihydro-2′-deoxyguanosine and other lesions along the coding strand of the exon 5 of the tumour suppressor gene P53 in a breast cancer case-control study

    PubMed Central

    Brancato, Beniamino; Munnia, Armelle; Cellai, Filippo; Ceni, Elisabetta; Mello, Tommaso; Bianchi, Simonetta; Catarzi, Sandra; Risso, Gabriella G.; Galli, Andrea; Peluso, Marco E.M.

    2016-01-01

    The next-generation sequencing studies of breast cancer have reported that the tumour suppressor P53 (TP53) gene is mutated in more than 40% of the tumours. We studied the levels of oxidative lesions, including 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), along the coding strand of the exon 5 in breast cancer patients as well as in a reactive oxygen species (ROS)-attacked breast cancer cell line using the ligation-mediated polymerase chain reaction technique. We detected a significant ‘in vitro’ generation of 8-oxodG between the codons 163 and 175, corresponding to a TP53 region with high mutation prevalence, after treatment with xanthine plus xanthine oxidase, a ROS-generating system. Then, we evaluated the occurrence of oxidative lesions in the DNA-binding domain of the TP53 in the core needle biopsies of 113 of women undergoing breast investigation for diagnostic purpose. An increment of oxidative damage at the −G− residues into the codons 163 and 175 was found in the cancer cases as compared to the controls. We found significant associations with the pathological stage and the histological grade of tumours. As the major news of this study, this largest analysis of genomic footprinting of oxidative lesions at the TP53 sequence level to date provided a first roadmap describing the signatures of oxidative lesions in human breast cancer. Our results provide evidence that the generation of oxidative lesions at single nucleotide resolution is not an event highly stochastic, but causes a characteristic pattern of DNA lesions at the site of mutations in the TP53, suggesting causal relationship between oxidative DNA adducts and breast cancer. PMID:27260513

  5. 8-Oxo-7,8-dihydro-2'-deoxyguanosine and other lesions along the coding strand of the exon 5 of the tumour suppressor gene P53 in a breast cancer case-control study.

    PubMed

    Brancato, Beniamino; Munnia, Armelle; Cellai, Filippo; Ceni, Elisabetta; Mello, Tommaso; Bianchi, Simonetta; Catarzi, Sandra; Risso, Gabriella G; Galli, Andrea; Peluso, Marco E M

    2016-08-01

    The next-generation sequencing studies of breast cancer have reported that the tumour suppressor P53 (TP53) gene is mutated in more than 40% of the tumours. We studied the levels of oxidative lesions, including 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), along the coding strand of the exon 5 in breast cancer patients as well as in a reactive oxygen species (ROS)-attacked breast cancer cell line using the ligation-mediated polymerase chain reaction technique. We detected a significant 'in vitro' generation of 8-oxodG between the codons 163 and 175, corresponding to a TP53 region with high mutation prevalence, after treatment with xanthine plus xanthine oxidase, a ROS-generating system. Then, we evaluated the occurrence of oxidative lesions in the DNA-binding domain of the TP53 in the core needle biopsies of 113 of women undergoing breast investigation for diagnostic purpose. An increment of oxidative damage at the -G- residues into the codons 163 and 175 was found in the cancer cases as compared to the controls. We found significant associations with the pathological stage and the histological grade of tumours. As the major news of this study, this largest analysis of genomic footprinting of oxidative lesions at the TP53 sequence level to date provided a first roadmap describing the signatures of oxidative lesions in human breast cancer. Our results provide evidence that the generation of oxidative lesions at single nucleotide resolution is not an event highly stochastic, but causes a characteristic pattern of DNA lesions at the site of mutations in the TP53, suggesting causal relationship between oxidative DNA adducts and breast cancer. PMID:27260513

  6. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

    PubMed Central

    Howell, A.; DeFriend, D. J.; Robertson, J. F.; Blamey, R. W.; Anderson, L.; Anderson, E.; Sutcliffe, F. A.; Walton, P.

    1996-01-01

    We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer. PMID:8688341

  7. Canine mammary tumours, an overview.

    PubMed

    Sleeckx, N; de Rooster, H; Veldhuis Kroeze, E J B; Van Ginneken, C; Van Brantegem, L

    2011-12-01

    Canine mammary tumours (CMTs) are the most common neoplasms in intact female dogs. Although the prevalence of these tumours decreases in regions where preventive ovari(ohyster)ectomy is performed, it remains an important disease entity in veterinary medicine. Moreover, treatment options are limited in comparison with human breast cancer. Nevertheless, recent human treatment protocols might have potential in bitches suffering from CMTs. PMID:21645126

  8. Effects of CDK4/6 Inhibition in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Cells with Acquired Resistance to Paclitaxel

    PubMed Central

    Trapé, Adriana Priscila; Liu, Shuying; Cortes, Andrea Carolina; Ueno, Naoto T.; Gonzalez-Angulo, Ana Maria

    2016-01-01

    Among patients with hormone receptor (HR)-positive breast cancer, those with residual disease after neoadjuvant chemotherapy have a higher risk of relapse and poorer survival than those with a complete response. Previous studies have revealed a correlation between activation of cell cycle-regulating pathways in HR-positive breast cancer, particularly cyclin-dependent kinase (CDK) 4 and 6/cyclin D1 signaling, and resistance to standard therapies. Although CDK4/6 inhibition by palbociclib in combination with endocrine therapy has shown potent antiproliferative effects in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the potential role of palbociclib in re-sensitizing chemotherapy-resistant HR-positive breast cancer is not well defined. We hypothesized that CDK4/6 inhibition by palbociclib re-sensitizes HR-positive/HER2-negative residual breast cancer to taxane-based adjuvant therapy. Using cell counting, flow cytometry, and western blotting, we evaluated the efficacy of palbociclib alone and in concurrent or sequential combination with paclitaxel in parental and paclitaxel-resistant T47D HR-positive/HER2-negative breast cancer cells. The CDK4/6 pathway was constitutively active in both parental and paclitaxel-resistant T47D cells; thus, both cell types were highly sensitive to the inhibitory effects of single-agent palbociclib on cell growth and cell cycle progression. However, palbociclib did not re-sensitize resistant cells to paclitaxel-induced G2/M arrest and cell death in any of the combinations tested. Our results suggest that CDK4/6 inhibition by palbociclib does not re-sensitize HR-positive/HER2-negative residual breast cancer to chemotherapy. Nevertheless, the fact that CDK4/6 activation remained intact in paclitaxel-resistant cells indicates that patients who have HR-positive/HER2-negative residual disease after taxane-based neoadjuvant chemotherapy may still benefit from palbociclib in combination with other regimens

  9. Peculiarities of hyperlipidaemia in tumour patients.

    PubMed Central

    Dilman, V. M.; Berstein, L. M.; Ostroumova, M. N.; Tsyrlina, Y. V.; Golubev, A. G.

    1981-01-01

    The study group included 684 cases: 258 patients with breast carcinoma, 113 males with lung cancer, 42 patients with rectal tumours, 42 patients with stomach tumours, 59 patients with fibroadenomatosis, and 170 healthy subjects of varying age (male and female). A relatively high blood triglyceride level was found in patients with breast, lung, rectal (females), and stomach (female) tumours. The blood concentration of high-density lipoprotein-cholesterol in patients with breast, lung, and stomach (female) tumours was relatively low. The elimination of tumour (breast carcinoma) did not lead to significant changes in lipid metabolism. There was no correlation between degree of lipidaemia and stage of tumour progression except in the cases of rectal cancer. Preliminary results are presented on the tentative classification of hyperlipoproteinaemia in tumour patients, using the lipid concentration threshold values advocated by Carlson et al. (1977); an increased frequency of Type IV hyperlipoproteinaemia proved to be the most characteristic feature of tumour patients. The results are discussed in terms of the concept of the importance of lipid metabolic disturbances, primarily those due to ageing, in the genesis of the syndrome of "cancerophilia" (predisposition to cancer). PMID:7248149

  10. Feasibility of preoperative 125I seed-guided tumoural tracer injection using freehand SPECT for sentinel lymph node mapping in non-palpable breast cancer

    PubMed Central

    2014-01-01

    Background This study was designed to explore the feasibility of replacing the conventional peri-/intratumoural ultrasound (US)-guided technetium-99m albumin nanocolloid (99mTc-nanocolloid) administration by an injection of the same tracer guided by a freehand single-photon emission computed tomography (SPECT) device in patients with non-palpable breast cancer with an iodine-125 (125I) seed as tumour marker, who are scheduled for a sentinel lymph node biopsy (SLNB). This approach aimed to decrease the workload of the radiology department, avoiding a second US-guided procedure. Methods In ten patients, the implanted 125I seed was primarily localised using freehand SPECT and subsequently verified by conventional US in order to inject the 99mTc-nanocolloid. The following 34 patients were injected using only freehand SPECT localisation. In these patients, additional SPECT/CT was acquired to measure the distance between the 99mTc-nanocolloid injection depot and the 125I seed. In retrospect, a group of 21 patients with US-guided 99mTc-nanocolloid administrations was included as a control group. Results The depth difference measured by US and freehand SPECT in ten patients was 1.6 ± 1.6 mm. In the following 36 125I seeds (34 patients), the average difference between the 125I seed and the centre of the 99mTc-nanocolloid injection depot was 10.9 ± 6.8 mm. In the retrospective study, the average distance between the 125I seed and the centre of the 99mTc-nanocolloid injection depot as measured in SPECT/CT was 9.7 ± 6.5 mm and was not significantly different compared to the freehand SPECT-guided group (two-sample Student's t test, p = 0.52). Conclusion We conclude that using freehand SPECT for 99mTc-nanocolloid administration in patients with non-palpable breast cancer with previously implanted 125I seed is feasible. This technique may improve daily clinical logistics, reducing the workload of the radiology department. PMID:24949282

  11. Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, and TERT promoter hotspot mutations and TERT gene amplification as likely drivers of progression.

    PubMed

    Piscuoglio, Salvatore; Ng, Charlotte Ky; Murray, Melissa; Burke, Kathleen A; Edelweiss, Marcia; Geyer, Felipe C; Macedo, Gabriel S; Inagaki, Akiko; Papanastasiou, Anastasios D; Martelotto, Luciano G; Marchio, Caterina; Lim, Raymond S; Ioris, Rafael A; Nahar, Pooja K; Bruijn, Ino De; Smyth, Lillian; Akram, Muzaffar; Ross, Dara; Petrini, John H; Norton, Larry; Solit, David B; Baselga, Jose; Brogi, Edi; Ladanyi, Marc; Weigelt, Britta; Reis-Filho, Jorge S

    2016-03-01

    Phyllodes tumours (PTs) are breast fibroepithelial lesions that are graded based on histological criteria as benign, borderline or malignant. PTs may recur locally. Borderline PTs and malignant PTs may metastasize to distant sites. Breast fibroepithelial lesions, including PTs and fibroadenomas, are characterized by recurrent MED12 exon 2 somatic mutations. We sought to define the repertoire of somatic genetic alterations in PTs and whether these may assist in the differential diagnosis of these lesions. We collected 100 fibroadenomas, 40 benign PTs, 14 borderline PTs and 22 malignant PTs; six, six and 13 benign, borderline and malignant PTs, respectively, and their matched normal tissue, were subjected to targeted massively parallel sequencing (MPS) using the MSK-IMPACT sequencing assay. Recurrent MED12 mutations were found in 56% of PTs; in addition, mutations affecting cancer genes (eg TP53, RB1, SETD2 and EGFR) were exclusively detected in borderline and malignant PTs. We found a novel recurrent clonal hotspot mutation in the TERT promoter (-124 C>T) in 52% and TERT gene amplification in 4% of PTs. Laser capture microdissection revealed that these mutations were restricted to the mesenchymal component of PTs. Sequencing analysis of the entire cohort revealed that the frequency of TERT alterations increased from benign (18%) to borderline (57%) and to malignant PTs (68%; p < 0.01), and TERT alterations were associated with increased levels of TERT mRNA (p < 0.001). No TERT alterations were observed in fibroadenomas. An analysis of TERT promoter sequencing and gene amplification distinguished PTs from fibroadenomas with a sensitivity and a positive predictive value of 100% (CI 95.38-100%) and 100% (CI 85.86-100%), respectively, and a sensitivity and a negative predictive value of 39% (CI 28.65-51.36%) and 68% (CI 60.21-75.78%), respectively. Our results suggest that TERT alterations may drive the progression of PTs, and may assist in the differential diagnosis

  12. Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection

    PubMed Central

    Lambros, Maryou B; Campion-Flora, Adriana; Rodrigues, Daniel Nava; Gauthier, Arnaud; Cabral, Cecilia; Pawar, Vidya; Mackay, Alan; A’Hern, Roger; Marchiò, Caterina; Palacios, Jose; Natrajan, Rachael; Weigelt, Britta; Reis-Filho, Jorge S

    2016-01-01

    The mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, the acquisition of new genetic aberrations or non-genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCIS and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDCs were retrieved from 13 patients and subjected to microarray-based comparative genomic hybridisation (aCGH), and Sequenom MassARRAY (Oncocarta v1.0 panel). Fluorescence in situ hybridisation and Sanger sequencing were employed to validate the aCGH and Sequenom findings, respectively. Although the genomic profiles of matched DCIS and IDCs were similar, in three of 13 matched pairs amplification of distinct loci (i.e. 1q41, 2q24.2, 6q22.31, 7q11.21, 8q21.2 and 9p13.3) was either restricted to, or more prevalent in, the modal population of cancer cells of one of the components. Sequenom MassARRAY identified PIK3CA mutations restricted to the DCIS component in two cases, and in a third case, the frequency of the PIK3CA mutant allele reduced from 49% in the DCIS to 25% in the IDC component. Despite the genomic similarities between synchronous DCIS and IDC, our data provide strong circumstantial evidence to suggest that in some cases the progression from DCIS to IDC is driven by the selection of non-modal clones that harbour a specific repertoire of genetic aberrations. PMID:22252965

  13. Alcohol and breast cancer tumor subtypes in a Spanish Cohort.

    PubMed

    Gago-Dominguez, Manuela; Castelao, J Esteban; Gude, Francisco; Fernandez, Maite Peña; Aguado-Barrera, Miguel E; Ponte, Sara Miranda; Redondo, Carmen M; Castelo, Manuel Enguix; Dominguez, Alejandro Novo; Garzón, Víctor Muñoz; Carracedo, Angel; Martínez, María Elena

    2016-01-01

    Although alcohol intake is an established risk factor for overall breast cancer, few studies have looked at the relationship between alcohol use and breast cancer risk by the four major subtypes of breast cancer and very few data exist in the alcohol-breast cancer relationship in Spanish women. A population-based case-control study was conducted in Galicia, Spain. A total of 1766 women diagnosed with invasive breast cancer between 1997 and 2014 and 833 controls participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. We examined the alcohol-breast cancer association according to the major breast cancer subtypes [hormone-receptor-positive, HER2-negative (luminal A); hormone-receptor-positive, HER2-positive (luminal B); hormone-receptor-negative, HER2-negative (TNBC); and hormone-receptor-negative, HER2-positive (HER2 overexpressing)] as well as grade and morphology in Spanish women. With the exception of HER2 overexpressing, the risk of all subtypes of breast cancer significantly increased with increasing alcohol intake. The association was similar for hormonal receptor positive breast cancer, i.e., luminal A and luminal B breast cancer (odds ratio, OR 2.16, 95 % confidence interval, CI 1.55-3.02; and OR 1.98, 95 % CI 1.11-3.53, respectively), and for TNBC (TNBC: OR 1.93, 95 % CI 1.07-3.47). The alcohol-breast cancer association was slightly more pronounced among lobular breast cancer (OR 2.76, 95 % CI 1.62-4.69) than among ductal type breast cancers (OR 2.21, 95 % CI 1.61-3.03). In addition, significant associations were shown for all grades, I, II and III breast cancer (OR 1.98, 95 % CI 1.26-3.10; OR 2.34, 95 % CI 1.66-3.31; and OR 2.16, 95 % CI 1.44-3.25 for Grades I, II and III, respectively). To our knowledge, this is the first study to examine the association of breast cancer subtypes and alcohol intake in Spanish women. Our findings indicate that breast cancer risk increased

  14. Delaying Chemotherapy in the Treatment of Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

    PubMed Central

    Brufsky, Adam M.

    2015-01-01

    Global guidelines for the management of locally advanced or metastatic hormone receptor–positive (HR-positive), human epidermal growth factor 2–negative (HER2-negative) breast cancer recommend endocrine therapy as first-line treatment for all patients, regardless of age or postmenopausal status. However, current practice patterns in the United States and Europe suggest that these modes of therapy are not being used as recommended, and many patients with advanced HR-positive, HER2-negative disease are being treated first-line with chemotherapy or switched to chemotherapy after a single endocrine therapy. Given that chemotherapy is associated with increased toxicity and reduced quality of life (QOL) compared with endocrine therapy, prolonging the duration of response obtained with endocrine therapy may help delay chemotherapy and its attendant toxicities. Several strategies to delay or overcome endocrine resistance and thereby postpone chemotherapy have been explored, including the use of second-line endocrine agents with different mechanisms of action, adding targeted agents that inhibit specific resistance pathways, and adding agents that act in complementary or synergistic ways to inhibit tumor cell proliferation. This review analyzes the different therapy options available to HR-positive, HER2-negative patients with advanced breast cancer that can be used to delay chemotherapy and enhance QOL. PMID:26793013

  15. Prognostic Significance of HER-2 Status in Women With Inflammatory Breast Cancer

    PubMed Central

    Dawood, Shaheenah; Broglio, Kristine; Gong, Yun; Yang, Wei-Tse; Cristofanilli, Massimo; Kau, Shu-Wan; Meric-Bernstam, Funda; Buchholz, Thomas A.; Hortobagyi, Gabriel N; Gonzalez-Angulo, Ana M.

    2015-01-01

    BACKGROUND Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer with poorly understood prognostic variables. The purpose of this study was to define the prognostic impact of HER-2 status on survival outcomes of patients with IBC. METHODS In all, 179 patients with IBC, diagnosed between 1989 and 2005, with known HER-2 status, and treated with an anthracycline-based chemotherapy regimen without trastuzumab, were included in the analysis. Patients with HER-2-positive disease who received trastuzumab at the time of disease recurrence were included. Survival outcomes were estimated by the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. A Cox proportional hazards model was fitted to determine the association of survival outcomes with HER-2 status after adjusting for patient and tumor characteristics. RESULTS A total of 111 patients (62%) had HER-2-negative disease and 68 (38%) had HER-2-positive disease. The median follow-up among all patients was 35 months. At the time of the analysis, 62 patients (55.9%) with HER-2-negative disease and 42 patients (61.8%) with HER-2-positive disease had a recurrence. Thirty-one patients (73.8%) with HER-2-positive disease who had a disease recurrence went on to receive trastuzumab. On univariate analysis, no statistically significant difference was observed for either recurrence-free survival (P = .75) or overall survival (P = .24) between patients who had HER-2-positive disease and those who had HER-2-negative disease. In a multivariate model, HER-2 status did not appear to significantly affect recurrence-free survival (hazards ratio [HR] of 0.75; 95% confidence interval [95% CI], 0.46–1.22 [P = .241]). In the multivariate model, patients with HER-2-positive disease had a decreased hazard of death (HR of 0.56; 95% CI, 0.34–0.93 [P = .024]) compared with patients with HER-2-negative disease. CONCLUSIONS HER-2 status, in the absence of trastuzumab, did not appear to

  16. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial

    PubMed Central

    Aft, Rebecca; Naughton, Michael; Trinkaus, Kathryn; Watson, Mark; Ylagan, Lourdes; Chavez-MacGregor, Mariana; Zhai, Jing; Kuo, Sacha; Shannon, William; Diemer, Kathryn; Herrmann, Virginia; Dietz, Jill; Ali, Amjad; Ellis, Matthew; Weiss, Peter; Eberlein, Timothy; Ma, Cynthia; Fracasso, Paula M; Zoberi, Imran; Taylor, Marie; Gillanders, William; Pluard, Timothy; Mortimer, Joanne; Weilbaecher, Katherine

    2013-01-01

    Summary Background Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. Methods Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m²) plus docetaxel (75 mg/m²) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. Findings Of the 120 patients initially enrolled, one withdrew after signing consent and one patient’s baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline

  17. Salad vegetables dietary pattern protects against HER-2-positive breast cancer: a prospective Italian study.

    PubMed

    Sant, Milena; Allemani, Claudia; Sieri, Sabina; Krogh, Vittorio; Menard, Sylvie; Tagliabue, Elda; Nardini, Elena; Micheli, Andrea; Crosignani, Paolo; Muti, Paola; Berrino, Franco

    2007-08-15

    Studies investigating the relation of diet to breast cancer have produced conflicting results. We hypothesized that dietary factors associated with breast cancer risk might differentially influence the HER-2 status of the cancers that develop, and investigated this hypothesis by analyzing the data of the ORDET prospective study. We analyzed 8,861 volunteer women residents of the Varese Province, Italy, for whom we had full data. By December 31, 2001, 238 cases had occurred in which HER-2 status was known. Four dietary patterns had been identified previously by factor analysis: salad vegetables (high consumption of raw vegetables and olive oil), prudent (cooked vegetables, poultry, fish), western (potatoes, meat, eggs, butter), and canteen (pasta, tomato sauce, wine). In our study, relative risks (RRs) of developing HER-2-positive and HER-2-negative breast cancers by tertiles of dietary pattern factor scores were assessed by multinomial logistic regression. The salad vegetables dietary pattern had a protective effect against HER-2-positive cancers (RR = 0.25, 95% CI 0.10-0.64, for the highest tertile; p(trend) = 0.001), much stronger than for HER-2-negative cancers (p(heterogeneity) = 0.039). This important finding that a salad vegetables dietary pattern protects mainly against a specific breast cancer subtype indicates that future studies on environmental/dietary risk factors should explicitly take account of the heterogeneity of breast cancer phenotypes. PMID:17455245

  18. Geographic differences in the distribution of molecular subtypes of breast cancer in Brazil

    PubMed Central

    2014-01-01

    Background To compare the distribution of the intrinsic molecular subtypes of breast cancer based on immunohistochemical profile in the five major geographic regions of Brazil, a country of continental dimension, with a wide racial variation of people. Methods The study was retrospective observational. We classified 5,687 invasive breast cancers by molecular subtype based on immunohistochemical expression of estrogen-receptor (ER), progesterone-receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 proliferation index. Cases were classified as luminal A (ER and/or PR positive and HER2 negative, Ki-67 < 14%), luminal B (ER and/or PR positive, HER2 negative, and Ki-67 > 14%), triple-positive (ER and/or PR positive and HER2 positive), HER2-enriched (ER and PR negative, and HER2- positive), and triple-negative (TN) (ER negative, PR negative, and HER2- negative). Comparisons of the ages of patients and molecular subtypes between different geographic regions were performed. Results South and Southeast regions with a higher percentage of European ancestry and higher socioeconomic status presented with the highest proportion of luminal tumors. The North region presented with more aggressive subtypes (HER2-enriched and triple-negative), while the Central-West region predominated triple-positive carcinomas. The Northeast—a region with a high African influence—presented intermediate frequency of the different molecular subtypes. The differences persisted in subgroups of patients under and over 50 years. Conclusions The geographic regions differ according to the distribution of molecular subtypes of breast cancer. However, other differences, beside those related to African ancestry, such as socioeconomic, climatic, nutritional, and geographic, have to be considered to explain our results. The knowledge of the differences in breast cancer characteristics among the geographic regions may help to organize healthcare programs in large countries

  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. Genes related to growth regulation, DNA repair and apoptosis in an oestrogen receptor-negative (MDA-231) versus an oestrogen receptor-positive (MCF-7) breast tumour cell line.

    PubMed

    Skog, Sven; He, Qimin; Khoshnoud, Reza; Fornander, Tommy; Rutqvist, Lars-Erik

    2004-01-01

    The molecular mechanism(s) behind the development of endocrine resistance in breast cancer remains controversial. Here, we compare the capability of oestrogen receptor (ER)-negative cells (MDA-231) versus ER-positive tamoxifen-sensitive cells (MCF-7) to handle DNA repair, transmit signals from damaged DNA, initiate cell death via apoptosis, and then to control transmitted signals from the cell cycle and to synthesize growth factors and receptors. Genes related to these events were studied by cDNA micro-array. Normal human breast cells (H2F) and human lymphoblastoid tumour cells (CEM) were used as controls. Of the 18 genes investigated, 10 genes showed differences in their expression between the cell types. The ER-negative cells showed higher expressions of BRCA1, BRCA2, cdc2, cyclin B1, cyclin D1, cyclin E, IGFBP-3, TGF-alpha, TGF beta 2 and a lower expression of TGF beta R1. No differences in the expressions of bax, bcl-2, p53, p21 and GADD45 were found between the two cell lines. We found that the ER-negative cells were characterized by: (1) a stimulated expression of growth factors and cell cycle regulation compounds, (2) improved DNA repair capacity, but (3) no change in DNA damage signals and apoptotic pathways. Improved DNA repair capacity of ER-negative cells would have a growth advantage over ER-positive tumours when receiving antitumour therapy. PMID:15192311

  1. Tumor biology in estrogen receptor-positive, human epidermal growth factor receptor type 2-negative breast cancer: Mind the menopausal status

    PubMed Central

    Yamashita, Hiroko

    2015-01-01

    Breast cancer is not one disease, but can be categorized into four major molecular subtypes according to hormone receptor [estrogen receptor (ER) and progesterone receptor (PgR)] and human epidermal growth factor receptor type 2 (HER2) expression status. Ki67 labeling index and/or multigene assays are used to classify ER-positive, HER2-negative breast cancer into luminal A and luminal B (HER2-negative) subtypes. To date, most studies analyzing predictive or prognostic factors in ER-positive breast cancer have been performed in postmenopausal women, mainly using patients and samples in adjuvant aromatase inhibitor trials. In contrast, even the clinical roles of PgR and Ki67 have been little analyzed so far in premenopausal women. PgR is one of the estrogen-responsive genes, and it has been reported that plasma estradiol levels are related to expression levels of estrogen-responsive genes including PGR in ER-positive breast cancer. In this article, biological differences, especially differences in expression of PgR and Ki67 in ER-positive breast cancer between pre- and postmenopausal women are discussed. Clinical roles of PgR and Ki67 in ER-positive breast cancer differ between pre- and postmenopausal women. We suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status. PMID:26677435

  2. Synchronous Bilateral Breast Cancers

    PubMed Central

    Subramanyan, Annapurneswari; Radhakrishna, Selvi

    2015-01-01

    Background Bilateral breast cancer (BBC) is not an uncommon entity in contemporary breast clinics. Improved life expectancy after breast cancer treatment and routine use of contra-lateral breast mammography has led to increased incidence of BBC. Our study objective was to define the epidemiological and tumour characteristics of BBC in India. Materials and Methods A total of 1251 breast cancer patients were treated during the period January 2007 to March 2015 and 30 patients were found to have BBC who constituted the study population (60 tumour samples). Synchronous bilateral breast cancers (SBC) was defined as two tumours diagnosed within an interval of 6 months and a second cancer diagnosed after 6 months was labelled as metachronous breast cancer (MBC). Analyses of patient and tumour characteristics were done in this prospective data base of BBC patients. Results Median patient age was 66 years (range 39-85). Majority of the patients had SBC (n=28) and in 12 patients the second tumour was clinically occult and detected only by mammography of the contra-lateral breast. The second tumour was found at lower tumour size compared to the first in 73% of cases and was negative for axillary metastasis in 80% of cases (24/30). Infiltrating ductal carcinoma was the commonest histological type (n=51) and majority of the tumours were ER/PR positive (50/60). Her2 was overexpressed in 13 tumours (21%). Over 70% (22/30) of patients had similar histology in both breasts and amongst them grade concordance was present in about 69% (15/22) of patients. Concordance rates of ER, PR and Her2 statuses were 83%, 80% and 90% respectively. Bilateral mastectomy was the commonest surgery performed in 80% of the patients followed by bilateral breast conservation in 13%. At the end of study period, 26 patients were alive and disease free. Median survival was 29 months (range 3-86 months). Conclusion In most patients with BBC, the second tumour is identified at an early stage than index

  3. Feasibility study of personalized peptide vaccination for metastatic recurrent triple-negative breast cancer patients

    PubMed Central

    2014-01-01

    Introduction Since treatment modalities for metastatic recurrent triple-negative breast cancer (mrTNBC) are limited, a novel treatment approach including immunotherapy is required. We have developed a novel regimen of personalized peptide vaccination (PPV), in which vaccine antigens are individually selected from a pool of different peptide candidates based on the pre-existing host immunity. Herein we conducted a phase II study of PPV for metastatic recurrent breast cancer patients to investigate the feasibility of PPV for mrTNBC. Methods Seventy-nine patients with metastatic recurrent breast cancer who had metastases and had failed standard chemotherapy and/or hormonal therapy were enrolled. They were subgrouped as the mrTNBC group (n = 18), the luminal/human epidermal growth factor receptor 2 (HER2)-negative group (n = 41) and the HER2-positive group (n = 18), while the remaining two patients had not been investigated. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher peptide-specific immunoglobulin G (IgG) responses in pre-vaccination plasma were selected from 31 pooled peptide candidates applicable for the four HLA-IA phenotypes (HLA-A2, -A24, or -A26 types, or HLA-A3 supertypes), and were subcutaneously administered weekly for 6 weeks and bi-weekly thereafter. Measurement of peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses along with other laboratory analyses were conducted before and after vaccination. Results No severe adverse events associated with PPV were observed in any of the enrolled patients. Boosting of CTL and/or IgG responses was observed in most of the patients after vaccination, irrespective of the breast cancer subtypes. There were three complete response cases (1 mrTNBC and 2 luminal/HER2-negative types) and six partial response cases (1 mrTNBC and 5 luminal/HER2-negative types). The median progression-free survival time and median overall survival time of mrTNBC patients were 7.5 and 11

  4. Genomic alterations in DNA repair and chromatin remodeling genes in estrogen receptor-positive metastatic breast cancer patients with exceptional responses to capecitabine.

    PubMed

    Levin, Maren K; Wang, Kai; Yelensky, Roman; Cao, Ying; Ramos, Corinne; Hoke, Nicholas; Pippen, John; Blum, Joanne L; Brooks, Barry; Palmer, Gary; Palma, Norma; Balasubramanian, Sohail; Ross, Jeffrey S; O'Shaughnessy, Joyce

    2015-08-01

    We analyzed the genomic and phosphoproteomic profiles of breast cancer tissue obtained from six patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer who had highly durable (≥ 5 years) and, in some cases, ongoing clinical responses with capecitabine. Formalin-fixed, paraffin-embedded tissue samples from patients' primary (n = 4) or metastatic (n = 2) breast cancers were utilized for targeted next-generation sequencing and reversed phase protein microarray. Two patients received capecitabine monotherapy. Four patients received capecitabine in combination with paclitaxel; three of these continued single-agent capecitabine after stopping paclitaxel. Capecitabine was discontinued for progressive disease after a mean of 66 months in four patients (range 54-86 months), and two patients remain on therapy, having received capecitabine for >91 months and >122 months, respectively. Three patients' cancers (50%) had likely functional alterations in DNA repair and chromatin remodeling genes, while three other patients' cancers had variants of unknown significance in these pathways. Mutations in PIK3CA, amplifications of FGFR1 or ZNF703, or phosphorylation of HER family receptors and their downstream proteins did not preclude exceptional responses to capecitabine. None of the patients' tumors harbored TP53 or PTEN mutations. Four of the patients had breast cancer tissue available for PTEN immunohistochemistry, and all four patients' cancers were positive for PTEN. These surprising findings in a group of phenotypically similar patients with ER-positive, endocrine therapy-pretreated, HER2-negative metastases, are supported by preclinical data showing that sensitivity to 5-fluorouracil is enhanced by deficiencies in chromatin remodeling and homologous recombination genes. Our findings suggest that mutations that inactivate homologous recombination and/or chromatin remodeling genes within ER-positive, HER2-negative breast cancers may predict for

  5. The impact of the Oncotype DX Recurrence Score on treatment decisions and clinical outcomes in patients with early breast cancer: the Maccabi Healthcare Services experience with a unified testing policy

    PubMed Central

    Siegelmann-Danieli, Nava; Silverman, Barbara; Zick, Aviad; Beit-Or, Anat; Katzir, Itzhak; Porath, Avi

    2013-01-01

    The Oncotype DX Recurrence Score is a validated prognosticator in oestrogen receptor positive (ER+) breast cancer. Our retrospective analysis of a prospectively defined cohort summarises the clinical implications associated with Oncotype DX testing according to the Maccabi Healthcare Services (MHS) policy. The MHS eligibility criteria for testing included ER+ N0/pN1mic invasive tumours, discussion of test implications with an oncologist, ductal carcinoma 0.6–1 cm Grade 2–3, HER2 negative ductal carcinomas with 1.1–4.0 cm Grade 1–2, or lobular carcinoma. Large (> 1 cm) Grade 3 tumours could have grade reassessed. We linked Recurrence Score results with patients’ information and used chi-squared tests to assess the associations thereof. Between January 2008 and December 2011, tests were performed on 751 patients (MHS-eligible, 713); 54%, 38%, and 8% of patients had low, intermediate, and high Recurrence Score results, respectively. Recurrence Score distribution varied significantly with age (P = 0.002), with increasing Recurrence Score values with decreasing age. The proportion of patients with high Recurrence Score results varied by grade/size combination and histology, occurring in 32% of small (≤ 1 cm) Grade 3 and 3% of larger (1.1–4 cm) Grade 1 ductal tumours and only in 2% of lobular carcinomas. Chemotherapy was administered to 1%, 13%, and 61% of patients with low, intermediate, and high Recurrence Score results, respectively (P < 0.0001), but only to 2% of intermediate score patients ≥ 65 years. Luteinising-hormone-releasing hormone agonists with tamoxifen were used in 27% of low Recurrence Score patients ≤ 50 years. With a median follow-up of 26 months, no systemic recurrences were documented, whereas four patients exhibited locoregional recurrences. In summary, in this low-to-moderate risk patient population, testing identified 46% of patients as intermediate/high risk. Treatment decisions were influenced by Recurrence Score results and

  6. Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information.

    PubMed

    Feeley, Linda P; Mulligan, Anna M; Pinnaduwage, Dushanthi; Bull, Shelley B; Andrulis, Irene L

    2014-04-01

    The objectives of this study were to determine the prognostic significance of subgrouping estrogen receptor (ER)-positive breast tumors into low- and high-risk luminal categories using Ki67 index, TP53, or progesterone receptor (PR) status. The study group comprised 540 patients with lymph node negative, invasive breast carcinoma. Luminal A subtype was defined as being ER positive, HER2 negative, and Ki67 low (<14% cells positive) and luminal B subtype as being ER positive, HER2 negative, and Ki67 high (≥ 14% cells positive). Luminal tumors were also subgrouped into risk categories based on the PR and TP53 status. Survival analysis was performed. Patients with luminal B tumors (n=173) had significantly worse disease-free survival compared to those with luminal A tumors (n=186) (log rank P-value=0.0164; univariate Cox regression relative risk 2.00; 95% CI, 1.12-3.58; P=0.0187). Luminal subtype remained an independent prognostic indicator on multivariate analysis including traditional prognostic factors (relative risk 2.12; 95% CI, 1.16-3.88; P=0.0151). Using TP53 status or PR negativity rather than Ki67 to classify ER-positive luminal tumors gave similar outcome results to those obtained using the proliferation index. However, it was a combination of the three markers, which proved the most powerful prognostically. Ki67 index, TP53 status, or PR negativity can be used to segregate ER-positive, HER2-negative tumors into prognostically meaningful subgroups with significantly different clinical outcomes. These biomarkers particularly in combination may potentially be used clinically to guide patient management. PMID:24051696

  7. [Thrombophlebitis in an Elderly Japanese Woman Treated with Tamoxifen for Breast Cancer].

    PubMed

    Takayanagi, Hiroyuki; Hayami, Ryosuke; Tsuneizumi, Michiko; Nakagami, Kazuhiko

    2015-10-01

    In this study, we report the rare case of an elderly woman who developed thrombophlebitis after being treated with tamoxifen for breast cancer. She visited our department with a lump in her left breast. She underwent core needle biopsy, and she was diagnosed with breast cancer (invasive ductal carcinoma, ER- and PgR-positive, HER2-negative). We chose hormonal therapy because surgical treatment was deemed too invasive considering her general status. She was administered tamoxifen (20 mg/day) instead of an aromatase inhibitor in consideration of her osteoporosis. Six months after initiating tamoxifen therapy, she exhibited swelling in her left leg. Computed tomography and ultrasound revealed thrombophlebitis in her left femoral vein. She stopped taking tamoxifen and started warfarin potassium as thrombolytic therapy, after which thrombophlebitis was relieved. Advanced age may be a risk factor for thrombophlebitis associated with tamoxifen treatment; therefore, precautions should be taken accordingly. PMID:26489549

  8. Breast cancer cell lines: friend or foe?

    PubMed Central

    Burdall, Sarah E; Hanby, Andrew M; Lansdown, Mark RJ; Speirs, Valerie

    2003-01-01

    The majority of breast cancer research is conducted using established breast cancer cell lines as in vitro models. An alternative is to use cultures established from primary breast tumours. Here, we discuss the pros and cons of using both of these models in translational breast cancer research. PMID:12631387

  9. Tumour macrophages as potential targets of bisphosphonates

    PubMed Central

    2011-01-01

    Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use. Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to

  10. Incidence, detection, and tumour stage of breast cancer in a cohort of Italian women with negative screening mammography report recommending early (short-interval) rescreen

    PubMed Central

    2010-01-01

    Background Although poorly described in the literature, the practice of early (short-interval) rescreen after a negative screening mammogram is controversial due to its financial and psychological burden and because it is of no proven benefit. Methods The present study targeted an Italian 2-yearly screening programme (Emilia-Romagna Region, 1997-2002). An electronic dataset of 647,876 eligible negative mammography records from 376,257 women aged 50-69 years was record-linked with the regional breast cancer registry. The statistical analysis addressed the following research questions: (1) the prevalence of recommendation for early (<24 months) rescreen (RES) among negative mammography reports; (2) factors associated with the likelihood of a women receiving RES; and (3) whether women receiving RES and women receiving standard negative reports differed in terms of proportional incidence of interval breast cancer, recall rate at the next rescreen, detection rate of breast cancer at the next rescreen and the odds of having late-stage breast cancer during the interscreening interval and at the next rescreen. Results RES was used in eight out of 13 screening centres, where it was found in 4171 out of 313,320 negative reports (average rate 1.33%; range 0.05%-4.33%). Reports with RES were more likely for women aged 50-59 years versus older women (odds ratio (OR) 1.33; 95% CI 1.25-1.42), for the first versus subsequent screening rounds (OR 1.91; 95% CI 1.79-2.04) and with a centre-specific recall rate below the average of 6.2% (OR 1.41; 95% CI 1.32-1.50). RES predicted a 3.51-fold (95% CI 0.94-9.29) greater proportional incidence of first-year interval cancers, a 1.90-fold (95% CI 1.62-2.22) greater recall rate at the next screen, a 1.72-fold (95% CI 1.01-2.74) greater detection rate of cancer at the next screen and a non-significantly decreased risk of late disease stage (OR 0.59; 95% CI 0.23-1.53). Conclusion The prevalence of RES was in line with the maximum standard

  11. Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness

    PubMed Central

    Avgustinova, Alexandra; Iravani, Marjan; Robertson, David; Fearns, Antony; Gao, Qiong; Klingbeil, Pamela; Hanby, Andrew M.; Speirs, Valerie; Sahai, Erik; Calvo, Fernando; Isacke, Clare M.

    2016-01-01

    Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome. PMID:26777421

  12. Breast cancer detection using time reversal

    NASA Astrophysics Data System (ADS)

    Sheikh Sajjadieh, Mohammad Hossein

    Breast cancer is the second leading cause of cancer death after lung cancer among women. Mammography and magnetic resonance imaging (MRI) have certain limitations in detecting breast cancer, especially during its early stage of development. A number of studies have shown that microwave breast cancer detection has potential to become a successful clinical complement to the conventional X-ray mammography. Microwave breast imaging is performed by illuminating the breast tissues with an electromagnetic waveform and recording its reflections (backscatters) emanating from variations in the normal breast tissues and tumour cells, if present, using an antenna array. These backscatters, referred to as the overall (tumour and clutter) response, are processed to estimate the tumour response, which is applied as input to array imaging algorithms used to estimate the location of the tumour. Due to changes in the breast profile over time, the commonly utilized background subtraction procedures used to estimate the target (tumour) response in array processing are impractical for breast cancer detection. The thesis proposes a new tumour estimation algorithm based on a combination of the data adaptive filter with the envelope detection filter (DAF/EDF), which collectively do not require a training step. After establishing the superiority of the DAF/EDF based approach, the thesis shows that the time reversal (TR) array imaging algorithms outperform their conventional conterparts in detecting and localizing tumour cells in breast tissues at SNRs ranging from 15 to 30dB.

  13. Molecular subtypes of breast carcinoma in Saudi Arabia

    PubMed Central

    Alnegheimish, Norah A.; Alshatwi, Razan A.; Alhefdhi, Reem M.; Arafah, Maha M.; AlRikabi, Ammar C.; Husain, Sufia

    2016-01-01

    Objectives: To determine the distribution of various molecular subtypes of breast cancer in Saudi Arabia and to assess the association between these subtypes and age at diagnosis, tumor size, histopathological type, grade, presence of carcinoma in-situ, and lymph node status. Methods: This observational retrospective study, between January 2010 and December 2014, was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia. We classified 359 breast cancers into 4 molecular subtypes, using immunohistochemistry: luminal A (estrogen receptor [ER], or progesterone receptor [PR] positive and human epidermal growth factor receptor 2 [HER2] negative), luminal B (ER and/or PR positive and HER2 positive), HER2-positive (ER and PR negative and HER2 positive), and triple negative (ER, PR, and HER2 negative). We evaluated the relationship between these subtypes and clinicopathological features using Chi square test. Results: The most prevalent subtype was luminal A (58.5%), followed in descending order of frequency by triple negative (14.8%), luminal B (14.5%), and HER2-positive (12.3%). The average age at diagnosis was 49.8 years, and average tumor size at diagnosis was 3.19 cm. Conclusion: Luminal A tumor was the most common molecular subtype and HER2-positive was the least common. Most lobular carcinomas were luminal A tumors. Human epidermal growth factor receptor 2-positive and triple negative tumors had a higher histologic grade and a larger tumor size at diagnosis, and they were more common in women under 50 years. Carcinoma-in-situ was least common in triple negative tumors. We found no association between lymph node status and molecular subtypes. PMID:27146612

  14. Approach to the Triple Negative Breast Cancer in New Drugs Area

    PubMed Central

    Mirzania, Mehrzad

    2016-01-01

    Triple negative breast cancers (TNBCs) are associated with aggressive course, higher rates of visceral and central nervous system metastases and lower survival rate than hormone receptor positive. Once metastasis has occurred, a median survival was approximately one year. Currently, chemotherapy in TNBC is similar to other HER2- negative breast cancers but in the near future, it will revolutionize. TNBCs are quite heterogeneous based on biomarkers and genetic variations. The series of new drugs have been tried; in this article, platinum, anti-epigenetic drugs, PARP inhibitors, epidermal growth factor receptor inhibitor, Src family kinase inhibitor, anti androgen, glycoprotein Non-metastatic melanoma B (gpNMB) antibody, LHRH conjugated to cytotoxic drugs and inhibition of the PI3K/AKT/mTOR pathway will be explained. What is the optimal therapy for TNBC patients? It is still not clear but it seems that the road map according to biological and genetic markers is taking shape. PMID:27252813

  15. Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes

    PubMed Central

    Jerusalem, Guy; Rorive, Andree; Collignon, Joelle

    2014-01-01

    Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR) inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus). This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus) are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease). Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is impossible to select patients not benefiting from addition of everolimus to exemestane. Side effects and impact on quality of life are other important issues discussed

  16. Tumour morphology predicts PALB2 germline mutation status

    PubMed Central

    Teo, Z L; Provenzano, E; Dite, G S; Park, D J; Apicella, C; Sawyer, S D; James, P A; Mitchell, G; Trainer, A H; Lindeman, G J; Shackleton, K; Cicciarelli, L; Buys, S S; Andrulis, I L; Mulligan, A M; Glendon, G; John, E M; Terry, M B; Daly, M; Odefrey, F A; Nguyen-Dumont, T; Giles, G G; Dowty, J G; Winship, I; Goldgar, D E; Hopper, J L; Southey, M C

    2013-01-01

    Background: Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status. Methods: Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations. Results: Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0–64.6; P=5 × 10−7). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers. Conclusion: This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2. PMID:23787919

  17. TOP2A RNA Expression and Recurrence in Estrogen Receptor-Positive Breast Cancer

    PubMed Central

    Sparano, Joseph A.; Goldstein, Lori J.; Davidson, Nancy E.; Sledge, George W.; Gray, Robert

    2016-01-01

    The purpose of this study is to evaluate the relationship between TOP2A RNA expression and recurrence in patients with operable estrogen receptor (ER) positive breast cancer. We evaluated TOP2A expression in a pooled analysis of 4 independent data sets with gene expression data including 752 patients with early stage, ER-positive, HER2-negative breast cancer, most of whom received either no adjuvant therapy or endocrine therapy without chemotherapy. We also used an algorithm to simulate the Oncotype DX Recurrence Score (simRS) and the proliferation component of the Recurrence Score (simPS). Results are expressed as the hazard ratio (HR) for estimates of the effect of a one standard deviation increase in the value of the log gene expression (x + 1SD vs. x) as a continuous function. TOP2A expression was significantly associated with recurrence (HR 1.56, p<0.0001), and after adjustment for simRS (HR 1.26, p=0.003). TOP2A correlated somewhat with simRS (0.45), but more strongly with simPS (0.69). For those with an intermediate simRS, high TOP2A expression (above the median) was associated with significantly higher relapse rates at five years (HR 1.82, p=0.007). TOP2A expression provides prognostic information in patients with ER-positive, HER2-negative breast cancer, a population known to have low incidence of TOP2A gene alterations. These findings confirm prior reports indicating that TOP2A expression provides prognostic information in ER-positive breast cancer. TOP2A expression may also be useful for identifying those with an intermediate RS who are more likely to relapse, although additional validation in datasets including measured rather than simulated RS will be required. PMID:22706628

  18. Mouse Models of Brain Metastasis for Unravelling Tumour Progression.

    PubMed

    Soto, Manuel Sarmiento; Sibson, Nicola R

    2016-01-01

    Secondary tumours in the brain account for 40 % of triple negative breast cancer patients, and the percentage may be higher at the time of autopsy. The use of in vivo models allow us to recapitulate the molecular mechanisms potentially used by circulating breast tumour cells to proliferate within the brain.Metastasis is a multistep process that depends on the success of several stages including cell evasion from the primary tumour, distribution and survival within the blood stream and cerebral microvasculature, penetration of the blood-brain barrier and proliferation within the brain microenvironment. Cellular adhesion molecules are key proteins involved in all of the steps in the metastatic process. Our group has developed two different in vivo models to encompass both seeding and colonisation stages of the metastatic process: (1) haematogenous dissemination of tumour cells by direct injection into the left ventricle of the heart, and (2) direct implantation of the tumour cells into the mouse brain.This chapter describes, in detail, the practical implementation of the intracerebral model, which can be used to analyse tumour proliferation within a specific area of the central nervous system and tumour-host cell interactions. We also describe the use of immunohistochemistry techniques to identify, at the molecular scale, tumour-host cell interactions, which may open new windows for brain metastasis therapy. PMID:27325270

  19. 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

  20. Clear Cell Carcinoma of the Breast: A Rare Breast Cancer Subtype – Case Report and Literature Review

    PubMed Central

    Ratti, Vilma; Pagani, Olivia

    2015-01-01

    Background Glycogen-rich clear cell breast carcinoma is a rare histological breast cancer subtype. Its prognosis may vary depending on specific clinical and pathological characteristics such as low grade, strong positivity of estrogen receptor (ER) expression and early diagnosis. Case Presentation We present the case of a 53-year-old woman with a bleeding 10-cm-diameter mass in the left breast. The histological examination showed a poorly differentiated tumor with malignant cells characterized by abundant clear cytoplasm. The diagnosis of clear cell carcinoma was based on the histological characteristics of the tumor, and a nonmammary origin was initially ruled out. The tumor was triple negative [i.e. ER, progesterone receptor (PR) and HER2 negative]. Four months after the initial locoregional treatment, the patient developed lung and distant lymph node metastases. Conclusions Glycogen-rich clear cell carcinoma of the breast is a rare tumor. Early diagnosis, absence of lymph node metastases and ER/PR positivity are associated with a better prognosis, as in other common breast cancer subtypes. PMID:26600782

  1. Brain and spinal tumour.

    PubMed

    Goh, C H; Lu, Y Y; Lau, B L; Oy, J; Lee, H K; Liew, D; Wong, A

    2014-12-01

    This study reviewed the epidemiology of brain and spinal tumours in Sarawak from January 2009 till December 2012. The crude incidence of brain tumour in Sarawak was 4.6 per 100,000 population/year with cumulative rate 0.5%. Meningioma was the most common brain tumour (32.3%) and followed by astrocytoma (19.4%). Only brain metastases showed a rising trend and cases were doubled in 4 years. This accounted for 15.4% and lung carcinoma was the commonest primary. Others tumour load were consistent. Primitive neuroectodermal tumour (PNET) and astrocytoma were common in paediatrics (60%). We encountered more primary spinal tumour rather than spinal metastases. Intradural schwannoma was the commonest and frequently located at thoracic level. The current healthcare system in Sarawak enables a more consolidate data collection to reflect accurate brain tumours incidence. This advantage allows subsequent future survival outcome research and benchmarking for healthcare resource planning. PMID:25934956

  2. Long-term analysis to objectify the tumour grading by means of automated microscopic image analysis of the nucleolar organizer regions (AgNORs) in the case of breast carcinoma

    PubMed Central

    2013-01-01

    Background Apart from a number of cases of inaccurate prognosis in regard to individual patients, the inter- and intra-observer variability of the classical, histological prognosis parameters have been under repeated discussion. For this reason, a long-term analysis was carried out in regard to overall survival by means of automated microscopic image analysis of the nucleolar organizer regions (AgNORs) to objectify tumour grading in the case of breast carcinoma. This consists of a selective representation of argyrophilic proteins that are associated with the nucleolus organising regions. Methods The evaluation included 244 female patients with an average age of 59.3 years. The characterisation of the histological sections was carried out on the basis of the AMBA/R system. With this software the histometric characterisation level was evaluated in terms of the nucleolus organizer regions. The post-observation data were obtained from the clinical register and were complemented by mortality data from the cancer registers and by data supplied by the residents’ registration office of Berlin. Results The average post-observation period was 106.6 months. With the Cox-Regression the influence of the co-variables (conventional prognosis parameters and AgNOR parameters) were examined. In the model, only the parameters pN, G and various AgNOR parameters remain present. Conclusion There is a strong correlation between survival and selected AgNOR parameters. These could replace the conventional grading as the standard measure for the mitosis rate together with the pleomorphism level. Instead of the-time consuming AMBA/R system originally used, a new implementation of AgNOR quantification with modern VM systems could be applied. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1449591192859058. PMID:23566354

  3. p53 alteration in morphologically normal/benign breast tissue in patients with triple-negative high-grade breast carcinomas: breast p53 signature?

    PubMed

    Wang, Xi; Stolla, Moritz; Ring, Brian Z; Yang, Qi; Laughlin, Todd S; Rothberg, Paul G; Skinner, Kristin; Hicks, David G

    2016-09-01

    p53 alterations have been identified in approximately 23% of breast carcinomas, particularly in hormone receptor-negative high-grade carcinomas. It is considered to be an early event in breast carcinogenesis. Nevertheless, the putative precursor lesion of high-grade breast carcinoma remains elusive. Breast excision specimens from 93 triple-negative high-grade invasive ductal carcinomas, 48 estrogen receptor (ER)-positive/progesterone receptor-positive/Her2-negative non-high-grade invasive ductal carcinomas, and 50 mammoplasty breasts were selected. At least 2 tissue blocks with tumor and adjacent benign tissue were sectioned and subjected to immunohistochemistry staining for p53. TP53 gene sequencing was performed on select tumors. Further immunohistochemistry staining for ER and Ki-67 was performed on consecutive sections of tissue with p53-positive normal/benign cells. Of the 93 high-grade carcinomas, 51 (55%) were positive for p53 alteration, whereas only 3 (6.25%) of the 48 non-high-grade carcinomas were p53 altered. Focal p53 positivity in adjacent normal/benign breast tissue was identified in 19 cases, and 18 of them also had p53 alteration in their carcinomas. Only 1 case had focal p53 staining in normal/benign tissue, but the tumor was negative for p53 alteration. No p53 staining positivity was identified in the mammoplasty specimens. The p53-stained normal/benign cells were ER negative and did not show an increase in the Ki-67 labeling index. These findings indicate that the p53 staining positivity in normal/benign breast tissue is not a random event. It could be considered as the "p53 signature" in breast and serve as an indicator for future potential risk of p53-positive high-grade breast carcinoma. PMID:27246177

  4. 75 FR 30045 - Oncologic Drugs Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-28

    ... cancer known as HER2-negative breast cancer, in combination with the chemotherapy drug docetaxel; and (2) first-line treatment of HER2-negative metastatic breast cancer in combination with one of two classes of... for their locally recurrent or metastatic HER2 negative breast cancer. FDA intends to make...

  5. Tumour progression and metastasis.

    PubMed

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour's survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible. PMID:26913068

  6. Carboplatin+Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting

    ClinicalTrials.gov

    2014-03-03

    Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  7. Use of thermography in the differential diagnosis of phylloides tumour.

    PubMed

    Pierart, J; Burmeister, R; Steinberg, J; Schalper, J; Cid, L

    1990-07-01

    Thermography can be used as a method of diagnosing breast masses. We report our results of its use in the differential diagnosis of fibroadenoma from phylloides tumours (n = 47 and 20 respectively). Thermographic resolution (Th) and the difference in temperature between the tumour and a similar zone in the contralateral breast (delta 2) were compared. Thermograms were class Th1 (with a similar thermal pattern in both breasts without hypervascularization or hot points) and Th2 (with hypervascularization or a hot area with a thermal difference with the same area in the opposite breast (delta 2) of less than 2 degrees C) in most (95.7 per cent) of the patients with fibroadenoma and were class Th5 (having one or more pathological sign) in 85 per cent of the patients with phylloides tumours. Patients with phylloides tumours had a mean delta 2 of 2.99 degrees C whereas most of the patients with a fibroadenoma showed no difference in temperature. Their mean delta 2 was 0.2 degrees C (P less than 0.0005). We conclude that thermography helps in differential diagnosis between a fibroadenoma and a phylloides tumour. PMID:2166612

  8. Synthesis, Characterization and In Vitro Study of Biocompatible Cinnamaldehyde Functionalized Magnetite Nanoparticles (CPGF Nps) For Hyperthermia and Drug Delivery Applications in Breast Cancer

    PubMed Central

    Wani, Kirtee D.; Kadu, Brijesh S.; Mansara, Prakash; Gupta, Preeti; Deore, Avinash V.; Chikate, Rajeev C.; Poddar, Pankaj; Dhole, Sanjay D.; Kaul-Ghanekar, Ruchika

    2014-01-01

    Cinnamaldehyde, the bioactive component of the spice cinnamon, and its derivatives have been shown to possess anti-cancer activity against various cancer cell lines. However, its hydrophobic nature invites attention for efficient drug delivery systems that would enhance the bioavailability of cinnamaldehyde without affecting its bioactivity. Here, we report the synthesis of stable aqueous suspension of cinnamaldehyde tagged Fe3O4 nanoparticles capped with glycine and pluronic polymer (CPGF NPs) for their potential application in drug delivery and hyperthermia in breast cancer. The monodispersed superparamagnetic NPs had an average particulate size of ∼20 nm. TGA data revealed the drug payload of ∼18%. Compared to the free cinnamaldehyde, CPGF NPs reduced the viability of breast cancer cell lines, MCF7 and MDAMB231, at lower doses of cinnamaldehyde suggesting its increased bioavailability and in turn its therapeutic efficacy in the cells. Interestingly, the NPs were non-toxic to the non-cancerous HEK293 and MCF10A cell lines compared to the free cinnamaldehyde. The novelty of CPGF nanoparticulate system was that it could induce cytotoxicity in both ER/PR positive/Her2 negative (MCF7) and ER/PR negative/Her2 negative (MDAMB231) breast cancer cells, the latter being insensitive to most of the chemotherapeutic drugs. The NPs decreased the growth of the breast cancer cells in a dose-dependent manner and altered their migration through reduction in MMP-2 expression. CPGF NPs also decreased the expression of VEGF, an important oncomarker of tumor angiogenesis. They induced apoptosis in breast cancer cells through loss of mitochondrial membrane potential and activation of caspase-3. Interestingly, upon exposure to the radiofrequency waves, the NPs heated up to 41.6°C within 1 min, suggesting their promise as a magnetic hyperthermia agent. All these findings indicate that CPGF NPs prove to be potential nano-chemotherapeutic agents in breast cancer. PMID:25268975

  9. Metastatic Tumours to the Oral Cavity: Report of Three Cases

    PubMed Central

    Astreidis, Ioannis T.; Kontos, Konstantinos I.; Lazaridou, Maria N.; Bourlidou, Eleni T.; Gerasimidou, Domniki K.; Vladika, Natalia P.; Mangoudi, Doxa L.

    2015-01-01

    ABSTRACT Background Metastatic tumours to the oral cavity from distant organs are uncommon and represent approximately 1 - 3% of all oral malignancies. Such metastases can occur to the bone or to the oral soft tissues. Almost any malignancy from any site is capable of metastasis to the oral cavity and a wide variety of tumours have been reported to spread to the mouth. Methods Careful examination of the oral cavity and a high degree of clinical suspicion as well as a multidisciplinary approach are suggested. Results In this article we present three patients, a female and two males with metastatic tumours to the oral cavity, who were referred to our Department. The primary tumours were invasive lobular breast carcinoma, gastric adenocarcinoma and small cell lung carcinoma respectively. Conclusions Metastases to the oral cavity are quite uncommon among population. They usually present with symptoms similar to odontogenic infections and benign tumours, causing a delayed diagnosis and treatment. PMID:26904182

  10. Management of older women with early-stage breast cancer.

    PubMed

    Punglia, Rinaa S; Hughes, Kevin S; Muss, Hyman B

    2015-01-01

    Breast cancer is a disease of aging. The average age at diagnosis is 61, and the majority of deaths occur after age 65. Caring for older women with breast cancer is a major challenge, as many have coexisting illness that can preclude optimal breast cancer treatment and which frequently have greater effect than the breast cancer itself. Older patients with cancer should be screened or have a brief geriatric assessment to detect potentially remediable problems not usually assessed by oncologists (e.g., self-care, falls, social support, nutrition). Older women with early-stage breast cancer should be treated initially with surgery unless they have an exceedingly short life expectancy. Primary endocrine therapy should be considered for patients who have hormone receptor-positive tumors and a very short life expectancy, an acute illness that delays surgery, or tumors that need to be downstaged to be resectable. Sentinel node biopsy should be considered for patients in whom it might affect treatment decisions. Breast irradiation after breast-conserving surgery may be omitted for selected older women, especially for those with hormone receptor-positive early-stage breast cancer that are compliant with adjuvant endocrine therapy. The majority of older women with stage I and II breast cancer have hormone receptor-positive, HER2-negative tumors, and endocrine therapy provides them with optimal systemic treatment. If these patients have life expectancies exceeding at least 5 years, they should be considered for genetic assays to determine the potential value of chemotherapy. Partnering care with geriatricians or primary care physicians trained in geriatrics should be considered for all vulnerable and frail older patients. PMID:25993142

  11. Tumours of the lung

    PubMed Central

    Stünzi, H.; Head, K. W.; Nielsen, S. W.

    1974-01-01

    Lung tumours are not common in domestic animals; there has not been the increase in epidermoid carcinomas and anaplastic small-cell carcinomas that has occurred in man this century. Adenocarcinoma is the most common type in animals. The biological behaviour of each type of tumour in animals seems to be much the same as in man. The tumours are described histologically, the main categories being: epidermoid carcinoma, anaplastic carcinoma, adenocarcinoma, combined epidermoid and adenocarcinoma, carcinoid tumours, bronchial gland tumours, benign tumours, and sarcomas. ImagesFig. 13Fig. 14Fig. 15Fig. 16Fig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12 PMID:4371738

  12. Tumour suppressor genes in chemotherapeutic drug response

    PubMed Central

    Lai, Dulcie; Visser-Grieve, Stacy; Yang, Xiaolong

    2012-01-01

    Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications. PMID:22762204

  13. New insights and emerging therapies for breast cancer brain metastases.

    PubMed

    Lim, Elgene; Lin, Nancy U

    2012-07-01

    Breast cancer brain metastases (BCBMs) are the second most frequent secondary central nervous system metastases following those associated with non-small-cell lung cancer. It is increasingly evident that BCBM arises as a function of the biology of the primary tumor and the metastatic niche, which combine to create a unique microenvironment in the brain impacting both metastatic colonization and therapeutic response. Clinical outcomes are improving for BCBM patients as a result of modern combinatorial therapies, challenging the traditionally nihilistic approach to this patient subgroup. This review will focus on the breast cancer subtypes with the highest incidence of BCBM-human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and triple-negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) breast cancer (TNBC)-and will characterize differences in the clinical behavior of brain metastases that arise from these different subtypes. We will also highlight some of the recent preclinical studies that may shed light on the biological mechanisms and mediators underlying brain metastases. Finally, we will review published and current prospective trials of systemic therapies specifically for BCBM, including novel pathway-specific therapies. PMID:22888567

  14. Tumour progression and metastasis

    PubMed Central

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour’s survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible. PMID:26913068

  15. Tumour ablation: technical aspects

    PubMed Central

    Bodner, Gerd; Bale, Reto

    2009-01-01

    Abstract Image-guided percutaneous radiofrequency ablation (RFA) is a minimally invasive, relatively low-risk procedure for tumour treatment. Local recurrence and survival rates depend on the rate of complete ablation of the entire tumour including a sufficient margin of surrounding healthy tissue. Currently a variety of different RFA devices are available. The interventionalist must be able to predict the configuration and extent of the resulting ablation necrosis. Accurate planning and execution of RFA according to the size and geometry of the tumour is essential. In order to minimize complications, individualized treatment strategies may be necessary for tumours close to vital structures. This review examines the state-of-the art of different device technologies, approaches, and treatment strategies for percutaneous RFA of liver tumours. PMID:19965296

  16. Open-Label, Phase II, Multicenter, Randomized Study of the Efficacy and Safety of Two Dose Levels of Pertuzumab, a Human Epidermal Growth Factor Receptor 2 Dimerization Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer

    PubMed Central

    Gianni, Luca; Lladó, Anna; Bianchi, Giulia; Cortes, Javier; Kellokumpu-Lehtinen, Pirkko-Liisa; Cameron, David A.; Miles, David; Salvagni, Stefania; Wardley, Andrew; Goeminne, Jean-Charles; Hersberger, Veronica; Baselga, José

    2010-01-01

    Purpose Pertuzumab is a humanized monoclonal antibody inhibiting human epidermal growth factor receptor 2 (HER2) dimerization. The aim of this phase II trial was to assess the antitumor activity and safety profile of pertuzumab monotherapy in patients with HER2-negative metastatic breast cancer. The utility of biomarkers detected in paraffin-embedded tissue as predictors of response was also explored. Patients and Methods This was an international, multicenter, open-label, randomized phase II study. Patients (n = 79) with centrally confirmed HER2-negative metastatic breast cancer were randomly assigned to receive pertuzumab once every 3 weeks with a loading dose of 840 mg followed thereafter by either 420 mg (arm A) or 1,050 mg (arm B). Patients were stratified by country and prior taxane therapy. Results Of 79 patients who were randomly assigned, 78 were included in the intent-to-treat population. In arm A (n = 41), two patients had partial responses, and 18 patients (44%) experienced stable disease (SD) lasting ≥ 12 weeks. In arm B (n = 37), SD was observed in 14 patients (38%). Overall, six of 78 patients responded or had SD ≥ 6 months. Pertuzumab was generally well tolerated, and most adverse events were mild to moderate. Decline in left ventricular ejection fraction of ≥ 10% and/or to less than 50% was observed in eight patients, with one case of congestive heart failure in arm A. Pharmacokinetic data supported a fixed dose of pertuzumab once every 3 weeks. Conclusion The limited efficacy observed in this study, generally SD of relatively short duration, suggested little benefit of further investigation of single-agent pertuzumab in unselected patients with HER2-negative disease. PMID:20124183

  17. The effects of delays in radiotherapy treatment on tumour control

    NASA Astrophysics Data System (ADS)

    Wyatt, R. M.; Beddoe, A. H.; Dale, R. G.

    2003-01-01

    There is often a considerable delay from initial tumour diagnosis to the start of radiotherapy treatment, which may be due to factors such as waiting lists and referral delays. This paper uses widely published models and clinical parameters to calculate the effect of delays in treatment on local tumour control for four different types of tumour - squamous cell carcinoma (head and neck), breast, cervix and prostate. The Poisson model for tumour control probability (TCP), an exponential function for tumour growth and the linear quadratic model of cell kill are used to calculate the change in TCP for delays between diagnosis and treatment of up to 100 days. Typical values of the clinical parameters have been taken from the literature; these include α and β, σα, tumour size at diagnosis, pre-treatment doubling time, delay in onset of accelerated repopulation and doubling time during treatment. It is acknowledged that there are limitations in the reliability of these data for predicting absolute values of tumour control, but models are still useful for predicting how changes in treatment parameters are likely to affect the outcome. It is shown that for fast-growing tumours a delay of 1-2 months can have a significant adverse effect on the outcome, whereas for slow-growing tumours such as Ca prostate a delay of a few months does not significantly reduce the probability of tumour control. These calculations show the importance of ensuring that delays from diagnosis through to treatment are minimized, especially for patients with rapidly proliferating tumours.

  18. Defining Breast Cancer Intrinsic Subtypes by Quantitative Receptor Expression

    PubMed Central

    Cheang, Maggie C.U.; Martin, Miguel; Nielsen, Torsten O.; Prat, Aleix; Voduc, David; Rodriguez-Lescure, Alvaro; Ruiz, Amparo; Chia, Stephen; Shepherd, Lois; Ruiz-Borrego, Manuel; Calvo, Lourdes; Alba, Emilio; Carrasco, Eva; Caballero, Rosalia; Tu, Dongsheng; Pritchard, Kathleen I.; Levine, Mark N.; Bramwell, Vivien H.; Parker, Joel; Bernard, Philip S.; Ellis, Matthew J.; Perou, Charles M.; Di Leo, Angelo

    2015-01-01

    Purpose. To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression. Methods. We merged 1,557 cases from three randomized phase III trials into a single data set. These breast tumors were centrally reviewed in each trial for quantitative ER, PR, and HER2 expression by immunohistochemistry (IHC) stain and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), with intrinsic subtyping by research-based PAM50 RT-qPCR assay. Results. Among 283 HER2-negative tumors with <1% HR expression by IHC, 207 (73%) were basal-like; other subtypes, particularly HER2-enriched (48, 17%), were present. Among the 1,298 HER2-negative tumors, borderline HR (1%–9% staining) was uncommon (n = 39), and these tumors were heterogeneous: 17 (44%) luminal A/B, 12 (31%) HER2-enriched, and only 7 (18%) basal-like. Including them in the definition of triple-negative breast cancer significantly diminished enrichment for basal-like cancer (p < .05). Among 106 HER2-positive tumors with <1% HR expression by IHC, the HER2-enriched subtype was the most frequent (87, 82%), whereas among 127 HER2-positive tumors with strong HR (>10%) expression, only 69 (54%) were HER2-enriched and 55 (43%) were luminal (39 luminal B, 16 luminal A). Quantitative HR expression by RT-qPCR gave similar results. Regardless of methodology, basal-like cases seldom expressed ER/ESR1 or PR/PGR and were associated with the lowest expression level of HER2/ERBB2 relative to other subtypes. Conclusion. Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HR IHC cut point was <1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderline HR staining are molecularly diverse and may require additional assays to clarify underlying biology. PMID:25908555

  19. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

    PubMed Central

    Le, Caroline P.; Nowell, Cameron J.; Kim-Fuchs, Corina; Botteri, Edoardo; Hiller, Jonathan G.; Ismail, Hilmy; Pimentel, Matthew A.; Chai, Ming G.; Karnezis, Tara; Rotmensz, Nicole; Renne, Giuseppe; Gandini, Sara; Pouton, Colin W.; Ferrari, Davide; Möller, Andreas; Stacker, Steven A.; Sloan, Erica K.

    2016-01-01

    Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. PMID:26925549

  20. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.

    PubMed

    Le, Caroline P; Nowell, Cameron J; Kim-Fuchs, Corina; Botteri, Edoardo; Hiller, Jonathan G; Ismail, Hilmy; Pimentel, Matthew A; Chai, Ming G; Karnezis, Tara; Rotmensz, Nicole; Renne, Giuseppe; Gandini, Sara; Pouton, Colin W; Ferrari, Davide; Möller, Andreas; Stacker, Steven A; Sloan, Erica K

    2016-01-01

    Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. PMID:26925549

  1. The effects of trastuzumab on the CD4+CD25+FoxP3+ and CD4+IL17A+ T-cell axis in patients with breast cancer.

    PubMed

    Horlock, C; Stott, B; Dyson, P J; Morishita, M; Coombes, R C; Savage, P; Stebbing, J

    2009-04-01

    In addition to the direct targeting effects on HER2-positive cells, trastuzumab may have a therapeutic role modulating the activity of the cellular immune system in patients with breast cancer. To investigate this further, the balance of T-regulatory (T(reg)), Th17, natural killer (NK) and NK T (NKT) cells before, during and after trastuzumab therapy was investigated. Sequential frequencies of circulating T(reg) cells, Th17 cells, NK and NKT cells were measured in peripheral blood of breast cancer patients and normal controls throughout therapy. Individuals with breast cancer had significantly higher T(reg) frequencies of peripheral blood compared with healthy controls (9.2 or 8.6 vs 6%; P<0.05), and no significant differences in T(reg) frequencies were observed between HER2-positive and HER2-negative individuals. The number of Th17 cells was lowest in HER2-positive patients compared with both healthy controls and HER2-negative patients (0.31 vs 0.75% or 0.84%; P=0.01). There appeared to be an inverse relationship between T(reg) and Th17 frequencies in metastatic breast cancer (MBC) with T(reg) levels significantly reduced during treatment with trastuzumab (P=0.04), whereas Th17 frequencies were concomitantly increased (P=0.04). This study supports earlier data that T(reg) cells are present at higher frequencies in breast cancer patients compared with healthy individuals. For the first time, we show that HER2-positive individuals with breast carcinomas have reduced numbers of circulating Th17 cells, which appear, in turn to have an inverse relationship with T(reg) frequency in MBC. The change in balance of the T(reg) : Th17 ratio appears to characterise the cancer state, and furthermore, is disrupted by trastuzumab therapy. PMID:19277040

  2. The impact of the 21-gene assay on adjuvant treatment decisions in oestrogen receptor-positive early breast cancer: a prospective study

    PubMed Central

    Kuchel, Anna; Robinson, Tim; Comins, Charles; Shere, Mike; Varughese, Mohini; Sparrow, Geoff; Sahu, Ajay; Saunders, Louise; Bahl, Amit; Cawthorn, Simon J; Braybrooke, Jeremy P

    2016-01-01

    Background: International guidelines, including NICE, recommend using the 21-gene Recurrence Score assay for guiding adjuvant treatment decisions in ER+, HER2-negative early breast cancer (BC). We investigated the impact of adding this assay to standard pathological tests on clinicians'/patients' treatment decisions and on patients' decisional conflict in the United Kingdom. Methods: In this prospective multicentre study, eligibility criteria included: ER+ HER2-negative BC (N0/Nmic for patients ⩽50 years; ⩽3 positive lymph nodes for patients >50 years) and being fit for chemotherapy. Physicians'/patients' treatment choices and patients' decisional conflict were recorded pre- and post testing. Results: The analysis included 137 patients. Overall, adjuvant treatment recommendations changed in 40.7% of patients, with the direction of the change consistent with the Recurrence Score results (net decrease in chemotherapy recommendation rate in low Recurrence Score patients and net increase in high Recurrence Score patients). Patients' choices were generally consistent with physicians' recommendations. Post-testing, patients' decisional conflict decreased significantly (P<0.0001). In the 67 patients meeting the NICE criteria for testing, the recommendation change rate was 49.3%. Conclusions: Recurrence Score testing significantly influenced treatment recommendations overall and in the subgroup of patients meeting the NICE criteria, suggesting that this test could substantially alter treatment patterns in the United Kingdom. PMID:26954715

  3. Molecular mechanisms for tumour resistance to chemotherapy.

    PubMed

    Pan, Shu-Ting; Li, Zhi-Ling; He, Zhi-Xu; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2016-08-01

    Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug-induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P-glycoprotein (P-gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it. PMID:27097837

  4. Phase II Study of Everolimus Beyond Progression

    ClinicalTrials.gov

    2016-03-22

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  5. Gastrointestinal stromal tumour.

    PubMed

    Joensuu, Heikki; Hohenberger, Peter; Corless, Christopher L

    2013-09-14

    Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract, usually in the stomach or the small intestine and rarely elsewhere in the abdomen. They can occur at any age, the median age being 60-65 years, and typically cause bleeding, anaemia, and pain. GISTs have variable malignant potential, ranging from small lesions with a benign behaviour to fatal sarcomas. Most tumours stain positively for the mast/stem cell growth factor receptor KIT and anoctamin 1 and harbour a kinase-activating mutation in either KIT or PDGFRA. Tumours without such mutations could have alterations in genes of the succinate dehydrogenase complex or in BRAF, or rarely RAS family genes. About 60% of patients are cured by surgery. Adjuvant treatment with imatinib is recommended for patients with a substantial risk of recurrence, if the tumour has an imatinib-sensitive mutation. Tyrosine kinase inhibitors substantially improve survival in advanced disease, but secondary drug resistance is common. PMID:23623056

  6. Transport processes in tumours.

    PubMed

    Quastel, J H

    1965-12-01

    The characteristic features of transport systems controlling influx into tumour cells of nutrients and other chemicals are briefly described. Two notable features of transport of amino acids into tumour cells have been observed: extensive accumulation against a concentration gradient and equal accumulations, whether conditions are aerobic or anaerobic, provided glucose is present. This combination of features has not been observed in the majority of normal mammalian tissues so far examined. Important for considerations of chemotherapy is the ability of tumour transport carriers to transfer substances related in structure to amino acids and other nutrients. Amino acid analogues, for example, can either block transport of natural amino acids or can be transported into the cell where they may interfere with various aspects of amino acid metabolism. The study of transport carriers is essential for an understanding of tumour-host relationships and for considerations of chemotherapy. PMID:5842595

  7. Improved tumour response by laser light treatment

    NASA Astrophysics Data System (ADS)

    Graschew, Georgi; Smith, Janice; Rakowsky, Stefan; Roelofs, Theo A.; Schlag, Peter M.; Stein, Ulrike

    2008-04-01

    Multidrug resistance (MDR) poses a serious barrier to the efficacy of clinical treatment of human cancers with chemotherapeutic drugs. This barrier might be reduced and eventually overcome by the simultaneous application of two or more treatment modalities. This study reports on the synergetic effect of combined application of laser light and cytostatic drugs to induce an improved tumour response in MDR cancer cells. The MDR breast cancer cell line MaTu/ADR, resistant to the drug adriamycin (ADR), was treated with a combination of ADR (125-1000 ng/ml) and laser light (488 nm with a total light dose between 6-18 J/cm2). This combined treatment leads to an additional reduction of the cell vitality by a factor of 2-3 as compared to treatment with ADR alone, suggesting that combined application of laser light and other treatment modalities might constitute a promising strategy for improvements in the tumour response.

  8. 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.

  9. Treatment strategies for advanced hormone receptor-positive and human epidermal growth factor 2-negative breast cancer: the role of treatment order.

    PubMed

    Perez, Edith A

    2016-01-01

    Although survival rates among patients with breast cancer have improved in recent years, those diagnosed with advanced disease with distant metastasis face a 5-year survival rate of less than 25%, making the management of these patients an area still in significant need of continued research. Selecting the optimal treatment order from among the variety of currently available therapy options presents a relevant challenge for medical oncologists. With the understanding that the majority of patients with breast cancer and those who succumb to this disease have HR-positive disease, this review will focus on treatment options and treatment order in patients with HR-positive advanced breast cancer. While endocrine therapy is considered the preferred treatment for first-line therapy in HR-positive/HER2-negative breast cancer, selection of the specific agent depends on the menopausal status of the patient. Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is also recommended as first-line treatment in patients with ER-positive/HER2-negative disease. In patients with endocrine therapy-resistant disease, specific strategies include sequencing of other antiestrogen receptor agents, or agents that target other molecular pathways. Future treatment strategies for patients with primary or secondary resistance to endocrine therapy for advanced disease are discussed. These strategies include first-line therapy with high-dose fulvestrant or everolimus (in combination with exemestane or letrozole or with other endocrine therapies), use of the PI3K inhibitors (e.g., buparlisib, alpelisib, pictilisib, taselisib), entinostat, CDK 4/6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib), and novel selective estrogen receptor degradation agents that may enhance the targeting of acquired mutations in the ESR1 gene. PMID:26830312

  10. [Tumours and liver transplants].

    PubMed

    Mejzlík, Vladimír; Husová, Libuše; Kuman, Milan; Štěpánková, Soňa; Ondrášek, Jiří; Němec, Petr

    2015-01-01

    Liver transplantation as a curative treatment method can be used for selected primary liver tumours, in particular for hepatocellular carcinoma and rather rare semi-malignant tumours such as epithelioid hemangioendothelioma, further for infiltration of liver by metastatic neuroendocrine tumours (provided that metastases are only located in the liver and the primary tumour was removed) and for benign tumours (hemangiomas and adenomas) with oppression symptoms and size progression. Cholangiocarcinoma is not indicated for liver transplantation at the CKTCH Brno. In recent years liver transplants for hepatocellular carcinoma have increased and hepatocellular carcinoma has also been more frequently found ex post, in the explanted livers. Liver transplantation is indicated in selected patients with a good chance of long-term survival after liver transplantation (a generally accepted limit is 5 year survival of 50 % after transplantation). By 20 March 2015 there were liver transplants carried out on 38 patients - in 25 of them was hepatocellular carcinoma diagnosed before transplantation and in 13 it was found in the liver explants. 5 year survival following transplantation is reached by 53 % of this cohort. 32 % patients suffered from chronic hepatitis C. The longest surviving (32 years) patient at CKTCH Brno had liver transplanted for a big fibrolamellar hepatocellular carcinoma, which points to the prognostic significance of tumour histology: the criterion only considered in some indication schemes for practical reasons. Benign liver tumours (adenomatosis, cystadenoma, hemangioma with oppression symptoms) are rather rare indications and the transplantation results are favourable. 4 patients underwent transplantation for infiltration of liver by carcinoid, tumour recurrence occurred in one. PMID:26375706

  11. Testicular germ cell tumours.

    PubMed

    Rajpert-De Meyts, Ewa; McGlynn, Katherine A; Okamoto, Keisei; Jewett, Michael A S; Bokemeyer, Carsten

    2016-04-23

    Testicular germ cell tumours are at the crossroads of developmental and neoplastic processes. Their cause has not been fully elucidated but differences in incidences suggest that a combination of genetic and environment factors are involved, with environmental factors predominating early in life. Substantial progress has been made in understanding genetic susceptibility in the past 5 years on the basis of the results of large genome-wide association studies. Testicular germ cell tumours are highly sensitive to radiotherapy and chemotherapy and hence have among the best outcomes of all tumours. Because the tumours occur mainly in young men, preservation of reproductive function, quality of life after treatment, and late effects are crucial concerns. In this Seminar, we provide an overview of advances in the understanding of the epidemiology, genetics, and biology of testicular germ cell tumours. We also summarise the consensus on how to treat testicular germ cell tumours and focus on a few controversies and improvements in the understanding of late effects of treatment and quality of life for survivors. PMID:26651223

  12. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT

    PubMed Central

    Sörensen, Jens; Velikyan, Irina; Sandberg, Dan; Wennborg, Anders; Feldwisch, Joachim; Tolmachev, Vladimir; Orlova, Anna; Sandström, Mattias; Lubberink, Mark; Olofsson, Helena; Carlsson, Jörgen; Lindman, Henrik

    2016-01-01

    Purpose: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with 68Ga-gallium ([68Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology. Experimental design: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [68Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [68Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [68Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization. Results: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [68Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients. Conclusion: [68Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer. PMID:26877784

  13. Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy

    PubMed Central

    Pivot, X.; Marmé, F.; Koenigsberg, R.; Guo, M.; Berrak, E.; Wolfer, A.

    2016-01-01

    Background Based on data from two multicenter, phase III clinical trials (Studies 301 and 305), eribulin (a microtubule dynamics inhibitor) is indicated in the European Union (EU) for patients with locally advanced or metastatic breast cancer (MBC) after ≥1 prior chemotherapy for advanced disease, including an anthracycline and a taxane in either the adjuvant or metastatic setting. Data from Studies 305 and 301 were pooled to investigate the efficacy of eribulin in various subgroups of patients who matched the EU label, including those with human epidermal growth factor receptor 2 (HER2)-negative and triple-negative disease. Patients and methods In Study 305 (NCT00388726), patients were randomized 2:1 to eribulin mesylate 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2 [expressed as free base]) intravenously on days 1 and 8 every 21 days] or treatment of physician's choice after 2–5 prior chemotherapies (≥2 for advanced disease), including an anthracycline and a taxane (in early/advanced setting). In Study 301 (NCT00337103), patients were randomized 1:1 to eribulin (as above) or capecitabine (1.25 g/m2 orally twice daily on days 1–14 every 21 days) following ≤3 prior chemotherapies (≤2 for advanced disease), including an anthracycline and a taxane. Efficacy end points were investigated in the intent-to-treat population and subgroups, pooled as discussed above. Results Overall, 1644 patients were included (eribulin: 946; control: 698); baseline characteristics were well matched. Overall survival was significantly longer with eribulin versus control (P < 0.01), as were progression-free survival and clinical benefit rate (both P < 0.05). Significant survival benefits with eribulin versus control were observed in a wide range of patient subgroups, including HER2-negative or triple-negative disease (all P < 0.05). Conclusion Our findings underline the survival benefit achieved by eribulin used according to EU label in the overall MBC population and in various

  14. Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer

    PubMed Central

    Carey, Lisa A.; Adamo, Barbara; Vidal, Maria; Tabernero, Josep; Cortés, Javier; Parker, Joel S.; Perou, Charles M.; Baselga, José

    2014-01-01

    Background The clinical impact of the biological heterogeneity within HER2-positive (HER2+) breast cancer is not fully understood. Here, we evaluated the molecular features and survival outcomes of the intrinsic subtypes within HER2+ breast cancer. Methods We interrogated The Cancer Genome Atlas (n = 495) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets (n = 1730) of primary breast cancers for molecular data derived from DNA, RNA and protein, and determined intrinsic subtype. Clinical HER2 status was defined according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines or DNA copy-number aberration by single nucleotide polymorphism arrays. Cox models tested the prognostic significance of each variable in patients not treated with trastuzumab (n = 1711). Results Compared with clinically HER2 (cHER2)-negative breast cancer, cHER2+ breast cancer had a higher frequency of the HER2-enriched (HER2E) subtype (47.0% vs 7.1%) and a lower frequency of Luminal A (10.7% vs 39.0%) and Basal-like (14.1% vs 23.4%) subtypes. The likelihood of cHER2-positivity in HER2E, Luminal B, Basal-like and Luminal A subtypes was 64.6%, 20.0%, 14.4% and 7.3%, respectively. Within each subtype, only 0.3% to 3.9% of genes were found differentially expressed between cHER2+ and cHER2-negative tumors. Within cHER2+ tumors, HER2 gene and protein expression was statistically significantly higher in the HER2E and Basal-like subtypes than either luminal subtype. Neither cHER2 status nor the new 10-subtype copy number-based classification system (IntClust) added independent prognostic value to intrinsic subtype. Conclusions When the intrinsic subtypes are taken into account, cHER2-positivity does not translate into large changes in the expression of downstream signaling pathways, nor does it affect patient survival in the absence of HER2 targeting. PMID:25139534

  15. Surgical implications of tumour immunology.

    PubMed Central

    Somers, S. S.

    1996-01-01

    The presence of immune infiltration of tumour deposits and the existence of effective in vitro anti-tumour immune responses would suggest the possibility of therapeutic manipulation against tumour cells. However, clinical immunotherapy has shown little promise as a cancer treatment. Numerous explanations for this inefficacy have been proposed, one of which involves the elaboration of immunosuppressive moieties from tumour cells. The results of studies presented below show that serum from patients with gastrointestinal and other tumours have immunosuppressive influences on normal lymphocytes. The degree of this in vitro inhibition is related to tumour 'bulk' and may reflect a systemic immunosuppressive influence of the tumour. Isolation and culture of lymphocytes from gastrointestinal tumour deposits demonstrated that these immune cells are functionally inert, suggesting the existence of an immunosuppressive tumour microenvironment. The isolation and partial purification of an immunosuppressive moiety from conditioned culture medium of a variety of human tumour cell lines further supports the hypothesis of tumour-mediated immunosuppression. A number of protein tumour cell products have been described with potent immunosuppressive properties. These include transforming growth factor-beta, interleukin-10, and the retroviral envelope protein p15E. The surgical implications of the proposed tumour-host immune relationship includes the hypothesis that clinically apparent disease may not be amenable to immune attack owing to tumour-mediated immune suppression. The use of immunostimulatory strategies as adjuvant perioperative therapy would seem a more effective environment for the activation of antitumour immune responses in the surgical patient. PMID:8678441

  16. Paramagnetic changes in cancer: DMBA-induced tumours studied in non-lyophilized and lyophilized tissues.

    PubMed Central

    Gutierrez, P. L.; Swartz, H. M.; Wilkinson, E. J.

    1979-01-01

    Electron spin resonance (ESR) studies were made on frozen samples of 7,12 dimethylbenzanthracene (DMBA)-induced rat breast tumours both before and after lyophilization. The primary purpose of these studies was to determine the relationship between ESR spectra under these two conditions and thereby hopefully resolve an apparent conflict as to the experimental findings and clinical implications of these findings. In contrast to the other system (Walker 256 carcinosarcoma) which we studied by a similar method, in the DMBA-induced tumours we found a close parallel between the ESR spectra before and after lyophilization. In both cases free-radical levels were elevated about two-fold in all tumours and showed little dependence on the age of the tumour. Studies of blood and liver before the development of tumours showed no change in free radicals levels in either nonlyophilized or lyophilized samples. In animals with tumours, the level of free radicals in the liver increased approximately 17%. Manganese (2+) levels were increased in breast tumours but the changes did not closely follow those of free radicals and were much more variable in the lyophilized samples. We conclude that: (1) there seems to be no general relationship between ESR spectra of tumours before and after lyophilization; (2) there appears to be no general pattern of ESR changes in lyophilized samples of tumours. PMID:223619

  17. Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

    PubMed Central

    2014-01-01

    Introduction BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy. Methods Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as non-BCRA-likeCGH. Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. Results Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-likeCGH tumors were ER-positive. Conclusions Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen

  18. Stromal influences on breast cancer cell growth.

    PubMed Central

    van Roozendaal, C. E.; van Ooijen, B.; Klijn, J. G.; Claassen, C.; Eggermont, A. M.; Henzen-Logmans, S. C.; Foekens, J. A.

    1992-01-01

    Paracrine influences from fibroblasts derived from different sources of breast tissue on epithelial breast cancer cell growth in vitro were investigated. Medium conditioned (CM) by fibroblasts derived from tumours, adjacent normal breast tissue, and normal breast tissue obtained from reduction mammoplasty or from skin tissue significantly stimulated the growth of the steroid-receptor positive cell lines MCF-7 and ZR 75.1. The proliferation index (PI) on MCF-7 cells with CM from fibroblasts derived from breast tumour tissue was significantly higher than that obtained with fibroblasts derived from adjacent normal breast tissue (2p less than 0.05, n = 8). The PI obtained with CM from normal fibroblast cultures from reduction mammoplasty tissue, like normal tissue adjacent to the tumour, fell in the lower range of values. Skin fibroblast, like tumour tissue derived fibroblast, CM caused a high range PI. MDA-MB-231 and Evsa-T, two steroid-receptor negative cell lines, showed only a minor growth stimulatory responses with some of the fibroblast CM's. Evsa-T was occasionally inhibited by CM's. In conclusion, stromal factors play a role in the growth regulation of human breast cancer cells. The effects on cancer cell growth are, however, varying depending on the source of the stroma and the characteristics of the epithelial tumour cells. PMID:1733444

  19. Tumours of the thymus

    PubMed Central

    Sellors, T. Holmes; Thackray, A. C.; Thomson, A. D.

    1967-01-01

    Eighty-eight cases of thymoma are discussed with the object of trying to co-ordinate the histological and clinical features. The pathological specimens were in all cases obtained at operation. The pathology classification introduced by Thomson and Thackray in 1957 has been found to correspond adequately with the clinical pattern. The most common groups of tumours are basically epithelial and can be separated into five or six subdivisions, each of which has a separate pattern of behaviour. Lymphoid and teratomatous tumours also occur, but there were only two examples in this series. Clinically, separation of patients who suffered from myasthenia (38) and those who did not (50) affords the first main grouping. The majority of patients who had myasthenia gravis had tumours classified as epidermoid (19) and lymphoepithelial (14), the former with a more malignant appearance and behaviour than the latter. Removal of the tumour with or without radiation gave considerable and sometimes complete relief from myasthenic symptoms. Non-myasthenic thymoma (50) was usually discovered as a result of pressure signs or in the course of routine radiography. Spindle or oval celled tumours followed a benign pattern whereas undifferentiated thymoma was in every sense malignant, as also were teratomatous growths. Granulomatous or Hodgkin-like thymomas were of special interest and had an unpredictable course, some patients surviving many years after what was regarded as inadequate treatment. The place of radiotherapy as a pre- or post-operative agent complementary to surgery is discussed. Images PMID:6033387

  20. Tumours of the ovary

    PubMed Central

    Nielsen, Svend W.; Misdorp, W.; McEntee, Kenneth

    1976-01-01

    Ovarian tumours are common in animals, the majority occurring in bitches and cows. The two most important germ cell tumours were dysgerminoma and teratoma; these morphologically resemble their counterparts in women, with the exception that teratomas in animals tend less to malignancy. The granulosa cell tumour is the most frequent sex cord-stromal tumour in all six species and it may contain luteinized areas or show differentiation towards a Sertoli cell pattern. The canine papillary adenoma and papillary adenocarcinoma, which are as common as granulosa tumours, have several features in common with their counterparts in women: they are of similar histological appearance, are frequently bilateral, and the adenocarcinomas have a great propensity for peritoneal implantation metastasis. Ovarian cysts are frequent in the bitch, sow, and cow and may originate from five different anatomical structures in the ovary. ImagesFig. 1Fig. 2 and 3Fig. 20-22Fig. 8-10Fig. 15 and 16Fig. 23Fig. 24Fig. 25Fig. 26Fig. 17-19Fig. 4 and 5Fig. 6 and 7Fig. 11Fig. 12Fig. 13 and 14 PMID:1086151

  1. Circadian clocks and breast cancer.

    PubMed

    Blakeman, Victoria; Williams, Jack L; Meng, Qing-Jun; Streuli, Charles H

    2016-01-01

    Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, and link this to increased tumour risk in women who work irregular shift patterns. Understanding the influence of circadian rhythms on breast cancer could lead to more efficacious therapies, reformed public health policy and improved patient outcome. PMID:27590298

  2. SWOG S0221: A Phase III Trial Comparing Chemotherapy Schedules in High-Risk Early-Stage Breast Cancer

    PubMed Central

    Budd, George T.; Barlow, William E.; Moore, Halle C.F.; Hobday, Timothy J.; Stewart, James A.; Isaacs, Claudine; Salim, Muhammad; Cho, Jonathan K.; Rinn, Kristine J.; Albain, Kathy S.; Chew, Helen K.; Burton, Gary V.; Moore, Timothy D.; Srkalovic, Gordan; McGregor, Bradley A.; Flaherty, Lawrence E.; Livingston, Robert B.; Lew, Danika L.; Gralow, Julie R.; Hortobagyi, Gabriel N.

    2015-01-01

    Purpose To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. Patients and Methods A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. Results Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative tumors (P = .067), with no differences seen with hormone receptor–positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). Conclusion Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor–negative/HER2-negative tumors. PMID:25422488

  3. Radiotherapy for ocular tumours.

    PubMed

    Stannard, C; Sauerwein, W; Maree, G; Lecuona, K

    2013-02-01

    Ocular tumours present a therapeutic challenge because of the sensitive tissues involved and the necessity to destroy the tumour while minimising visual loss. Radiotherapy (RT) is one of several modalites used apart from surgery, laser, cryotherapy, and chemotherapy. Both external beam RT (EBRT) and brachytherapy are used. Tumours of the bulbar conjunctiva, squamous carcinoma and malignant melanoma, can be treated with a radioactive plaque: strontium-90, ruthenium-106 (Ru-106), or iodine-125 (I-125), after excision. If the tumour involves the fornix or tarsal conjunctiva, proton therapy can treat the conjunctiva and spare most of the eye. Alternatively, an I-125 interstitial implant can be used with shielding of the cornea and lens. Conjunctival mucosal-associated lymphoid tissue lymphoma can be treated with an anterior electron field with lens shielding and 25-30 Gray (Gy) in 2 Gy fractions. Discrete retinoblastoma (RB), too large for cryotherapy or thermolaser, or recurrent after these modalities, can be treated with plaque therapy, I-125, or Ru-106. For large RB, multiple tumours, or vitreous seeds the whole eye can be treated with an I-125 applicator, sparing the bony orbit, or with EBRT, under anaesthetic, using X-rays or proton therapy with vacuum contact lenses to fix the eyes in the required position. Post-enucleated orbits at risk for recurrent RB can be treated with an I-125 implant with shielding to reduce the dose to the bony orbit. Uveal malignant melanomas can be treated with plaque or proton therapy with excellent local control. Preservation of vision will depend on the initial size and location of the tumour. PMID:23174750

  4. Radiotherapy for ocular tumours

    PubMed Central

    Stannard, C; Sauerwein, W; Maree, G; Lecuona, K

    2013-01-01

    Ocular tumours present a therapeutic challenge because of the sensitive tissues involved and the necessity to destroy the tumour while minimising visual loss. Radiotherapy (RT) is one of several modalites used apart from surgery, laser, cryotherapy, and chemotherapy. Both external beam RT (EBRT) and brachytherapy are used. Tumours of the bulbar conjunctiva, squamous carcinoma and malignant melanoma, can be treated with a radioactive plaque: strontium-90, ruthenium-106 (Ru-106), or iodine-125 (I-125), after excision. If the tumour involves the fornix or tarsal conjunctiva, proton therapy can treat the conjunctiva and spare most of the eye. Alternatively, an I-125 interstitial implant can be used with shielding of the cornea and lens. Conjunctival mucosal-associated lymphoid tissue lymphoma can be treated with an anterior electron field with lens shielding and 25–30 Gray (Gy) in 2 Gy fractions. Discrete retinoblastoma (RB), too large for cryotherapy or thermolaser, or recurrent after these modalities, can be treated with plaque therapy, I-125, or Ru-106. For large RB, multiple tumours, or vitreous seeds the whole eye can be treated with an I-125 applicator, sparing the bony orbit, or with EBRT, under anaesthetic, using X-rays or proton therapy with vacuum contact lenses to fix the eyes in the required position. Post-enucleated orbits at risk for recurrent RB can be treated with an I-125 implant with shielding to reduce the dose to the bony orbit. Uveal malignant melanomas can be treated with plaque or proton therapy with excellent local control. Preservation of vision will depend on the initial size and location of the tumour. PMID:23174750

  5. Immunology of naturally transmissible tumours.

    PubMed

    Siddle, Hannah V; Kaufman, Jim

    2015-01-01

    Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution. PMID:25187312

  6. Immunology of naturally transmissible tumours

    PubMed Central

    Siddle, Hannah V; Kaufman, Jim

    2015-01-01

    Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution. PMID:25187312

  7. Segmentation of breast cancer cells positive 1+ and 3+ immunohistochemistry

    NASA Astrophysics Data System (ADS)

    Labellapansa, Ause; Muhimmah, Izzati; Indrayanti

    2016-03-01

    Breast cancer is a disease occurs as a result of uncontrolled cells growth. One examination method of breast cancer cells is using Immunohistochemistry (IHC) to determine status of Human Epidermal Growth Factor Receptor2 (HER2) protein. This study helps anatomic pathologist to determine HER2 scores using image processing techniques to obtain HER2 overexpression positive area percentages of 1+ and 3+ scores. This is done because the score of 0 is HER2 negative cells and 2+ scores have equivocal results, which means it could not be determined whether it is necessary to give targeted therapy or not. HER2 overexpression positive area percentage is done by dividing the area with a HER2 positive tumor area. To obtain better tumor area, repair is done by eliminating lymphocytes area which is not tumor area using morphological opening. Results of 10 images IHC scores of 1+ and 3+ and 10 IHC images testing without losing lymphocytes area in tumor area, has proven that the system has been able to provide an overall correct classification in accordance with the experts analysis. However by doing operation to remove non-tumor areas, classification can be done correctly 100% for scores of 3+ and 65% for scores of 1+.

  8. Pathophysiology of tumour-induced microangiopathic haemolytic anaemia.

    PubMed

    Chalasani, Pavani; Segar, Jennifer M; Marron, Marilyn; Stopeck, Alison

    2016-01-01

    Cancer-associated microangiopathic haemolytic anaemia (CA-MAHA) is a syndrome characterised by Coombs-negative haemolytic anaemia and thrombocytopenia. It is primarily seen in advanced solid tumours and is distinct from thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome. Diagnosis is often delayed and patients have a high mortality. We present the case of CA-MAHA in a patient with metastatic breast cancer treated successfully with early initiation of chemotherapy. In addition, we report longitudinal laboratory evaluation of circulating tumour cells and microparticles and suggest a hypothesis for the mechanism behind CA-MAHA. PMID:26744538

  9. Parallel evolution of tumour subclones mimics diversity between tumours.

    PubMed

    Martinez, Pierre; Birkbak, Nicolai Juul; Gerlinger, Marco; McGranahan, Nicholas; Burrell, Rebecca A; Rowan, Andrew J; Joshi, Tejal; Fisher, Rosalie; Larkin, James; Szallasi, Zoltan; Swanton, Charles

    2013-08-01

    Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome. PMID:23716380

  10. Eribulin Mesylate Combined with Local Treatment for Brain Metastasis from Breast Cancer: Two Case Reports

    PubMed Central

    Byun, Kyung-Do; Ahn, Sung Gwe; Baik, Hyung Joo; Lee, Anbok; Bae, Ki Beom; An, Min Sung; Kim, Kwang Hee; Shin, Jae Ho; Park, Ha Kyoung; Cho, Heunglae; Jeong, Joon

    2016-01-01

    The prognosis associated with brain metastasis arising from breast cancer is very poor. Eribulin is a microtubule dynamic inhibitor synthesized from halichondrin B, a natural marine product. In a phase III study (EMBRACE), eribulin improved overall survival in patients with heavily pretreated metastatic breast cancers. However, these studies included few patients with brain metastases. Metastatic brain tumors (MBT) were detected during first-line palliative chemotherapy in a 43-year-old woman with breast cancer metastasis to the lung and mediastinal nodes; the genetic subtype was luminal B-like human epidermal growth factor receptor 2 (HER2)-negative. Whole brain radiotherapy (WBRT) followed by eribulin treatment continuously decreased the size, and induced regression, of the MBT with systemic disease stability for 12 months. Another 48-year-old woman with metastatic breast cancer (HER2+ subtype) presented with MBT. Following surgical resection of the tumor, eribulin with concurrent WBRT showed regression of the MBT without systemic progression for 18 months. PMID:27382400

  11. Eribulin Mesylate Combined with Local Treatment for Brain Metastasis from Breast Cancer: Two Case Reports.

    PubMed

    Byun, Kyung-Do; Ahn, Sung Gwe; Baik, Hyung Joo; Lee, Anbok; Bae, Ki Beom; An, Min Sung; Kim, Kwang Hee; Shin, Jae Ho; Park, Ha Kyoung; Cho, Heunglae; Jeong, Joon; Kim, Tae Hyun

    2016-06-01

    The prognosis associated with brain metastasis arising from breast cancer is very poor. Eribulin is a microtubule dynamic inhibitor synthesized from halichondrin B, a natural marine product. In a phase III study (EMBRACE), eribulin improved overall survival in patients with heavily pretreated metastatic breast cancers. However, these studies included few patients with brain metastases. Metastatic brain tumors (MBT) were detected during first-line palliative chemotherapy in a 43-year-old woman with breast cancer metastasis to the lung and mediastinal nodes; the genetic subtype was luminal B-like human epidermal growth factor receptor 2 (HER2)-negative. Whole brain radiotherapy (WBRT) followed by eribulin treatment continuously decreased the size, and induced regression, of the MBT with systemic disease stability for 12 months. Another 48-year-old woman with metastatic breast cancer (HER2+ subtype) presented with MBT. Following surgical resection of the tumor, eribulin with concurrent WBRT showed regression of the MBT without systemic progression for 18 months. PMID:27382400

  12. Differential involvement of RASSF2 hypermethylation in breast cancer subtypes and their prognosis

    PubMed Central

    Perez-Janices, Noemi; Blanco-Luquin, Idoia; Torrea, Natalia; Liechtenstein, Therese; Escors, David; Cordoba, Alicia; Vicente-Garcia, Francisco; Jauregui, Isabel; De La Cruz, Susana; Illarramendi, José Juan; Coca, Valle; Berdasco, Maria; Kochan, Grazyna; Ibañez, Berta; Lera, José Miguel; Guerrero-Setas, David

    2015-01-01

    Breast cancer is a heterogeneous disease that can be subdivided into clinical, histopathological and molecular subtypes (luminal A-like, luminal B-like/HER2-negative, luminal B-like/HER2-positive, HER2-positive, and triple-negative). The study of new molecular factors is essential to obtain further insights into the mechanisms involved in the tumorigenesis of each tumor subtype. RASSF2 is a gene that is hypermethylated in breast cancer and whose clinical value has not been previously studied. The hypermethylation of RASSF1 and RASSF2 genes was analyzed in 198 breast tumors of different subtypes. The effect of the demethylating agent 5-aza-2′-deoxycytidine in the re-expression of these genes was examined in triple-negative (BT-549), HER2 (SK-BR-3), and luminal cells (T-47D). Different patterns of RASSF2 expression for distinct tumor subtypes were detected by immunohistochemistry. RASSF2 hypermethylation was much more frequent in luminal subtypes than in non-luminal tumors (p = 0.001). The re-expression of this gene by lentiviral transduction contributed to the differential cell proliferation and response to antineoplastic drugs observed in luminal compared with triple-negative cell lines. RASSF2 hypermethylation is associated with better prognosis in multivariate statistical analysis (P = 0.039). In conclusion, RASSF2 gene is differently methylated in luminal and non-luminal tumors and is a promising suppressor gene with clinical involvement in breast cancer. PMID:26284587

  13. Improving Pathological Assessment of Breast Cancer by Employing Array-Based Transcriptome Analysis

    PubMed Central

    Mihály, Zsuzsanna; Győrffy, Balázs

    2013-01-01

    Breast cancer research has paved the way of personalized oncology with the introduction of hormonal therapy and the measurement of estrogen receptor as the first widely accepted clinical biomarker. The expression of another receptor—HER2/ERBB2/neu—was initially a sign of worse prognosis, but targeted therapy has granted improved outcome for these patients so that today HER2 positive patients have better prognosis than HER2 negative patients. Later, the introduction of multigene assays provided the pathologists with an unbiased assessment of the tumors’ molecular fingerprint. The recent FDA approval of complete microarray pipelines has opened new possibilities for the objective classification of breast cancer samples. Here we review the applications of microarrays for determining ER and HER2 status, molecular subtypes as well as predicting prognosis and grade for breast cancer patients. An open question remains the role of single genes within such signatures. Openly available microarray datasets enable the execution of an independent cross-validation of new marker and signature candidates. In summary, we review the current state regarding clinical applications of microarrays in breast cancer molecular pathology.

  14. Differential involvement of RASSF2 hypermethylation in breast cancer subtypes and their prognosis.

    PubMed

    Perez-Janices, Noemi; Blanco-Luquin, Idoia; Torrea, Natalia; Liechtenstein, Therese; Escors, David; Cordoba, Alicia; Vicente-Garcia, Francisco; Jauregui, Isabel; De La Cruz, Susana; Illarramendi, José Juan; Coca, Valle; Berdasco, Maria; Kochan, Grazyna; Ibañez, Berta; Lera, José Miguel; Guerrero-Setas, David

    2015-09-15

    Breast cancer is a heterogeneous disease that can be subdivided into clinical, histopathological and molecular subtypes (luminal A-like, luminal B-like/HER2-negative, luminal B-like/HER2-positive, HER2-positive, and triple-negative). The study of new molecular factors is essential to obtain further insights into the mechanisms involved in the tumorigenesis of each tumor subtype. RASSF2 is a gene that is hypermethylated in breast cancer and whose clinical value has not been previously studied. The hypermethylation of RASSF1 and RASSF2 genes was analyzed in 198 breast tumors of different subtypes. The effect of the demethylating agent 5-aza-2'-deoxycytidine in the re-expression of these genes was examined in triple-negative (BT-549), HER2 (SK-BR-3), and luminal cells (T-47D). Different patterns of RASSF2 expression for distinct tumor subtypes were detected by immunohistochemistry. RASSF2 hypermethylation was much more frequent in luminal subtypes than in non-luminal tumors (p = 0.001). The re-expression of this gene by lentiviral transduction contributed to the differential cell proliferation and response to antineoplastic drugs observed in luminal compared with triple-negative cell lines. RASSF2 hypermethylation is associated with better prognosis in multivariate statistical analysis (P = 0.039). In conclusion, RASSF2 gene is differently methylated in luminal and non-luminal tumors and is a promising suppressor gene with clinical involvement in breast cancer. PMID:26284587

  15. PI3K/Akt/mTOR inhibitors in breast cancer

    PubMed Central

    Lee, Joycelyn JX; Loh, Kiley; Yap, Yoon-Sim

    2015-01-01

    Activation of the phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase I to III trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR (PAM) pathway. PMID:26779371

  16. Association of adiposity, dysmetabolisms, and inflammation with aggressive breast cancer subtypes: a cross-sectional study.

    PubMed

    Agresti, Roberto; Meneghini, Elisabetta; Baili, Paolo; Minicozzi, Pamela; Turco, Alberto; Cavallo, Ilaria; Funaro, Francesco; Amash, Hade; Berrino, Franco; Tagliabue, Elda; Sant, Milena

    2016-05-01

    Obesity and metabolic syndrome are risk and prognostic factors for breast cancer (BC) and are associated with chronic inflammation. We investigated the association between distinct BC subtypes and markers of adiposity, dysmetabolisms, and inflammation. We analyzed 1779 patients with primary invasive BC treated at a single institution, for whom anthropometric and clinical-pathological data were archived. BC subtypes were classified by immunohistochemical staining of ER, PR, HER2, and Ki67, and their relations with the study markers were assessed by multinomial logistic regression. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated taking luminal A as reference. All subtypes more aggressive than luminal A were significantly more frequent in younger (<45 years) than older women. Before menopause, luminal B HER2-negative tumors were positively associated with large waist (OR 2.55, 95 % CI 1.53-4.24) and insulin resistance (OR 1.90, 95 % CI 1.05-3.41); luminal B HER2-positive tumors with large waist (OR 2.11, 95 % CI 1.03-4.35) and triple-negative tumors with overweight (OR 3.04, 95 % CI 1.43-6.43) and high C-reactive protein (p trend = 0.026). In postmenopausal women aged <65, luminal B HER2-negative (OR 1.94, 95 % CI 1.16-3.24) and luminal B HER2-positive tumors (OR 2.48, 95 % CI 1.16-5.27) were positively related with metabolic syndrome. Dysmetabolisms and inflammation may be related to different BC subtypes. Before menopause, triple-negative cancers were related to obesity and chronic inflammation, and aggressive luminal subtypes to abdominal adiposity. After menopause, in women aged <65 these latter subtypes were related to metabolic syndrome. Control of adiposity and dysmetabolism can reduce the risk of aggressive BC subtypes, improving the prognosis. PMID:27117160

  17. Clinicopathological characteristics and prognosis of breast cancer patients with type 2 diabetes mellitus

    PubMed Central

    HE, DE; BAI, JING-WEN; LIU, JING; DU, CAI-WEN; HUANG, WEN-HE; ZHANG, GUO-JUN

    2015-01-01

    Type 2 diabetes mellitus (T2DM) can increase the risk of several common cancers, including breast cancer (BC). The purpose of the present study was to investigate the clinicopathological features and prognosis of BC patients with or without T2DM. Seventy-eight patients were diagnosed with T2DM prior to the diagnosis of BC in the Cancer Hospital of Shantou University Medical College (Shantou, China) between 2002 and 2008. A total of 300 BC patients without T2DM were randomly selected as study controls during the same period. The clinicopathological characteristics, overall survival (OS) and disease-free survival (DFS) rates of these two groups were compared. Fifty-five BC patients and 133 control patients with T2DM were >50 years old (70.5 and 44.3%, respectively). There were more T2DM BC patients with body mass index (BMI) ≥25 kg/m2 (46.2 vs. 23.3%) and these patients had a higher rate of lymph node involvement (67.9 vs. 55.0%). The DFS of the two groups was 32.1 vs. 22.3%. The OS of the two groups was 24.4 vs. 13.7%. Following adjustment for BMI, tumor-node metastasis stage and stratification of age, the relapse risk of T2DM BC patients was >2-fold higher than that of the control group in the estrogen receptor/progesterone receptor (ER/PR)-positive patients. In Her-2-negative BC patients, the relapse risk of T2DM patients was 2.237-fold higher than that of the non-T2DM patients. In conclusion, T2DM BC patients were significantly older and more likely to be overweight, and had more lymph nodes involvement. T2DM was associated with poor prognosis in ER/PR positive or Her-2-negative BC patients. PMID:26137275

  18. Diagnosis, classification and grading of canine mammary tumours as a model to study human breast cancer: an Clinico-Cytohistopathological study with environmental factors influencing public health and medicine

    PubMed Central

    2013-01-01

    Background The human “Elston and Ellis grading method” was utilized in dogs with mammary tumor to examine its relation to prognosis in this species, based on a 2-year follow-up period. Although cytopathology is widely used for early diagnosis of human neoplasms, it is not commonly performed in veterinary medicine. Our objectives in this study were to identify cytopathology criteria of malignancy for canine mammary tumors and the frequency of different types of mammary lesions and their relationship with histologic grade was investigated. Another aim of this study was to differentiate the simple and adenocarcinoma tumors from the complex or mixed tumor described by Elston and Ellis grading method. Methods The study was performed in 15 pure or mixed-breed female dogs submitted to surgical resections of mammary tumours. The mammary tumours were excised by simple mastectomy or regional mastectomy, with or without the superficial inguinal lymph nodes. Female dogs were mainly terriers (9 dogs) or mixed (3 dogs), the 3 other animals were a German shepherd, Dachshund and Pekingese. Before surgical excision of the tumour, FNAC was performed using a 0.6 mm diameter needle attached to a 10 ml syringe held in a standard metal syringe holder. The cytological sample was smeared onto a glass slide and either air-dried for May-Grünwald-stain, or ethanol-fixed for Papanicolaou stain and masses were surgically removed, the tumours were grossly examined and tissue samples were fixed in 10%-buffered-formalin and embedded in paraffin. Sections 4 μm thick were obtained from each sample and H&E stained. Results We obtained a correct cytohistological correlation in 14/15 cases (93.3%) when all cytopathological examinations were considered. Of the 15 cases examined, 2(13.3%) had well-differentiated (grade I), 6(40%) had moderately differentiated (grade II) and 7(46.7%) had poorly differentiated (grade III) tumours. Classification of all canine mammary gland lesions revealed 13

  19. Heterogeneity of Bcl-2 expression in metastatic breast carcinoma.

    PubMed

    Subhawong, Andrea Proctor; Nassar, Hind; Halushka, Marc K; Illei, Peter B; Vang, Russell; Argani, Pedram

    2010-08-01

    Bcl-2 is an antiapoptotic protein that promotes cell survival, but also may block proliferation. In breast cancer, bcl-2 expression correlates with favorable prognosis and estrogen receptor (ER) positivity. However, experimental data have paradoxically suggested that bcl-2 promotes chemoresistance and metastasis. A direct and comprehensive comparison of bcl-2 expression between primary breast carcinomas and paired distant metastases has not been performed. We completed rapid autopsies on 17 patients with archived primary tumors and metastatic breast carcinoma, and created single-patient tissue microarrays containing each patient's primary tumor and matched metastases. Expression of bcl-2, ER, progesterone receptor, and HER-2 in primary tumors and matched metastases were compared by immunohistochemistry. All 11 ER-positive cases showed bcl-2 labeling in the primary tumor, whereas only 3 of 6 ER-negative cases did (P=0.029). In 10 cases, bcl-2 labeling in metastases was similar to that of the primary, although 3 cases showed significant variation among metastases. In six other cases, bcl-2 labeling was lost or significantly diminished in metastases. Five of the latter cases were Luminal A (ER-positive, HER-2-negative) primaries, three of which lost hormone receptors in metastases. Only 1 of 17 cases showed an increase in bcl-2 labeling in metastases compared with the paired primary tumor. In conclusion, bcl-2 is infrequently upregulated in metastatic breast carcinoma. Instead, downregulation of bcl-2 expression may occur in the setting of hormone therapy resistance. Our findings call into question the potential utility of anti-bcl-2 therapy in metastatic breast cancer. PMID:20495533

  20. Tumour Cell Heterogeneity

    PubMed Central

    Gay, Laura; Baker, Ann-Marie; Graham, Trevor A.

    2016-01-01

    The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment. PMID:26973786

  1. Epidemiological and Clinicopathological Trends of Breast Cancer in Chinese Patients During 1993 to 2013: A Retrospective Study.

    PubMed

    Si, Wen; Li, Ying; Han, Yingjie; Zhang, Fan; Wang, Yingzhe; Li, Ying; Linghu, Rui Xia; Zhang, Xingyang; Yang, Junlan

    2015-07-01

    This study aimed to summarize the epidemiological and pathological trends of breast cancer in Chinese women.The clinical data of 4968 breast cancer patients treated at the Chinese PLA General Hospital from 1993 to 2013 were retrospectively reviewed.The mean ± standard deviation (SD) age was 47.4 ± 11.3 years before the year 2001, 49.2 ± 11.2 years during 2001 to 2010, and 50.6 ± 11.4 years after the year 2010, respectively (P < 0.001). The ratio of premenopausal women to postmenopausal women was 1.6 and no significant changes were found during the period (P = 0.121). The proportion of patients with Scarff Bloom Richardson III breast cancer showed significant increase along with time (P = 0.015). The breast cancer was accounting for 31.7% at stage I and DCIS/LCIS and tend to be diagnosed with early stage around time (P < 0.001). The proportion of DCIS/LCIS and stage I increased with time during the 20 years from 14.6% to 33.2%, whereas the proportion of stage III to IV decreased.The proportion of Luminal A-like subtype gradually reduced and Luminal B-like (HER2-negative) increased and developed to the predominant type. Older age and earlier stage at diagnosis, as well as the alternation of predominant molecular subtypes, have become the developed trends of breast cancer. PMID:26131834

  2. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer

    PubMed Central

    Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Le Marchand, Loïc; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

    2012-01-01

    Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. PMID:22037553

  3. Everolimus Plus Exemestane for the Treatment of Advanced Breast Cancer: A Review of Subanalyses from BOLERO-21

    PubMed Central

    Hortobagyi, Gabriel N.

    2015-01-01

    Hormone receptor–positive breast cancer is typically managed with endocrine therapies. However, resistance to endocrine therapy results in disease progression in a large proportion of breast cancers. Through the understanding of the mechanisms of endocrine resistance, identification of implicated pathways and targets has led to the development of novel agents targeting these pathways. Phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway aberrations are common in breast cancer, with increased PI3K/AKT/mTOR signaling associated with resistance to endocrine and human epidermal growth factor receptor 2 (HER2)–targeted therapies. The mTOR inhibitor everolimus, in combination with exemestane, has been approved for patients with advanced hormone receptor–positive/HER2-negative breast cancer who progress on prior nonsteroidal aromatase inhibitor therapy based on results reported in the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study. This review will summarize the overall findings from BOLERO-2 and will consider available subanalyses by age, Asian origin, visceral or bone metastases, and prior therapy, with the aim of identifying populations most likely to benefit from everolimus therapy. The review will also summarize safety findings and their management and the effects of everolimus on quality of life. PMID:25810012

  4. Recapitulating tumour microenvironment in chitosan–gelatin three-dimensional scaffolds: an improved in vitro tumour model

    PubMed Central

    Arya, Neha; Sardana, Viren; Saxena, Meera; Rangarajan, Annapoorni; Katti, Dhirendra S.

    2012-01-01

    Owing to the reduced co-relationship between conventional flat Petri dish culture (two-dimensional) and the tumour microenvironment, there has been a shift towards three-dimensional culture systems that show an improved analogy to the same. In this work, an extracellular matrix (ECM)-mimicking three-dimensional scaffold based on chitosan and gelatin was fabricated and explored for its potential as a tumour model for lung cancer. It was demonstrated that the chitosan–gelatin (CG) scaffolds supported the formation of tumoroids that were similar to tumours grown in vivo for factors involved in tumour-cell–ECM interaction, invasion and metastasis, and response to anti-cancer drugs. On the other hand, the two-dimensional Petri dish surfaces did not demonstrate gene-expression profiles similar to tumours grown in vivo. Further, the three-dimensional CG scaffolds supported the formation of tumoroids, using other types of cancer cells such as breast, cervix and bone, indicating a possible wider potential for in vitro tumoroid generation. Overall, the results demonstrated that CG scaffolds can be an improved in vitro tool to study cancer progression and drug screening for solid tumours. PMID:22977099

  5. Patients' experiences following breast cancer treatment: an exploratory survey of personal and work experiences of breast cancer patients from three European countries.

    PubMed

    Braybrooke, J P; Mimoun, S; Zarca, D; Elia, D; Pinder, B; Lloyd, A J; Breheny, K; Lomazzi, M; Borisch, B

    2015-09-01

    Improved treatments for early breast cancer have led to a significant increase in overall survival. While evidence regarding potential long-term sequelae of adjuvant treatments exists, relatively little research reports patients' own perceptions of change before and after adjuvant chemotherapy (AC). This study aimed to identify key ongoing issues associated with AC in daily life. An online survey developed for this study was completed by 198 women (mean age 49.7 years) in the UK, France and Germany who had AC 1-5 years previously for oestrogen receptor positive, HER2 negative early breast cancer. Women without AC and endocrine therapy, those treated with Trastuzumab or who had recurrent disease were excluded. A third of women who responded were currently unable to perform their former family role. The majority had needed support, particularly with child care, during treatment. While 54% were in full-time employment before diagnosis this had reduced to 32% following AC. Of those women still working, over half reported difficulties with tiredness or concentration. Most (85.8%) were satisfied with healthcare professionals' treatment information, but only 29.7% received information about returning to work. This exploratory survey highlights areas of women's lives affected 1-5 years following AC for early breast cancer. The impact on returning to work and issues surrounding childcare particularly, require further study. PMID:25053521

  6. Prognostic value of Ki67 and p53 in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer: Validation of the cut-off value of the Ki67 labeling index as a predictive factor

    PubMed Central

    OHARA, MASAHIRO; MATSUURA, KAZUO; AKIMOTO, ETSUSHI; NOMA, MIDORI; DOI, MIHOKO; NISHIZAKA, TAKASHI; KAGAWA, NAOKI; ITAMOTO, TOSHIYUKI

    2016-01-01

    The aim of this study was to evaluate the significance of the Ki67 labeling index and p53 status as prognostic and predictive indicators of operable estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Among 697 consecutive patients with primary breast cancer who underwent curative surgery between 2002 and 2013, 308 patients with ER-positive and HER2-negative breast cancer were assessed. The results of the multivariate Cox analysis demonstrated that a high Ki67 labeling index was significantly associated with a short recurrence-free interval (RFI) (p=0.004) and was marginally associated with a worse overall survival (p=0.074). A positive p53 status was not associated with worse outcomes. To validate the cut-off values of the Ki67 labeling index for identifying patients who may benefit from additional chemotherapy, prognostic factors were investigated in breast cancer patients treated postoperatively with endocrine therapy alone. Analysis of receiver operating characteristic curves demonstrated that a Ki67 labeling index cut-off of 20.0% was optimal for predicting recurrence among patients who did not receive adjuvant chemotherapy. The 5-year RFIs for patients with Ki67 <20 and ≥20% were 97.2 and 86.6%, respectively (p=0.0244). A high Ki67 labeling index (≥20%) was significantly associated with large tumors (p<0.01), lymph node metastasis (p=0.0236) and positive p53 status (p<0.001). The univariate analysis demonstrated that Ki67 labeling index ≥20%, lymph node metastasis and progesterone receptor negativity were significant worse prognostic factors for RFI (p=0.0333, 0.0116 and 0.0573, respectively). The Ki67 labeling index was found to be a useful prognostic factor in patients with ER-positive and HER2-negative breast cancer and the cut-off values of the Ki67 labeling index for making a decision regarding adjuvant treatment were validated. PMID:27073684

  7. Fatty tumours of the uterus.

    PubMed Central

    Pounder, D J

    1982-01-01

    Uterine fatty tumours (UFT) are uncommon and have received little attention in the English literature. They have aroused interest as a consequence of occasional diagnostic confusion with sarcomas and the continuing unresolved dispute as to their histogenesis. Three cases of UFT are described and the pathological features of note discussed. The viewpoint that these tumours are hamartomas/choristomas is rejected. UFT most probably represent tumour metaplasia within a leiomyoma. There is no uniform accepted nomenclature for such tumours and it is suggested that they be designated "uterine fatty tumours" and subdivided into "lipoma" and "mixed lipoma/leiomyoma" (synonym lipoleiomyoma). Images PMID:7174848

  8. Triple positive breast cancer: a distinct subtype?

    PubMed

    Vici, Patrizia; Pizzuti, Laura; Natoli, Clara; Gamucci, Teresa; Di Lauro, Luigi; Barba, Maddalena; Sergi, Domenico; Botti, Claudio; Michelotti, Andrea; Moscetti, Luca; Mariani, Luciano; Izzo, Fiorentino; D'Onofrio, Loretta; Sperduti, Isabella; Conti, Francesca; Rossi, Valentina; Cassano, Alessandra; Maugeri-Saccà, Marcello; Mottolese, Marcella; Marchetti, Paolo

    2015-02-01

    Breast cancer is a heterogeneous disease, and within the HER-2 positive subtype this is highly exemplified by the presence of substantial phenotypical and clinical heterogeneity, mostly related to hormonal receptor (HR) expression. It is well known how HER-2 positivity is commonly associated with a more aggressive tumor phenotype and decreased overall survival and, moreover, with a reduced benefit from endocrine treatment. Preclinical studies corroborate the role played by functional crosstalks between HER-2 and estrogen receptor (ER) signaling in endocrine resistance and, more recently, the activation of ER signaling is emerging as a possible mechanism of resistance to HER-2 blocking agents. Indeed, HER-2 positive breast cancer heterogeneity has been suggested to underlie the variability of response not only to endocrine treatments, but also to HER-2 blocking agents. Among HER-2 positive tumors, HR status probably defines two distinct subtypes, with dissimilar clinical behavior and different sensitivity to anticancer agents. The triple positive subtype, namely, ER/PgR/Her-2 positive tumors, could be considered the subset which most closely resembles the HER-2 negative/HR positive tumors, with substantial differences in biology and clinical outcome. We argue on whether in this subgroup the "standard" treatment may be considered, in selected cases, i.e., small tumors, low tumor burden, high expression of both hormonal receptors, an overtreatment. This article review the existing literature on biologic and clinical data concerning the HER-2/ER/PgR positive tumors, in an attempt to better define the HER-2 subtypes and to optimize the use of HER-2 targeted agents, chemotherapy and endocrine treatments in the various subsets. PMID:25554445

  9. Neoadjuvant Bevacizumab plus Chemotherapy versus Chemotherapy Alone to Treat Non-Metastatic Breast Cancer: A Meta-Analysis of Randomised Controlled Trials

    PubMed Central

    Liu, Min-feng; Chen, Lu-jia; Hu, Xiao-lei; Ye, Chang-sheng

    2015-01-01

    Purpose Results from previous randomised controlled trials (RCTs) investigating whether the addition of bevacizumab to neoadjuvant chemotherapy (NAC) could statistically significantly increase the pathological complete response (pCR) and to identify which subgroup would benefit most from such regimens have produced conflicting results. This meta-analysis was designed to assess the efficacy and safety of bevacizumab plus chemotherapy compared with chemotherapy alone in the neoadjuvant setting. Methods A literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane library was performed to identify eligible studies. The primary endpoint of interest was pCR. The secondary endpoints were clinical complete rate (cCR), surgery rate, breast-conserving surgery (BCS) rate, and toxicity. The meta-analysis was performed using Review Manager software version 5.3. Results Nine RCTs matched the selection criteria, yielding a total of 4967 patients (bevacizumab plus chemotherapy: 50.1%, chemotherapy alone: 49.9%). The results of this meta-analysis demonstrated that the addition of bevacizumab to NAC significantly increased the pCR rate (odds ratio [OR] = 1.34 [1.18–1.54]; P < 0.0001) compared with chemotherapy alone. Subgroup analysis showed that the effect of bevacizumab was more pronounced in patients with HER2-negative cancer (OR = 1.34 [1.17–1.54]; P < 0.0001) compared with HER2-positive cancer (OR = 1.69 [0.90–3.20]; P = 0.11). Similarly, in patients with HER2-negative cancer, the effect of bevacizumab was also more pronounced in patients with HR-negative cancer (OR = 1.38 [1.09–1.74]; P = 0.007) compared with HR-positive cancer (OR = 1.36 [0.78–2.35]; P = 0.27). No significant differences were observed between the groups with respect to cCR, surgery rate, or BCS rate. Additionally bevacizumab was associated with a higher incidence of neutropenia, febrile neutropenia, and hand–foot syndrome. Conclusions Higher proportions of patients achieved pCR when

  10. 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

    Background The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC). Materials and Methods Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67low); luminal B (ER/PgR-positive, HER2-negative, Ki67high); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive). Results After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31–2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62–3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2

  11. Regulation of the breast cancer stem cell phenotype by hypoxia-inducible factors.

    PubMed

    Semenza, Gregg L

    2015-12-01

    The small subpopulation of breast cancer cells that possess the capability for self-renewal and formation of secondary tumours that recapitulate the heterogeneity of the primary tumour are referred to as tumour-initiating cells or BCSCs (breast cancer stem cells). The hypoxic tumour microenvironment and chemotherapy actively induce the BCSC phenotype. HIFs (hypoxia-inducible factors) are required and molecular mechanisms by which they promote the BCSC phenotype have recently been delineated. HIF inhibitors block chemotherapy-induced enrichment of BCSCs, suggesting that their use may improve the response to chemotherapy and increase the survival of breast cancer patients. PMID:26405042

  12. Glomus tumour of the stomach.

    PubMed

    Troller, Rebekka; Soll, Christopher; Breitenstein, Stefan

    2016-01-01

    Glomus tumours are benign tumours typically arising from the glomus bodies and primarily found under the fingernails or toenails. These rare neoplasms account for <2% of all soft tissue tumours and are generally not found in the gastrointestinal tract. We report a case of a 40-year-old man presenting with recurrent epigastric pain and pyrosis. Endoscopy revealed a solitary tumour in the antrum of the stomach. Fine-needle aspiration biopsy was suspicious for a gastrointestinal stroma tumour. After CT indicated the resectability of the tumour, showing neither lymphatic nor distant metastases, a laparoscopic-assisted gastric wedge resection was performed. Surprisingly, histology revealed a glomus tumour of the stomach. PMID:27343282

  13. Immunohistochemical analysis of CD146 expression in canine skin tumours.

    PubMed

    Abou Asa, S; Anwar, Sh; Yanai, T; Sakai, H

    2016-04-01

    CD146, a cell adhesion molecule, is overexpressed in a variety of carcinomas, including melanoma, prostate cancer, epithelial ovarian cancer, and breast cancer. The level of expression is directly correlated with tumour progression and metastatic potential. The most commonly affected organ for both neoplastic and non-neoplastic tumours is the skin. The objective of this study is to investigate the immunohistochemical expression of CD146 in canine skin tumours of epidermal or follicular origin in 53 squamous cell carcinomas (SCCs), 9 squamous papillomas, 7 infundibular keratinizing acanthomas (IKA), 21 trichoepitheliomas, 13 trichoblastomas, and 3 pilomatricomas. Immunohistochemical results showed that SCCs (90.6%), squamous papilloma (33.3%), IKA (85.7%), trichoepithelioma (85.9%), trichoblastoma (30.8%) and pilomatricoma (100%), respectively, were positive for CD146. The significant expression of CD146 in SCCs supports its importance as a useful treatment target. CD146 could also be used in differentiation of trichoepithelioma and trichoblastoma. PMID:26573287

  14. Male breast cancer.

    PubMed

    Jepson, A S; Fentiman, I S

    1998-01-01

    Male breast cancer is a rare disease, often with a late presentation and poor prognosis. The mainstay of treatment is modified radical mastectomy, with axillary node dissection to assess stage, prognosis and the need for adjuvant treatment. When matched for age, tumour size, grade and axillary nodal status, the prognosis is similar for males and females. Concerted efforts must be made to educate both the public and health professionals, in order to make earlier diagnoses and thereby improve prognosis. PMID:10622057

  15. Prognostically Distinctive Subgroup in Pathologic N3 Breast Cancer

    PubMed Central

    Kim, Yun Yeong; Lee, Kyung Hee; Kim, Kwan Il; Chun, Yong Soon

    2016-01-01

    Purpose The aim of this retrospective study was to investigate whether there are prognostically different subgroups among patients with pathologic N3 (pN3) breast cancer. Methods The records of 220 patients who underwent surgery for pN3 breast cancer from January 2006 to September 2012 were reviewed. All patients received adjuvant therapy according to standard protocols. The primary outcome was disease-free survival (DFS). Results Patients were followed for a median time of 68.3 months after their primary surgery (range, 10–122 months), during which time 75 patients (34.1%) had developed disease recurrence and 48 patients (21.8%) had died. The DFS and overall survival were 67.8% and 86.1%, respectively, at 5 years. Multiple logistic regression analysis showed that young age (<35 years, p=0.009), high serum neutrophil/lymphocyte ratio (>3.0) (p=0.020), high nodal ratio (number of metastatic lymph nodes divided by number of removed nodes) (>0.65) (p=0.062), and molecular phenotype (p=0.012) were significantly associated with tumor recurrence. Tumor biological subtype was the most significant predictor of recurrence. The 5-year DFS rates in patients with hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative, HR+HER2+, HR–HER2+, and triple negative subtypes were 82%, 63%, 58%, and 37%, respectively. Conclusion Clinical outcomes of patients with extensive nodal metastasis were heterogeneous in terms of prognosis. Tumor biological subtype was the most important prognostic factor for pN3 disease. The prognosis of patients with HR+HER2– subtype in pN3 breast cancer was similar to that of patients with stage II breast cancer. PMID:27382392

  16. Borderline ovarian tumours.

    PubMed

    Tropé, Claes Göran; Kaern, Janne; Davidson, Ben

    2012-06-01

    Borderline ovarian tumours account for 10-20% of all epithelial ovarian cancer. Historically, standard primary surgery has included borderline ovarian tumours, omentectomy, peritoneal washing and multiple biopsies. As one-third of borderline ovarian tumours are diagnosed in women under the age of 40 years, fertility-sparing treatment has been more frequently used in the past 10 years. Fertility drugs are well tolerated in women with infertility after fertility-sparing surgery. Careful selection of candidates is necessary. Laparoscopic techniques can be used, but should be reserved for oncologic surgeons. This conservative treatment increases the rate of recurrence, albeit with no effect on survival. The pregnancy rate is nearly 50%, and most are achieved spontaneously. These women should be closely followed up. The question is whether this is acceptable from a gynaecologic oncologic point of view. For this reason, we will discuss recently published studies and gynaecologic oncologic concerns about the mode of fertility-sparing surgery and its consequences. PMID:22321906

  17. Tumours of the kidney

    PubMed Central

    Nielsen, Svend W.; Mackey, L. J.; Misdorp, W.

    1976-01-01

    The most frequent renal tumours of animals are renal cell carcinoma and nephroblastoma. Renal cell carcinomas are seen mainly in dogs and cattle and nephroblastoma is encountered in pigs, puppies, and calves. Renal cell carcinomas are usually papillary in the dog. They show a marked propensity for vascular invasion, penetration of the posterior vena cava, and subsequent pulmonary metastasis. Nephroblastoma, which is morphologically identical to Wilms' tumour of children, is almost always a benign tumour in animals. It is one of the most frequent neoplasms of pigs, possibly owing to the fact that most pigs are slaughtered (and examined) when a few months old. Lymphosarcoma involving the kidney is particularly frequent in the cat, but is also seen in other species as part of a generalized disease. ImagesFig. 5,6Fig. 7Fig. 8Fig. 1,2Fig. 3,4Fig. 16,17,18,19Fig. 9,10Fig. 11Fig. 12Fig. 13Fig. 14,15 PMID:1086154

  18. Aggressive solitary intracranial metastatic malignant melanoma from a primary mediastinal tumour.

    PubMed

    Sivaraju, Laxminadh; Aryan, Saritha; Hegde, Vinay S; Ghosal, Nandita; Hegde, Alangar S

    2016-08-01

    Malignant melanoma is the third most common tumour to cause cerebral metastases, following breast and lung cancer. Central nervous system metastases occur in 10-40% of patients with melanoma. Intracranial metastasis from a primary malignant melanoma of the anterior mediastinum is uncommon. We report a case of solitary intracranial metastatic melanoma arising from a primary mediastinal tumour. We then discuss the clinico-radiological features and treatment options. PMID:27145991

  19. Clinical features of gastroenteropancreatic tumours

    PubMed Central

    Czarnywojtek, Agata; Bączyk, Maciej; Ziemnicka, Katarzyna; Fischbach, Jakub; Wrotkowska, Elżbieta; Ruchała, Marek

    2015-01-01

    Gastroenteropancreatic (GEP) endocrine tumours (carcinoids and pancreatic islet cell tumours) are composed of multipotent neuroendocrine cells that exhibit a unique ability to produce, store, and secrete biologically active substances and cause distinct clinical syndromes. The classification of GEP tumours as functioning or non-functioning is based on the presence of symptoms that accompany these syndromes secondary to the secretion of hormones, neuropeptides and/or neurotransmitters (functioning tumours). Non-functioning tumours are considered to be neoplasms of neuroendocrine differentiation that are not associated with obvious symptoms attributed to the hypersecretion of metabolically active substances. However, a number of these tumours are either capable of producing low levels of such substances, which can be detected by immunohistochemistry but are insufficient to cause symptoms related to a clinical syndrome, or alternatively, they may secrete substances that are either metabolically inactive or inappropriately processed. In some cases, GEP tumours are not associated with the production of any hormone or neurotransmitter. Both functioning and non-functioning tumours can also produce symptoms due to mass effects compressing vital surrounding structures. Gastroenteropancreatic tumours are usually classified further according to the anatomic site of origin: foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, and right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups the biological and clinical characteristics of the tumours vary considerably, but this classification is still in use because a significant number of previous studies, mainly observational, have used it extensively. PMID:26516377

  20. Biophysical models of tumour growth

    NASA Astrophysics Data System (ADS)

    Tracqui, P.

    2009-05-01

    Tumour growth is a multifactorial process, which has stimulated in recent decades the development of numerous models trying to figure out the mechanisms controlling solid tumours morphogenesis. While the earliest models were focusing on cell proliferation kinetics, modulated by the availability of supplied nutrients, new modelling approaches emphasize the crucial role of several biophysical processes, including local matrix remodelling, active cell migration and traction, and reshaping of host tissue vasculature. After a brief presentation of this experimental background, this review will outline a number of representative models describing, at different scales, the growth of avascular and vascularized tumours. Special attention will be paid to the formulation of tumour-host tissue interactions that selectively drive changes in tumour size and morphology, and which are notably mediated by the mechanical status and elasticity of the tumour microenvironment. Emergence of invasive behaviour through growth instabilities at the tumour-host interface will be presented considering both reaction-diffusion and mechano-cellular models. In the latter part of the review, patient-oriented implications of tumour growth modelling are outlined in the context of brain tumours. Some conceptual views of the adaptive strategies and selective barriers that govern tumour evolution are presented in conclusion as potential guidelines for the development of future models.

  1. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    PubMed Central

    Turner, Natalie; Pestrin, Marta; Galardi, Francesca; De Luca, Francesca; Malorni, Luca; Di Leo, Angelo

    2014-01-01

    Circulating tumor cell (CTC) count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach. PMID:24670368

  2. Genomic Instability: A Stronger Prognostic Marker Than Proliferation for Early Stage Luminal Breast Carcinomas

    PubMed Central

    Vincent-Salomon, Anne; Benhamo, Vanessa; Gravier, Eléonore; Rigaill, Guillem; Gruel, Nadège; Robin, Stéphane; de Rycke, Yann; Mariani, Odette; Pierron, Gaëlle; Gentien, David; Reyal, Fabien; Cottu, Paul; Fourquet, Alain; Rouzier, Roman; Sastre-Garau, Xavier; Delattre, Olivier

    2013-01-01

    Background The accurate prognosis definition to tailor treatment for early luminal invasive breast carcinoma patients remains challenging. Materials and Methods Two hundred fourteen early luminal breast carcinomas were genotyped with single nucleotide polymorphisms (SNPs) array to determine the number of chromosomal breakpoints as a marker of genomic instability. Proliferation was assessed by KI67 (immunohistochemistry) and genomic grade index (transcriptomic analysis). IHC3 (IHC4 score for HER2 negative tumors) was also determined. Results In the training set (109 cases), the optimal cut-off was 34 breakpoints with a specificity of 0.94 and a sensitivity of 0.57 (Area under the curve (AUC): 0.81[0.71; 0.91]). In the validation set (105 cases), the outcome of patients with > 34 breakpoints (11 events / 22 patients) was poorer (logrank test p < 0.001; Relative Risk (RR): 3.7 [1.73; 7.92]), than that of patients with < 34 breakpoints (19 events / 83 patients).Whereas genomic grade and KI67 had a significant prognostic value in univariate analysis in contrast to IHC3 that failed to have a statistical significant prognostic value in this series, the number of breakpoints remained the only significant parameter predictive of outcome (RR: 3.47, Confidence Interval (CI [1.29; 9.31], p = 0.014)) in multivariate analysis . Conclusion Genomic instability, defined herein as a high number of chromosomal breakpoints, in early stage luminal breast carcinoma is a stronger prognostic marker than proliferation. PMID:24143191

  3. A Review of Systemic Treatment in Metastatic Triple-Negative Breast Cancer

    PubMed Central

    Zeichner, Simon B.; Terawaki, Hiromi; Gogineni, Keerthi

    2016-01-01

    Patients with breast cancer along with metastatic estrogen and progesterone receptor (ER/PR)- and human epidermal growth factor receptor 2 (HER2)-negative tumors are referred to as having metastatic triple-negative breast cancer (mTNBC) disease. Although there have been many new treatment options approved by the Food and Drug Administration for ER/PR-positive and Her2/neu-amplified metastatic breast cancer, relatively few new agents have been approved for patients with mTNBC. There have been several head-to-head chemotherapy trials performed within the metastatic setting, and much of what is applied in clinical practice is extrapolated from chemotherapy trials in the adjuvant setting, with taxanes and anthracyclines incorporated early on in the patient’s treatment course. Select synergistic combinations can produce faster and more significant response rates compared with monotherapy and are typically used in the setting of visceral threat or symptomatic disease. Preclinical studies have implicated other possible targets and mechanisms in mTNBC. Ongoing clinical trials are underway assessing new chemotherapeutic strategies and agents, including targeted therapy and immunotherapy. In this review, we evaluate the standard systemic and future treatment options in mTNBC. PMID:27042088

  4. Differential diagnosis of lung lesion in breast carcinoma: a metachronous neoplasm or metastasis?

    PubMed

    Maddala, Raja Naga Mahesh; Udupa, Karthik; Thomas, Joseph; Pai, Kanthilatha

    2016-01-01

    A 34-year-old woman-a diagnosed case of pT1N1MO, stage IIa, estrogen and progesterone receptor positive (ER, PR) positive, Her2 negative carcinoma of the left breast-was managed with modified radical mastectomy and adjuvant chemotherapy. While planning for radiotherapy, she was found to have a well-defined enhancing lesion with spiculated margins in the superior segment of the right lower lobe along with a heterogeneously enhancing right hilar lymph node on CT. Histopathological evaluation of the lesion was suggestive of adenocarcinoma. The lesion was negative for ER, PR receptors, mammoglobin and gross cystic disease fluid protein. Thyroid transcription factor 1 (TTF-1) was positive, suggesting a primary lung adenocarcinoma rather than metastatic lesion from the breast. This case clearly signifies the importance of histopathological diagnosis of suspicious metastatic lesions in the setting of early breast cancer. We would also like to highlight the importance of TTF-1 in differentiating primary lung malignancy from metastasis. PMID:27170610

  5. Pertuzumab in human epidermal growth-factor receptor 2-positive breast cancer: clinical and economic considerations

    PubMed Central

    Lamond, Nathan WD; Younis, Tallal

    2014-01-01

    In the absence of specific therapy, the 15%–20% of breast cancers demonstrating human epidermal growth-factor receptor 2 (HER2) protein overexpression and/or gene amplification are characterized by a more aggressive phenotype and poorer prognosis compared to their HER2-negative counterparts. Trastuzumab (Herceptin), the first anti-HER2-targeted therapy, has been associated with improved survival outcomes in HER2-positive breast cancer. However, many patients with early stage disease continue to relapse, and metastatic disease remains incurable. In order to further improve these outcomes, several novel HER2-targeted agents have recently been developed. Pertuzumab (Perjeta), a monoclonal antibody against the HER2 dimerization domain, has also been associated with improved patient outcomes in clinical trials, and has recently been approved in combination with chemotherapy and trastuzumab for neoadjuvant therapy of early stage, HER2-positive breast cancer and first-line treatment of metastatic disease. This review briefly summarizes pertuzumab’s clinical development as well as the published evidence supporting its use, and highlights some of the currently unanswered questions that will influence pertuzumab’s incorporation into clinical practice. PMID:24876795

  6. Breast Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Breast Cancer What is Breast Cancer? How Tumors Form The body is made up ... tumors form in the breast tissue. Who Gets Breast Cancer? Breast cancer is one of the most common ...

  7. Clinical-Pathologic Features and Long-Term Outcomes of Tubular Carcinoma of the Breast Compared With Invasive Ductal Carcinoma Treated With Breast Conservation Therapy

    SciTech Connect

    Liu, Gene-Fu F.; Yang Qifeng; Haffty, Bruce G.; Moran, Meena S.

    2009-12-01

    Purpose: To evaluate our institutional experience of treating tubular carcinoma of the breast (TC) and invasive ductal carcinoma (IDC) with conservative surgery and radiation therapy, to compare clinical-pathologic features and long-term outcomes. Methods and Materials: A review of our institution's tumor registry from 1975 to 2007, followed by a central pathology review of available slides, yielded 71 cases of Stage I/II TC and 2,238 cases of Stage I/II IDC treated with breast conservation therapy. Clinical-pathologic features and outcomes were analyzed by subtype to detect significant differences. Results: The median follow-up was 7 years. The TC cohort presented more frequently with pT1 disease (97% vs. 80%, p = 0.0007), pN0 disease (95% vs. 74%, p = 0.0004), hormone-receptor positivity (ER+, 89% vs. 62%, p = 0.0001; PR+, 81% vs. 52%, p = 0.0001), and HER-2 negativity (89% vs. 71%, p = 0.04). Clinical outcomes also favored the TC cohort, with lower rates of breast cancer-related death (1% vs. 10%; p = 0.0109) and distant metastasis (1% vs. 13%; p = 0.0028) and higher rates of 10-year overall (90% vs. 80%; p = 0.033), cause-specific (99% vs. 86%; p = 0.011), and disease-free (99% vs. 82%; p = 0.003) survival. There was a nonsignificant trend toward improved breast cancer relapse-free survival for the TC cohort (95% vs. 87%; p = 0.062) but no difference in nodal relapse-free survival or contralateral breast cancer relapse-free survival (all p values >0.05) between the cohorts. Conclusion: Our institutional experience suggests that TC, when compared with IDC, is associated with more favorable clinical-pathologic features and comparable, if not superior, outcomes after breast conservation therapy, suggesting the appropriateness of a conservative approach to this rare subtype.

  8. Maspin as a Tumour Suppressor in Salivary Gland Tumour

    PubMed Central

    Ashok, Nipun; Sheirawan, Mohammad Kinan; Altamimi, Mohammed Alsakran; Alenzi, Faris; Azzeghaiby, Saleh Nasser; Baroudi, Kusai; Nassani, Mohammad Zakaria

    2014-01-01

    Maspin is a protein that belongs to serin protease inhibitor (serpin) superfamily. The purpose of this study was to review the literature concerning the expression of maspin in salivary gland tumours. A literature search was done using MEDLINE, accessed via the National Library of Medicine PubMed interface. Statistical analysis was not done because only seven studies were available in literature, the collected data were different and the results could not be compared. Expression of maspin was down regulated in more aggressive salivary gland tumours. Maspin may function as a tumour suppressor in salivary gland tumours. PMID:25654053

  9. Estrogen Receptor and HER2 Status on Disseminated Tumor Cells and Primary Tumor in Patients with Early Breast Cancer

    PubMed Central

    Jäger, Bernadette A.S.; Finkenzeller, Charlotte; Bock, Carolin; Majunke, Leonie; Jueckstock, Julia K.; Andergassen, Ulrich; Neugebauer, Julia K.; Pestka, Aurelia; Friedl, Thomas W.P.; Jeschke, Udo; Janni, Wolfgang; Doisneau-Sixou, Sophie F.; Rack, Brigitte K.

    2015-01-01

    BACKGROUND: We evaluated both estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status on disseminated tumor cells (DTCs) in the bone marrow of 54 patients with early breast cancer and compared these with the corresponding primary tumor (PT). MATERIALS AND METHODS: Bone marrow aspirates were obtained at the time of first surgery, and ER and HER2 status on DTCs was assessed simultaneously by immunocytochemistry using a triple fluorescence staining method. RESULTS: The median number of DTCs was 13 (range 1-95). The concordance rate between ER status on DTC and PT was 74%. Patients with an ER-positive PT were significantly more likely to have at least one ER-positive DTC (34 out of 42) than patients with an ER-negative PT (6 out of 12; P = .031). Thirty-nine (93%) of the 42 patients with ER-positive PT had at least one ER-negative DTC. The concordance rate between HER2 status on DTC and PT was 52%. The probability of having at least one HER2-positive DTC was not related to the HER2 status of the PT (P = 0.56). Twenty-two (46%) of the 48 patients with a HER2-negative PT had at least one HER2-positive DTC. All the six patients with a HER2-positive PT had at least one HER2-negative DTC. CONCLUSION: Taken together, our study confirms that ER and/or HER2 status may differ between DTC and PT. This discordance could be important for patients lacking ER or HER2 expression on the PT but showing ER-positive or HER2-positive DTC because they might benefit from an endocrine and/or HER2-targeted therapy. PMID:26692533

  10. A software tool based on the Surface Evolver for precise location of tumours as a preoperative procedure to partial mastectomy

    NASA Astrophysics Data System (ADS)

    Elias Fabris, Antonio; Zanchetta do Nascimento, Marcelo; Ramos Batista, Valério

    2015-09-01

    We present a fast and reliable program that gives precise location of breast tumours for a partial mastectomy. Our program is fully implemented in the Surface Evolver, which is a general-purpose simulator of physical experiments. By starting from the mammograms that show a tumour one takes its 2D coordinates in each view (CC and MLO). These coordinates, together with some measurements of the patient's breast, are given as input to our simulator. From this point on the simulator reproduces all main steps of taking mammography with a virtual transparent breast that matches the patient's. The virtual mammography procedure is graphically displayed on the computer screen, so that users can track the virtual tumour inside the breast. As output we have the coordinates of the tumour position when the woman lies on the operating table for the surgery. With these coordinates the surgeon can make a small incision into the breast and reach the tumour for its removal. The whole structure of the breast is preserved after a simple plastic correction.

  11. Surgical Resection of Phyllodes Tumour: a Radical Approach as a Safeguard Against Local Recurrence.

    PubMed

    Badwe, Rajendra A; Kataria, Kamal; Srivastava, Anurag

    2015-04-01

    Phyllodes tumour is a rare benign neoplasm of the breast. It is a mixed tumour of epithelial and mesenchymal origin. The epithelial element is characterized by proliferation of ductolobular units. The fibrous tissue and collagen bundles represent the mesenchymal element. It is also known as "cystosarcoma" phyllodes to characterize some important features, viz. cyst-like or cleft-like spaces within the mass along with a leaf- or frond-like pattern of the stromal element. The tumour is well known for its high potential for local recurrence. Most patients in developing countries present with very large breast tumours with close proximity to the skin and pectoralis major. In these cases, there is a need to perform a three-dimensional en bloc removal of the mass with overlying skin and underlying muscle(s). If a skin flap is raised in the vicinity of the tumour, there is a risk of cutting close to the tumour, increasing risk of local recurrence. Here, we describe a surgical technique that permits a three-dimensional en bloc removal of phyllodes tumour. PMID:26139976

  12. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320.

    PubMed

    Bronisz, A; Godlewski, J; Wallace, J A; Merchant, A S; Nowicki, M O; Mathsyaraja, H; Srinivasan, R; Trimboli, A J; Martin, C K; Li, F; Yu, L; Fernandez, S A; Pécot, T; Rosol, T J; Cory, S; Hallett, M; Park, M; Piper, M G; Marsh, C B; Yee, L D; Jimenez, R E; Nuovo, G; Lawler, S E; Chiocca, E A; Leone, G; Ostrowski, M C

    2012-02-01

    PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten-miR-320-Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression. PMID:22179046

  13. 19p13.1 is a triple negative-specific breast cancer susceptibility locus

    PubMed Central

    Stevens, Kristen N.; Fredericksen, Zachary; Vachon, Celine M.; Wang, Xianshu; Margolin, Sara; Lindblom, Annika; Nevanlinna, Heli; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Vrieling, Alina; Flesch-Janys, Dieter; Sinn, Hans-Peter; Wang-Gohrke, Shan; Nickels, Stefan; Brauch, Hiltrud; Ko, Yon-Dschun; Fischer, Hans-Peter; Schmutzler, Rita K.; Meindl, Alfons; Bartram, Claus R.; Schott, Sarah; Engel, Christof; Godwin, Andrew K.; Weaver, JoEllen; Pathak, Harsh B.; Sharma, Priyanka; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Miron, Penelope; Yannoukakos, Drakoulis; Stavropoulou, Alexandra; Fountzilas, George; Gogas, Helen J.; Swann, Ruth; Dwek, Miriam; Perkins, Annie; Milne, Roger L.; Benítez, Javier; Zamora, M Pilar; Pérez, José Ignacio Arias; Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Børge G; Flyger, Henrik; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Cordina-Duverger, Emilie; Burwinkel, Barbara; Marmé, Frederick; Schneeweiss, Andreas; Sohn, Christof; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J.; Peto, Julian; Johnson, Nichola; Fletcher, Olivia; Silva, Isabel dos Santos; Fasching, Peter A.; Beckmann, Matthias W.; Hartmann, Arndt; Ekici, Arif B.; Lophatananon, Artitaya; Muir, Kenneth; Puttawibul, Puttisak; Wiangnon, Surapon; Schmidt, Marjanka K; Broeks, Annegien; Braaf, Linde M; Rosenberg, Efraim H; Hopper, John L.; Apicella, Carmel; Park, Daniel J.; Southey, Melissa C.; Swerdlow, Anthony J.; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk J.; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Huan-Ming; Hsiung, Chia-Ni; Hamann, Ute; Dünnebier, Thomas; Rüdiger, Thomas; Ulmer, Hans Ulrich; Pharoah, Paul P.; Dunning, Alison M; Humphreys, Manjeet K.; Wang, Qin; Cox, Angela; Cross, Simon S.; Reed, Malcom W.; Hall, Per; Czene, Kamila; Ambrosone, Christine B.; Ademuyiwa, Foluso; Hwang, Helena; Eccles, Diana M.; Garcia-Closas, Montserrat; Figueroa, Jonine D.; Sherman, Mark E.; Lissowska, Jolanta; Devilee, Peter; Seynaeve, Caroline; Tollenaar, R.A.E.M.; Hooning, Maartje J.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; John, Esther M.; Miron, Alexander; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne-Lise; Giles, Graham G.; Baglietto, Laura; McLean, Catriona A; Severi, Gianluca; Kosel, Matthew L.; Pankratz, V.S.; Slager, Susan; Olson, Janet E.; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Lambrechts, Diether; Hatse, Sigrid; Dieudonne, Anne-Sophie; Christiaens, Marie-Rose; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Soini, Ylermi; Easton, Douglas F.; Couch, Fergus J.

    2012-01-01

    The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 – 1.15, p=3.49 × 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 – 1.31, p=2.22 × 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 – 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 – 1.33, p=3.31 × 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways. PMID:22331459

  14. Applications of microarray technology in breast cancer research

    PubMed Central

    Cooper, Colin S

    2001-01-01

    Microarrays provide a versatile platform for utilizing information from the Human Genome Project to benefit human health. This article reviews the ways in which microarray technology may be used in breast cancer research. Its diverse applications include monitoring chromosome gains and losses, tumour classification, drug discovery and development, DNA resequencing, mutation detection and investigating the mechanism of tumour development. PMID:11305951

  15. MEK inhibition prevents tumour-shed transforming growth factor-β-induced T-regulatory cell augmentation in tumour milieu.

    PubMed

    Hossain, Dewan M S; Panda, Abir K; Chakrabarty, Sreeparna; Bhattacharjee, Pushpak; Kajal, Kirti; Mohanty, Suchismita; Sarkar, Irene; Sarkar, Diptendra K; Kar, Santosh K; Sa, Gaurisankar

    2015-04-01

    Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4(+)  CD25(+)  FoxP3(+) T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-β (TGF-β) production in tumour cells that essentially blocked TGF-β-SMAD3/SMAD4-mediated induction of CD25/interleukin-2 receptor α on CD4(+) T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-β-induced Treg cell augmentation. PMID:25284464

  16. Moderate level of HER2 expression and its prognostic significance in breast cancer with intermediate grade.

    PubMed

    Ignatov, Tanja; Eggemann, Holm; Burger, Elke; Fettke, Franziska; Costa, Serban Dan; Ignatov, Atanas

    2015-06-01

    Overexpression of human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive marker of response to anti-HER2 therapy in breast cancer. Our goal was to analyze the prognostic significance of moderate expression of HER2 in breast cancer with intermediate differentiation grade. We performed a multicenter retrospective register study of 8494 patients with primary non-metastatic breast cancer admitted between 2000 and 2011 to eight Clinics in Saxony-Anhalt, federal state of Germany. Patients were divided into three groups according to their HER2 score: 4073 were classified as HER2 negative (HER2 0 and 1+), 822 HER2 moderate (HER2 2+/HER2), and 1238 HER2 positive (HER2 3+ or HER2 2+/HER2+). HER2-positive cases were excluded from analysis. Tumors with moderate HER2 (HER2 2+) expression demonstrated an aggressive behavior and worse patient survival compared with HER2 0 and 1+ status. HER2 2+ status was associated with shorter median overall survival (OS) (P < 0.0001) in breast cancer patients with an intermediate grade of differentiation. Comparing low-grade and high-grade tumors, HER2 moderate expression did not significantly influence patient survival. In multivariate analysis after adjustment for other prognostic factors HER2 2+ status remained an unfavorable prognostic factor for OS (HR 1.224, 95 % CI 1.059-1.415, P = 0.006) in breast cancer patients with an intermediate grade of differentiation. HER2 2+ status is an unfavorable prognostic factor regarding the OS of breast cancer patients with intermediate grade of differentiation and could be used to identify patients, who may benefit from adjuvant therapy. PMID:25926338

  17. Cystic carcinoma of the breast: a trap for the unwary.

    PubMed Central

    Ravichandran, D.; Carty, N. J.; al-Talib, R. K.; Rubin, C.; Royle, G. T.; Taylor, I.

    1995-01-01

    Cystic breast masses are a common presentation to breast clinics. While the majority of cysts can be managed by simple aspiration, a small proportion are malignant. Histology records for a 10-year period have been examined to identify patients with cystic breast carcinomas. In all, 31 patients were identified. Of these, 18 had cystic degeneration of high-grade tumours, while 13 had intracystic papillary carcinoma. Both of these tumour types were diagnosed by a combination of cyst fluid cytology and breast imaging. The prognosis of high-grade tumours was poor, while that of intracystic papillary carcinomas was excellent. After cyst aspiration, bloodstained fluid should be sent for cytology and breast imaging arranged in all patients. Patients in whom a cyst refills within 2 week of aspiration require a careful re-evaluation. Cysts in postmenopausal women should be viewed with suspicion. Excision should be performed in patients with positive cytology or imaging. Images Figure 1 PMID:7793801

  18. Triple negative breast cancer: the role of metabolic pathways.

    PubMed

    Dean, S J R; Rhodes, A

    2014-12-01

    The incidence of breast cancer in Malaysia and other Asian countries is on the increase, reflecting lifestyle changes some of which are known risk factors for the development of breast cancer. Most breast cancers are amenable to adjuvant therapies that target hormone receptors or HER2 receptors on the surface of the cancer cells and bring about significant improvement in survival. However, approximately 17% of Malaysian women with breast cancer, present with tumours that are devoid of these receptors and are consequently termed 'triple negative' breast cancers. These triple negative breast cancers typically occur in women of a younger age than receptor positive cancers, are predominantly of high grade tumours and the prognosis is usually poor. There is therefore a pressing need to understand the biological pathways that drive these tumours, in order that effective strategies are developed to treat these aggressive tumours. With the increasing affluence of developing countries, obesity and Type II Diabetes are also on the rise. These diseases are associated with an increased risk of developing a range of cancers including those of the breast. In particular, the metabolic syndrome has been shown to be associated with triple negative breast cancer. This article reviews some of the metabolic pathways and biomarkers which have been shown to be aberrantly expressed in triple negative breast cancer and highlights some of the ongoing work in this area. PMID:25500513

  19. Abcc10 status affects mammary tumour growth, metastasis, and docetaxel treatment response

    PubMed Central

    Domanitskaya, N; Wangari-Talbot, J; Jacobs, J; Peiffer, E; Mahdaviyeh, Y; Paulose, C; Malofeeva, E; Foster, K; Cai, K Q; Zhou, Y; Egleston, B; Hopper-Borge, E

    2014-01-01

    Background: Resistance to chemotherapeutic agents is a major obstacle to cancer treatment. A group of ABC efflux pumps, the Multidrug Resistance Proteins, is a source of resistance. Herein, we investigated the role of ABCC10 in mammary tumours, given the important role we have defined for ABCC10 in transporting taxanes, and the recognition that some ABCC proteins have roles in tumour growth. Methods: ABCC10 expression was correlated to human breast cancer subtype using breast tissue microarrays. Real-time quantitative PCR and western blot analysis were used to examine ABCC10 expression in human breast cancer lines. Abcc10−/− mice were crossed to MMTV-PyVmT mice to produce Abcc10−/− vs Abcc10+/+ mammary tumours and derivative cell lines. We used allograft and cellular assays to perform baseline and drug sensitization analysis of tumours and cell lines. Results: Clinical sample analyses indicated that ABCC10 was more highly expressed in Her2+ and ER+ than in Her2−, ER−, and triple-negative breast cancer. Unexpectedly, PyVmT; Abcc10−/− tumours grew more rapidly than PyVmT; Abcc10+/+ tumours and were associated with significantly reduced apoptosis and metastasis. PyVmT; Abcc10−/− lines were less migratory than PyVmT; Abcc10+/+ lines. Finally, we showed increased survival of docetaxel-treated MMTV-PyVmT; Abcc10−/− mice compared with wild-type mice. Conclusions: These data identify roles for Abcc10 in breast cancer pathogenesis and in vivo docetaxel resistance. PMID:24937672

  20. Primary cardiac sarcoma after breast cancer.

    PubMed

    Ramalho, Joana; Nunes, Sandra; Marques, Irene; Marques, Franklim

    2013-01-01

    Primary cardiac sarcomas are rare tumours carrying poor prognosis. Postradiation sarcoma has been reported in patients with breast, cervical and head and neck cancers. We report a case of a 56-year-old woman with stage IIA breast cancer diagnosed in 1997, submitted to mastectomy, adjuvant chemotherapy, radiotherapy and hormonotherapy. Pulmonary metastasis were detected in 2008 and treated with chemotherapy and hormonotherapy, being in complete remission since August 2009. She was admitted in December 2009 with a 3-week history of fever, dyspnoea, polyarthralgias and leg oedema. An echocardiography showed a mass in the left atrium. She was submitted to a surgical tumour resection and the histology revealed a sarcoma of intermediate degree of differentiation. Chemoradiation therapy was started and she remains alive after 3 years, without tumour regrowth or metastasis. This case is a therapeutic challenge, because the previous therapies for breast cancer hampered the options for extra chemoradiation therapy. PMID:23608855

  1. Radiation dose and second breast cancer.

    PubMed Central

    Basco, V. E.; Coldman, A. J.; Elwood, J. M.; Young, M. E.

    1985-01-01

    Amongst 14,000 women with breast cancer treated between 1946 and 1982, 194 developed a second primary tumour in the contralateral breast more than one year after diagnosis of the first primary. The radiation dose to the contralateral breast was calculated for each member of this group and also for members of a control group matched for age, year of diagnosis and survival time. Comparison of the groups provides no evidence for radiation induced carcinogenesis on the contralateral breast in these patients. PMID:4041361

  2. One very rare and one new tracheal tumour found by electron microscopy: glomus tumour and acinic cell tumour resembling carcinoid tumours by light microscopy.

    PubMed Central

    Heard, B E; Dewar, A; Firmin, R K; Lennox, S C

    1982-01-01

    Tracheal tumours were removed surgically from two patients and diagnosed as carcinoid tumours by routine light microscopy. At a later date, electron microscopy was performed on stored tumour tissue and no neurosecretory granules were found in either case. One showed features of a glomus tumour and the other of an acinic cell tumour. Only two glomus tumours appear to have been reported previously in the trachea, and no acinic cell tumours. Electron microscopy is thus sometimes of great assistance in diagnosing accurately unusual tumours of the lower respiratory tract. Images PMID:6281934

  3. Metabolic reprogramming of the tumour microenvironment.

    PubMed

    Xing, Yazhi; Zhao, Shimin; Zhou, Binhua P; Mi, Jun

    2015-10-01

    Tumour cells, stromal cells and the stroma comprise the tumour microenvironment. The metabolism of both tumour cells and several types of tumour stromal cells, such as cancer-associated fibroblasts and tumour-associated macrophages, is reprogrammed. Current studies have found that stromal cells promote tumour progression and metastasis, through not only the paracrine secretion of cytokines or chemokines, but also intermediate metabolites. Here, we summarize the latest insights into the mechanism of metabolic reprogramming in cancer cells, cancer-associated fibroblasts and tumour-associated macrophages, and their potential roles in tumour progression and metastasis. PMID:26255648

  4. 99mTc-labelled SM3 in the preoperative evaluation of axillary lymph nodes and primary breast cancer with change detection statistical processing as an aid to tumour detection.

    PubMed Central

    Biassoni, L.; Granowska, M.; Carroll, M. J.; Mather, S. J.; Howell, R.; Ellison, D.; MacNeill, F. A.; Wells, C. A.; Carpenter, R.; Britton, K. E.

    1998-01-01

    The extent of primary surgery for breast cancer could be tailored to the patient if previous information on the presence or absence of lymph node involvement could be reliably determined. Prospective radioimmunoscintigraphy in 29 patients with primary breast cancer that was found on screening has been undertaken with 555 MBq (15 mCi) 99mTc SM3, an Imperial Cancer Research Fund (ICRF) murine monoclonal antibody, 0.5 mg with images at 10 min and 22 h, and analysis using a change detection algorithm. Sites of significant change between the early and later images were displayed as a map of probabilities. Image-positive and -negative axillary lymph nodes were compared by histology in the 28 evaluable patients. The correct identification of the presence or absence of node involvement, even if impalpable, has been shown in 24 out of 28 patients (29 lymph node groups). Sensitivity was 90% (nine out of ten), specificity 84% (16 out of 19) and accuracy 86%. These results encourage further assessment of this technique. Images Figure 1 Figure 2 PMID:9459158

  5. Recurrent hyperphosphatemic tumoural calcinosis

    PubMed Central

    Amit, Sonal; Agarwal, Asha; Nigam, Anand; Rao, Yashwant Kumar

    2012-01-01

    Tumoural calcinosis (TC) is a benign gradually developing disorder that can occur in a variety of clinical settings, characterised by subcutaneous deposition of calcium phosphate with or without giant cell reaction. We describe a case of 11-year-old girl presenting with recurrent hard swellings in the vicinity of shoulder and hip joints associated with elevated serum phosphate and normal serum calcium levels. TC has been mainly reported from Africa, with very few cases reported from India. After the diagnosis of hyperphosphatemic TC was established, the patient was treated with oral sevelamer and is under constant follow-up to detect recurrence, if any. The present case highlights the fact that although an uncommon lesion, TC must be considered in the differential diagnosis of subcutaneous hard lump in the vicinity of a joint. PMID:23010461

  6. Surface impedance based microwave imaging method for breast cancer screening: contrast-enhanced scenario

    NASA Astrophysics Data System (ADS)

    Güren, Onan; Çayören, Mehmet; Tükenmez Ergene, Lale; Akduman, Ibrahim

    2014-10-01

    A new microwave imaging method that uses microwave contrast agents is presented for the detection and localization of breast tumours. The method is based on the reconstruction of breast surface impedance through a measured scattered field. The surface impedance modelling allows for representing the electrical properties of the breasts in terms of impedance boundary conditions, which enable us to map the inner structure of the breasts into surface impedance functions. Later a simple quantitative method is proposed to screen breasts against malignant tumours where the detection procedure is based on weighted cross correlations among impedance functions. Numerical results demonstrate that the method is capable of detecting small malignancies and provides reasonable localization.

  7. Ultrasound - Breast

    MedlinePlus

    ... discharge) and to characterize potential abnormalities seen on mammography or breast magnetic resonance imaging (MRI). Ultrasound imaging ... supply in breast lesions . Supplemental Breast Cancer Screening Mammography is the only screening tool for breast cancer ...

  8. Breast pain

    MedlinePlus

    Pain - breast; Mastalgia; Mastodynia; Breast tenderness ... There are many possible causes for breast pain. For example, hormone level changes from menstruation or pregnancy often cause breast tenderness. Some swelling and tenderness just before your period ...

  9. Breast lift

    MedlinePlus

    ... enable JavaScript. A breast lift, or mastopexy, is cosmetic breast surgery to lift the breasts. The surgery ... the position of the areola and nipple. Description Cosmetic breast surgery can be done at an outpatient ...

  10. Implementation of TMA and digitalization in routine diagnostics of breast pathology.

    PubMed

    Rossing, Henrik Holm; Talman, Maj-Lis Møller; Laenkholm, Anne-Vibeke; Wielenga, Vera Timmermans

    2012-04-01

    To ensure optimal treatment of breast cancer patients, breast tumours are classified based on clinico-pathological features. As part of this process, routine diagnostics of breast tumours includes histological typing and grading, as well as profiling by use of an immunohistochemistry panel of antibodies, probes and in situ hybridization. This will, as a minimum, include assessment of oestrogen receptor (OR) and HER2. The individual preparation and staining of many breast tumours in a large laboratory with this standard panel is thus time consuming and costly. Herein, we show that in breast cancer routine diagnostics the use of the tissue microarray technique in combination with digitalization of the stained multi-slides is not only economical, with a considerable cost reduction, but it also enhances standardization of tumour profiling. We demonstrate that 2 mm breast tumour cores correlate with the corresponding tumour on whole mount slides, regarding staining/hybridizing results with the biomarkers in our panel consisting of human epidermal growth factor receptor 2, OR and Topiomerase IIa. Furthermore, we show that simultaneous staining/hybridizing of multiple breast tumour specimens reduces variation of staining/hybridizing quality, hereby increasing reliability of interpretation. By scanning and digitalization of the stained and hybridized multi-slides, we could optimize documentation and filing of the results. Our work is an example of translational research by implementing a tool in daily diagnostics originally developed for high throughput analyses in the search for prognostic and predictive markers in targeted medicine. PMID:22429216

  11. Triple-negative breast cancer exhibits a favorable response to neoadjuvant chemotherapy independent of the expression of topoisomerase IIα

    PubMed Central

    NOGI, HIROKO; UCHIDA, KEN; KAMIO, MAKIKO; KATO, KUMIKO; TORIUMI, YASUO; AKIBA, TADASHI; MORIKAWA, TOSHIAKI; SUZUKI, MASAAKI; KOBAYASHI, TADASHI; TAKEYAMA, HIROSHI

    2016-01-01

    The present study retrospectively analyzed the utility of topoisomerase IIα expression as a prognostic marker to predict the neoadjuvant chemotherapeutic response and survival among different breast cancer subtypes. The patients were subtyped and the expression of topoisomerase IIα was determined using immunohistochemistry. All patients (n=147) received an anthracycline-containing regimen preoperatively, and 139 (95%) patients also received docetaxel. Of the 147 patients, 25 (17%) were triple-negative and 20 (17%) were human epidermal growth factor receptor 2 (HER2)-positive. Among these subtypes, a significantly higher a rate (P<0.0001) and higher incidence of topoisomerase IIα expression (P=0.036) were observed compared with that in the hormone receptor-positive and HER2-negative breast cancer types. However, the expression of topoisomerase IIα revealed no correlation with the treatment response or survival in any of the subtypes. Therefore, these results indicated that the favorable response to anthracycline-containing chemotherapy among triple-negative and HER2-positive breast cancer was independent of the expression of topoisomerase IIα. PMID:26998288

  12. Human plasma metabolomics for identifying differential metabolites and predicting molecular subtypes of breast cancer

    PubMed Central

    Chen, Zhuo; Li, Jin; Liu, Qun; Alolga, Raphael N; Chen, Yan; Lai, Mao-De; Li, Ping; Zhu, Wei; Qi, Lian-Wen

    2016-01-01

    Purpose This work aims to identify differential metabolites and predicting molecular subtypes of breast cancer (BC). Methods Plasma samples were collected from 96 BC patients and 79 normal participants. Metabolic profiles were determined by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry based on multivariate statistical data analysis. Results We observed 64 differential metabolites between BC and normal group. Compared to human epidermal growth factor receptor 2 (HER2)-negative patients, HER2-positive group showed elevated aerobic glycolysis, gluconeogenesis, and increased fatty acid biosynthesis with reduced Krebs cycle. Compared with estrogen receptor (ER)-negative group, ER-positive patients showed elevated alanine, aspartate and glutamate metabolism, decreased glycerolipid catabolism, and enhanced purine metabolism. A panel of 8 differential metabolites, including carnitine, lysophosphatidylcholine (20:4), proline, alanine, lysophosphatidylcholine (16:1), glycochenodeoxycholic acid, valine, and 2-octenedioic acid, was identified for the classification of BC subtypes. These markers showed potential diagnostic value with average area under the curve at 0.925 (95% CI 0.867-0.983) for the training set (n=51) and 0.893 (95% CI 0.847-0.939) for the test set (n=45). Conclusion Human plasma metabolomics is useful in identifying differential metabolites and predicting breast cancer subtypes. PMID:26848530

  13. PI3K mutations in breast cancer: prognostic and therapeutic implications

    PubMed Central

    Mukohara, Toru

    2015-01-01

    The PI3K pathway is the most frequently enhanced oncogenic pathway in breast cancer. Among mechanisms of PI3K enhancement, PIK3CA mutations are most frequently (∼30%) observed, along with protein loss of PTEN. Since the first discovery of PIK3CA mutations in solid malignancies in 2004, numerous studies have revealed the prognostic and therapeutic implications of these mutations. Although many issues remain unconfirmed, some have been carved in stone by the level of consistency they have shown among studies: 1) PIK3CA mutations are most likely to be observed in ER-positive/HER2-negative tumors, and are associated with other good prognostic characters; 2) PIK3CA mutations can coexist with other PI3K-enhancing mechanisms, such as HER2 amplification and PTEN protein loss; 3) PIK3CA mutations are potentially a good prognostic marker; 4) PIK3CA may predict a poorer tumor response to trastuzumab-based therapies, but its impact on disease-free survival and overall survival is uncertain; and 5) based on reports of early clinical trials, PIK3CA mutations do not guarantee a dramatic response to PI3K inhibitors. Collectively, there is currently no sufficient evidence to recommend routine genotyping of PIK3CA in clinical practice. Given that PIK3CA-mutant breast cancer appears to have a distinct tumor biology, development of more individualized targeted therapies based on the PIK3CA genotype is awaited. PMID:26028978

  14. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases. PMID:27431631

  15. Prognostic Typing in Breast Cancer

    PubMed Central

    Hartveit, F.

    1971-01-01

    Infiltrating breast carcinomas in which recurrence takes place 10 years or more after operation are reported to contain tumour cells of characteristic morphology. The cytological features of these tumour cells form the basis of the system of classification described here. Three cytological types are recognized, prognosis being best in type III. Typing is carried out on specimens stained with haematoxylin and eosin. The results of typing were reproducible in over 90% of cases and independent of the histology of the lesion. Correlation to survival time was shown in a total of 222 cases. ImagesFIG. 1 PMID:4107964

  16. [Drug therapy for neuroendocrine tumours].

    PubMed

    Tóth, Miklós

    2013-09-29

    The author aims to review the established medical treatment options of neuroendocrine tumours, which have expanded greatly in recent years and present the most important aspects to be considered in planning patients' management. Medical treatment is usually considered in advanced stages of these tumours, as well as in cases of hormone overproduction. Somatostatin analogues have been known to be effective in alleviating hormone excess syndromes, especially carcinoid syndrome for the past 25 years. There is a convincing evidence that the somatostatin analogue octreotide is useful as an antitumor agent, at least in well-differentiated small intestinal neuroendocrine tumours and probably also in those of pancreatic origin. Interferons may be also used and the indications for their use may be almost the same. Optimal patient selection is mandatory for the use of cytotoxic chemotherapy. Streptozotocin- and, recently, temozolomide-based chemotherapies should be considered in progressive phases of well differentiated (G1/G2) pancreatic neuroendocrine tumours. A cisplatin-etoposide combination is the first choice for the treatment of G3 neuroendocrine carcinomas of any origin. Recently, the mammalian target of rapamycin inhibitor everolimus and the combined tyrosine kinase inhibitor sunitinib were registered for the treatment of G1/G2 pancreatic neuroendocrine tumours. The most recent drug treatment recommendations and therapeutic algorithms to improve systemic therapy in patients with neuroendocrine tumours are summarized and novel drug candidates with particular potential for future management of these tumours are outlined. PMID:24058101

  17. Tumours of bones and joints

    PubMed Central

    Misdorp, W.; Van Der Heul, R. O.

    1976-01-01

    Tumours of bones and joints are not infrequent in dogs but are rare in other domestic animals. In the dog, most bone tumours are malignant; osteosarcomas are by far the most frequently encountered tumours, especially in giant breeds and boxers. The following main categories of bone tumour are described: bone-forming, cartilage-forming, giant cell, marrow, vascular, miscellaneous, metastatic, unclassified, and tumour-like lesions. The tumours of joints and related structures are classified as synovial sarcomas, fibroxanthomas, and malignant giant cell tumour of soft tissues. ImagesFig. 21Fig. 22Fig. 23Fig. 24Fig. 17Fig. 18Fig. 19Fig. 20Fig. 29Fig. 30Fig. 31Fig. 32Fig. 33Fig. 34Fig. 35Fig. 36Fig. 25Fig. 26Fig. 27Fig. 28Fig. 1Fig. 2Fig. 3Fig. 4Fig. 37Fig. 38Fig. 39Fig. 40Fig. 5Fig. 6Fig. 7Fig. 8Fig. 13Fig. 14Fig. 15Fig. 16Fig. 9Fig. 10Fig. 11Fig. 12 PMID:1086157

  18. Detection of disseminated tumor cells from the bone marrow of patients with early breast cancer is associated with high 21-gene recurrence score.

    PubMed

    Hartkopf, Andreas D; Wallwiener, Markus; Kommoss, Stefan; Taran, Florin-Andrei; Brucker, Sara Y

    2016-02-01

    High 21-gene recurrence score (RS) is associated with an impaired prognosis in patients with HR-positive/HER2-negative early breast cancer (EBC) and predictive of response to adjuvant chemotherapy. Detection of disseminated tumor cells (DTCs) in the bone marrow is a surrogate of minimal residual disease and of prognostic value. The aim of this study was to compare DTC detection with the 21-gene RS. DTCs were identified in bone marrow aspirates of HR-positive/HER2-negative EBC patients by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology at primary surgery. The 21-gene RS was assessed in paraffin-embedded tumor tissue samples using Oncotype DX (Genomic Health). A total of 114 patients were included in this study. DTCs were detected in 13 of these (11 %). Of the women with a low RS (<18), 5/75 (7 %) were DTC positive. Of the women with an intermediate/high RS (≥18), 8/39 (21 %) were DTC positive (p = 0.03, Chi-squared test). The median RS in DTC-negative patients was significantly lower as compared to DTC-positive patients (15 vs. 20, p = 0.04, Mann-Whitney U test). In conclusion, detection of DTCs in patients with EBC is associated with high 21-gene recurrence score. These findings are meaningful for further basic research that aims to investigate the biological mechanism of tumor cell spread and cancer progression and may have prognostic and/or predictive clinical implications that should be evaluated in future clinical trials. PMID:26911294

  19. Effect of Metformin on Breast Ductal Carcinoma In Situ Proliferation in a Randomized Presurgical Trial.

    PubMed

    DeCensi, Andrea; Puntoni, Matteo; Guerrieri-Gonzaga, Aliana; Cazzaniga, Massimiliano; Serrano, Davide; Lazzeroni, Matteo; Vingiani, Andrea; Gentilini, Oreste; Petrera, Marilena; Viale, Giuseppe; Cuzick, Jack; Bonanni, Bernardo; Pruneri, Giancarlo

    2015-10-01

    Metformin is associated with lower breast cancer risk in epidemiologic studies and showed decreased proliferation in HER2-positive breast cancer in a presurgical trial. To provide insight into its preventive potential, we measured proliferation by Ki-67 labeling index (LI) of intraepithelial lesions surrounding breast cancer. We randomly assigned 200 nondiabetic patients diagnosed with invasive breast cancer in core biopsies to metformin, 1,700 mg or placebo once daily for 28 days before surgery. Upon surgery, five to seven specimens of cancer adjacent (≤1 cm) and distant (>1 cm) tissue were screened for LCIS, ductal carcinoma in situ (DCIS), and ductal hyperplasia (DH). The prevalence of LCIS, DCIS, and DH was 4.5% (9/200), 67% (133/200), and 35% (69/200), respectively. Overall, metformin did not affect Ki-67 LI in premalignant disorders. The median posttreatment Ki-67 LI (IQR) in the metformin and placebo arm was, respectively, 15% (5-15) versus 5% (4-6) in LCIS (P = 0.1), 12% (8-20) versus 10% (7-24) in DCIS (P = 0.9), and 3% (1-4) versus 3% (1-4) in DH (P = 0.5). However, posttreatment Ki-67 in HER2-positive DCIS lesions was significantly lower in women randomized to metformin especially when ER was coexpressed: 22% (11-32) versus 35% (30-40) in HER2-positive DCIS (n = 22, P = .06); 12% (7-18) versus 32% (27-42) in ER-positive/HER2-positive DCIS (n = 15, P = .004). Eight of 22 (36%) HER2-positive DCIS were adjacent to HER2-negative invasive breast cancer. In tissue samples obtained following 4 weeks of study drug, proliferation was lower in HER2-positive DCIS for women randomized to metformin versus placebo. An adjuvant trial incorporating metformin in HER2-positive DCIS is warranted. PMID:26276754

  20. Epidemiological and Clinicopathological Trends of Breast Cancer in Chinese Patients During 1993 to 2013

    PubMed Central

    Si, Wen; Li, Ying; Han, Yingjie; Zhang, Fan; Wang, Yingzhe; Li, Ying; Linghu, Rui Xia; Zhang, Xingyang; Yang, Junlan

    2015-01-01

    Abstract This study aimed to summarize the epidemiological and pathological trends of breast cancer in Chinese women. The clinical data of 4968 breast cancer patients treated at the Chinese PLA General Hospital from 1993 to 2013 were retrospectively reviewed. The mean ± standard deviation (SD) age was 47.4 ± 11.3 years before the year 2001, 49.2 ± 11.2 years during 2001 to 2010, and 50.6 ± 11.4 years after the year 2010, respectively (P < 0.001). The ratio of premenopausal women to postmenopausal women was 1.6 and no significant changes were found during the period (P = 0.121). The proportion of patients with Scarff Bloom Richardson III breast cancer showed significant increase along with time (P = 0.015). The breast cancer was accounting for 31.7% at stage I and DCIS/LCIS and tend to be diagnosed with early stage around time (P < 0.001). The proportion of DCIS/LCIS and stage I increased with time during the 20 years from 14.6% to 33.2%, whereas the proportion of stage III to IV decreased. The proportion of Luminal A-like subtype gradually reduced and Luminal B-like (HER2-negative) increased and developed to the predominant type. Older age and earlier stage at diagnosis, as well as the alternation of predominant molecular subtypes, have become the developed trends of breast cancer. PMID:26131834

  1. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer

    PubMed Central

    2010-01-01

    Introduction In breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype. Methods The clinical, pathological and biological features of claudin-low tumors were compared to the other tumor subtypes using an updated human tumor database and multiple independent data sets. These main features of claudin-low tumors were also evaluated in a panel of breast cancer cell lines and genetically engineered mouse models. Results Claudin-low tumors are characterized by the low to absent expression of luminal differentiation markers, high enrichment for epithelial-to-mesenchymal transition markers, immune response genes and cancer stem cell-like features. Clinically, the majority of claudin-low tumors are poor prognosis estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and epidermal growth factor receptor 2 (HER2)-negative (triple negative) invasive ductal carcinomas with a high frequency of metaplastic and medullary differentiation. They also have a response rate to standard preoperative chemotherapy that is intermediate between that of basal-like and luminal tumors. Interestingly, we show that a group of highly utilized breast cancer cell lines, and several genetically engineered mouse models, express the claudin-low phenotype. Finally, we confirm that a prognostically relevant differentiation hierarchy exists across all breast cancers in which the claudin-low subtype most closely resembles the mammary epithelial stem cell. Conclusions These results should help to improve our understanding of the biologic heterogeneity of breast cancer and provide tools for the further evaluation of the unique biology of claudin-low tumors and cell lines. PMID:20813035

  2. Tumours of the urinary bladder

    PubMed Central

    Pamukcu, A. M.

    1974-01-01

    Tumours of the urinary bladder are uncommon in all domestic animals except cattle in certain regions. Where cattle eat bracken (Pteridium aquilinum) there is a high incidence of these tumours. Epithelial tumours are the most frequently encountered neoplasms in cattle and in dogs—the two species most studied. They are described under the following names: papilloma, adenoma, transitional cell carcinoma (with variants), squamous cell carcinoma, adenocarcinoma, and undifferentiated carcinoma. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 13Fig. 14Fig. 15Fig. 16 PMID:4371741

  3. EGFR and microvessel density in canine malignant mammary tumours.

    PubMed

    Carvalho, Maria Isabel; Guimarães, Maria João; Pires, Isabel; Prada, Justina; Silva-Carvalho, Ricardo; Lopes, Carlos; Queiroga, Felisbina L

    2013-12-01

    The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor which has been shown to have an important role in human breast cancer. Its role appears to be associated with increased angiogenesis and metastasis. In order to clarify its role in canine mammary tumours (CMT), 61 malignant neoplasms were studied by using immunohistochemistry, comparing expression of EGFR, microvessel density (MVD) by CD31 immunolabelling and characteristics of tumour aggressiveness. High EGFR immunoexpression was statistically significantly associated with tumour size, tumour necrosis, mitotic grade, histological grade of malignancy and clinical stage. High CD31 immunoreactivity was statistically significantly associated with tubule formation, histological grade of malignancy and clinical stage. A positive correlation between EGFR and CD31 immunoexpression (r = 0.843; P < 0.001) was also observed. Results suggest that an over-expression of EGFR may contribute to increased angiogenesis and aggression in malignant CMT, presenting the possibility of using EGFR inhibitors in the context of metastatic disease treatment. PMID:24091029

  4. Distribution of Photofrin between tumour cells and tumour associated macrophages.

    PubMed Central

    Korbelik, M.; Krosl, G.; Olive, P. L.; Chaplin, D. J.

    1991-01-01

    Photofrin levels in cells derived from SCCVII tumours, excised from mice that previously received the drug, were measured using a fluorescence activated cell sorter (FACS). Concomitantly, in the same cells the FACS was used to measure fluorescein isothiocyanate (FITC) fluorescence that originated from FITC-conjugated antimouse IgG added to the cell suspension before sorting. This later measurement enabled discrimination between IgG negative tumour malignant cells and IgG positive host cells (primarily macrophages). In addition, cellular Photofrin content in 'tumour' and 'host' cells sorted by FACS was determined by chemical extraction. The measurements were performed for the time intervals 1-96 h post Photofrin administration. The data showed consistently higher Photofrin levels in the 'host cells', i.e., tumour associated macrophages (TAM), than in 'tumour' cells. On a per cell basis, at any time point studied there was a minimum of 1.7 times more Photofrin in 'host' than in 'tumour cells', while at 4-12 h postadministration, ratios of up to 3.0 times were observed. This corresponds to ratio values greater than 9, when based on Photofrin content per micrograms cell protein. PMID:1832927

  5. Rewiring macrophages for anti-tumour immunity.

    PubMed

    Lee, Yunqin; Biswas, Subhra K

    2016-06-28

    Tumour-associated macrophages facilitate cancer progression, but whether they can be reprogrammed to elicit an anti-tumour response remains unclear. Deletion of the microRNA-processing enzyme Dicer is now shown to rewire macrophages to an anti-tumour mode, leading to an enhanced response to immunotherapy and inhibition of tumour progression. PMID:27350442

  6. [Unilateral gigantomastia of pregnancy: case-report of a giant breast hamartoma].

    PubMed

    Kuhn-Beck, F; Foessel, L; Bretz-Grenier, M-F; Akladios, C Youssef; Mathelin, C

    2014-06-01

    Breast hamartoma is a benign tumour consisting of fat, fibrous and glandular tissue. A young woman in her 19th week of pregnancy underwent exceptional surgery for a unilateral gigantomastia secondary to a rapid-growth giant hamartoma during her second pregnancy. Rigourous clinical and ultrasonographic examinations were performed followed by multiple biopsies. The decision to perform surgery was guided by the risk to skin integrity and of tumour infarct. Our report provides detailed information on gestational benign breast tumours, on the specificities of medical imaging and breast surgery in pregnant patients. PMID:24852910

  7. Future treatment options with capecitabine in solid tumours.

    PubMed

    Wilke, H

    2002-02-01

    The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years. PMID:11841932

  8. Quantifying tumour heterogeneity with CT

    PubMed Central

    Miles, Kenneth A.

    2013-01-01

    Abstract Heterogeneity is a key feature of malignancy associated with adverse tumour biology. Quantifying heterogeneity could provide a useful non-invasive imaging biomarker. Heterogeneity on computed tomography (CT) can be quantified using texture analysis which extracts spatial information from CT images (unenhanced, contrast-enhanced and derived images such as CT perfusion) that may not be perceptible to the naked eye. The main components of texture analysis can be categorized into image transformation and quantification. Image transformation filters the conventional image into its basic components (spatial, frequency, etc.) to produce derived subimages. Texture quantification techniques include structural-, model- (fractal dimensions), statistical- and frequency-based methods. The underlying tumour biology that CT texture analysis may reflect includes (but is not limited to) tumour hypoxia and angiogenesis. Emerging studies show that CT texture analysis has the potential to be a useful adjunct in clinical oncologic imaging, providing important information about tumour characterization, prognosis and treatment prediction and response. PMID:23545171

  9. Leydig cell tumours in childhood.

    PubMed

    Mengel, W; Knorr, D

    1983-01-01

    Two cases of Leydig cell tumours in childhood are presented. In one case, delayed diagnosis and operation led to pubertas praecox vera whereas in the other case normal growth and development occurred after early diagnosis and operation. PMID:6878724

  10. A rare benign ovarian tumour.

    PubMed

    Palmeiro, Marta Morna; Cunha, Teresa Margarida; Loureiro, Ana Luisa; Esteves, Gonçalo

    2016-01-01

    Sclerosing stromal tumour (SST) of the ovary is an extremely rare and benign ovarian neoplasm, accounting for 6% of the sex cord stromal ovarian tumours subtype. Usually, it is found during the second and third decades of life. Patients commonly present with pelvic pain, a palpable pelvic mass or menstrual irregularity. We report a case of a 20-year-old woman reporting of mild pelvic pain, with normal laboratory data. On imaging examinations, a large right adnexal tumour was found, with features suggesting an ovarian sex cord tumour. The patient underwent right salpingo-oophorectomy, diagnosing a SST of the ovary. This paper also reviews the literature, and emphasises the typical pathological and imaging characteristics of these rare benign ovarian lesions, and their impact, in a conservative surgery. PMID:26933186

  11. Multicellular Streaming in Solid Tumours

    NASA Astrophysics Data System (ADS)

    Kas, Josef

    As early as 400 BCE, the Roman medical encyclopaedist Celsus recognized that solid tumours are stiffer than surrounding tissue. However, cancer cell lines are softer, and softer cells facilitate invasion. This paradox raises several questions: Does softness emerge from adaptation to mechanical and chemical cues in the external microenvironment, or are soft cells already present inside a primary solid tumour? If the latter, how can a more rigid tissue contain more soft cells? Here we show that in primary tumour samples from patients with mammary and cervix carcinomas, cells do exhibit a broad distribution of rigidities, with a higher fraction of softer and more contractile cells compared to normal tissue. Mechanical modelling based on patient data reveals that, surprisingly, tumours with a significant fraction of very soft cells can still remain rigid. Moreover, in tissues with the observed distributions of cell stiffnesses, softer cells spontaneously self-organize into lines or streams, possibly facilitating cancer metastasis.

  12. Role of nuclear receptors in breast cancer stem cells.

    PubMed

    Papi, Alessio; Orlandi, Marina

    2016-03-26

    The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells, capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells (CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs (BCSCs) are likely to sustain the growth of the primary tumour mass, as well as to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and pro-inflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the anti-inflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse. PMID:27022437

  13. Role of nuclear receptors in breast cancer stem cells

    PubMed Central

    Papi, Alessio; Orlandi, Marina

    2016-01-01

    The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells, capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells (CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs (BCSCs) are likely to sustain the growth of the primary tumour mass, as well as to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and pro-inflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the anti-inflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse. PMID:27022437

  14. Breast cancer epidemiology and risk factors.

    PubMed

    Broeders, M J; Verbeek, A L

    1997-09-01

    Breast cancer is the most common malignancy among women in the Western society. Over the past decades it has become apparent that breast cancer incidence rates are increasing steadily, whereas the mortality rates for breast cancer have remained relatively constant. Information through the media on this rising number of cases has increased breast health awareness but has also introduced anxiety in the female population. This combination of factors has made the need for prevention of breast cancer an urgent matter. Breast cancer does not seem to be a single disease entity. A specific etiologic factor may therefore have more influence on one form of breast cancer than another. So far though, as shown in our summary of current knowledge on established and dubious risk factors, no risk factors have been identified that can explain a major part of the incidence. Efforts to identify other ways for primary prevention have also been discouraging, even though breast cancer is one of the most investigated tumours world-wide. Thus, at this point in time, the most important strategy to reduce breast cancer mortality is early detection through individual counselling and organised breast screening programs. The recent isolation of breast cancer susceptibility genes may introduce new ways to reduce the risk of breast cancer in a small subset of women. PMID:9274126

  15. Imaging of skull base tumours.

    PubMed

    Thust, Stefanie Catherine; Yousry, Tarek

    2016-01-01

    The skull base is a highly complex and difficult to access anatomical region, which constitutes a relatively common site for neoplasms. Imaging plays a central role in establishing the differential diagnosis, to determine the anatomic tumour spread and for operative planning. All skull base imaging should be performed using thin-section multiplanar imaging, whereby CT and MRI can be considered complimentary. An interdisciplinary team approach is central to improve the outcome of these challenging tumours. PMID:27330416

  16. What Is Breast Cancer?

    MedlinePlus

    ... Next Topic Types of breast cancers What is breast cancer? Breast cancer starts when cells in the breast ... breast cancer? ” and Non-cancerous Breast Conditions . How Breast Cancer Spreads Breast cancer can spread through the lymph ...

  17. Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients With Breast Cancer and Brain Metastases

    SciTech Connect

    Sperduto, Paul W.; Kased, Norbert; Roberge, David; Xu Zhiyuan; Shanley, Ryan; Luo, Xianghua; Sneed, Penny K.; Chao, Samuel T.; Weil, Robert J.; Suh, John; Bhatt, Amit; Jensen, Ashley W.; Brown, Paul D.; Shih, Helen A.; Kirkpatrick, John; Gaspar, Laurie E.; Fiveash, John B.; and others

    2012-04-01

    Purpose: The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. Methods and Materials: A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. Results: Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. Conclusions: The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

  18. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN.

    PubMed Central

    Gray, I. C.; Stewart, L. M.; Phillips, S. M.; Hamilton, J. A.; Gray, N. E.; Watson, G. J.; Spurr, N. K.; Snary, D.

    1998-01-01

    The chromosomal region 10q23-24 is frequently deleted in a number of tumour types, including prostate adenocarcinoma and glioma. A candidate tumour-suppressor gene at 10q23.3, designated PTENor MMAC1, with putative actin-binding and tyrosine phosphatase domains has recently been described. Mutations in PTEN have been identified in cell lines derived from gliomas, melanomas and prostate tumours and from a number of tumour specimens derived from glial, breast, endometrial and kidney tissue. Germline mutations in PTEN appear to be responsible for Cowden disease. We identified five PTEN mutations in 37 primary prostatic tumours analysed and found that 70% of tumours showed loss or alteration of at least one PTEN allele, supporting the evidence for PTEN involvement in prostate tumour progression. We raised antisera to a peptide from PTEN and showed that reactivity occurs in numerous small cytoplasmic organelles and that the protein is commonly expressed in a variety of cell types. Northern blot analysis revealed multiple RNA species; some arise as a result of alternative polyadenylation sites, but others may be due to alternative splicing. Images Figure 1 Figure 2 Figure 3 PMID:9823969

  19. Low Dose, Low Cost Estradiol Pellets Can Support MCF-7 Tumour Growth in Nude Mice without Bladder Symptoms

    PubMed Central

    Dall, Genevieve; Vieusseux, Jessica; Unsworth, Ashleigh; Anderson, Robin; Britt, Kara

    2015-01-01

    MCF-7 cells are a slow growing estrogen receptor (ER) positive human breast cancer cell line that is commonly used to model estrogen responsive breast cancer cell growth in-vitro and tumour growth in-vivo. These tumours require estrogen supplementation, and in-vivo doses of between 0.72mg and 2mg estradiol pellets are commonly implanted in the dorsal flank of ovariectomised, immunocompromised mice. We wanted to grow MCF-7 tumours in immunocompromised mice without the need to be ovariectomised. When we treated immunocompromised mice with 0.72mg pellets to induce MCF7 tumour growth, the mice developed urosepsis. We have now shown that lower doses of estradiol pellets, 0.3mg and 0.5mg, induce elevated serum estrogen levels and maintain tumour growth, without causing urosepsis. Supplementation for only one week did not support sustained MCF7 tumour growth. In conclusion, 0.3mg and 0.5mg silastic pellets can be used to stimulate ER+ breast cancer growth in ovary-intact, immune compromised mice. PMID:26640593

  20. DNA methylation profiling reveals a predominant immune component in breast cancers

    PubMed Central

    Dedeurwaerder, Sarah; Desmedt, Christine; Calonne, Emilie; Singhal, Sandeep K; Haibe-Kains, Benjamin; Defrance, Matthieu; Michiels, Stefan; Volkmar, Michael; Deplus, Rachel; Luciani, Judith; Lallemand, Françoise; Larsimont, Denis; Toussaint, Jérôme; Haussy, Sandy; Rothé, Françoise; Rouas, Ghizlane; Metzger, Otto; Majjaj, Samira; Saini, Kamal; Putmans, Pascale; Hames, Gérald; van Baren, Nicolas; Coulie, Pierre G; Piccart, Martine; Sotiriou, Christos; Fuks, François

    2011-01-01

    Breast cancer is a molecularly, biologically and clinically heterogeneous group of disorders. Understanding this diversity is essential to improving diagnosis and optimizing treatment. Both genetic and acquired epigenetic abnormalities participate in cancer, but the involvement of the epigenome in breast cancer and its contribution to the complexity of the disease are still poorly understood. By means of DNA methylation profiling of 248 breast tissues, we have highlighted the existence of previously unrecognized breast cancer groups that go beyond the currently known ‘expression subtypes’. Interestingly, we showed that DNA methylation profiling can reflect the cell type composition of the tumour microenvironment, and in particular a T lymphocyte infiltration of the tumours. Further, we highlighted a set of immune genes having high prognostic value in specific tumour categories. The immune component uncovered here by DNA methylation profiles provides a new perspective for the importance of the microenvironment in breast cancer, holding implications for better management of breast cancer patients. PMID:21910250

  1. Therapy-induced tumour secretomes promote resistance and tumour progression

    PubMed Central

    Obenauf, Anna C.; Zou, Yilong; Ji, Andrew L.; Vanharanta, Sakari; Shu, Weiping; Shi, Hubing; Kong, Xiangju; Bosenberg, Marcus C.; Wiesner, Thomas; Rosen, Neal; Lo, Roger S.; Massagué, Joan

    2015-01-01

    Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer1,2. Here we show that targeted therapy with BRAF, ALK, or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed melanoma and lung adenocarcinoma cells. This therapy-induced secretome (TIS) stimulates the outgrowth, dissemination, and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The vemurafenib reactive secretome in melanoma is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of multiple signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and PI3K/AKT/mTOR pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant melanoma tumours, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy. PMID:25807485

  2. Absence of canine papillomavirus sequences in canine mammary tumours.

    PubMed

    Sardon, D; Blundell, R; Burrai, G P; Alberti, A; Tore, G; Passino, E Sanna; Antuofermo, E

    2015-01-01

    Human papillomaviruses (PVs) are found in human breast cancer tissue; however, it remains controversial as to whether these viruses play a role in the aetiology of this tumour. There has been minimal study of whether PVs are found in normal or abnormal mammary glands of animals. The present study investigated whether a PV sequence could be found in the mammary glands of 33 female dogs by rolling circle amplification and polymerase chain reaction. No PV DNA was found in normal or neoplastic canine mammary tissues, suggesting that canine PVs are probably not involved in the pathogenesis of canine mammary neoplasia. PMID:25435511

  3. Extramedullary myeloid cell tumours--the NIMS experience.

    PubMed

    Paul, T Roshni; Sundaram, C; Gayathri, K; Prayaga, Aruna; Rao, D Raghunadha

    2005-07-01

    Extramedullary myeloid cell tumours are rare clinical entities, which often pose diagnostic problems. From the pathology record files of Nizam's Institute of Medical Sciences, Hyderabad, 16 cases of EMCTs were traced, over a period of 14 years. The clinical details, follow-up were noted and morphology re-evaluated, and immunohistochemistry with LCA was performed. Of the 16 cases, the distribution was as follows--skin and subcutaneous nodules, lymph nodes, extradural masses presenting with cord compression and one case each with eyelid, orbital and breast masses. The problems in diagnosis are presented and a panel of immunohistochemical markers suggested for proper diagnosis and treatment. PMID:16761741

  4. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers

    PubMed Central

    Lips, E H; Mulder, L; Oonk, A; van der Kolk, L E; Hogervorst, F B L; Imholz, A L T; Wesseling, J; Rodenhuis, S; Nederlof, P M

    2013-01-01

    Background: BRCAness is defined as shared tumour characteristics between sporadic and BRCA-mutated cancers. However, how to exactly measure BRCAness and its frequency in breast cancer is not known. Assays to establish BRCAness would be extremely valuable for the clinical management of these tumours. We assessed BRCAness characteristics frequencies in a large cohort of triple-negative breast cancers (TNBCs). Methods: As a measure of BRCAness, we determined a specific BRCA1-like pattern by array Comparative Genomic Hybridisation (aCGH), and BRCA1 promoter methylation in 377 TNBCs, obtained from 3 different patient cohorts. Clinicopathological data were available for all tumours, BRCA1-germline mutation status and chemotherapy response data were available for a subset. Results: Of the tumours, 66–69% had a BRCA1-like aCGH profile and 27–37% showed BRCA1 promoter methylation. BRCA1-germline mutations and BRCA1 promoter methylation were mutually exclusive events (P=1 × 10−5). BRCAness was associated with younger age and grade 3 tumours. Chemotherapy response was significantly higher in BRCA1-mutated tumours, but not in tumours with BRCAness (63% (12 out of 19) vs 35% (18 out of 52) pathological complete remission rate, respectively). Conclusion: The majority of the TNBCs show BRCAness, and those tumours share clinicopathological characteristics with BRCA1-mutated tumours. A better characterisation of TNBC and the presence of BRCAness could have consequences for both hereditary breast cancer screening and the treatment of these tumours. PMID:23558900

  5. Breast lump

    MedlinePlus

    ... new lumps or breast changes. Ask about your risk factors for breast cancer, and screening and prevention for breast cancer. When ... from you. You will be asked about your factors that may increase the risk of breast cancer . The provider will perform a thorough breast exam. ...

  6. Image-guided focused ultrasound ablation of breast cancer: current status, challenges, and future directions

    PubMed Central

    Schmitz, A. C.; Gianfelice, D.; Daniel, B. L.; Mali, W. P. Th. M.

    2008-01-01

    Image-guided focussed ultrasound (FUS) ablation is a non-invasive procedure that has been used for treatment of benign or malignant breast tumours. Image-guidance during ablation is achieved either by using real-time ultrasound (US) or magnetic resonance imaging (MRI). The past decade phase I studies have proven MRI-guided and US-guided FUS ablation of breast cancer to be technically feasible and safe. We provide an overview of studies assessing the efficacy of FUS for breast tumour ablation as measured by percentages of complete tumour necrosis. Successful ablation ranged from 20% to 100%, depending on FUS system type, imaging technique, ablation protocol, and patient selection. Specific issues related to FUS ablation of breast cancer, such as increased treatment time for larger tumours, size of ablation margins, methods used for margin assessment and residual tumour detection after FUS ablation, and impact of FUS ablation on sentinel node procedure are presented. Finally, potential future applications of FUS for breast cancer treatment such as FUS-induced anti-tumour immune response, FUS-mediated gene transfer, and enhanced drug delivery are discussed. Currently, breast-conserving surgery remains the gold standard for breast cancer treatment. PMID:18351348

  7. Giant pseudoangiomatous stromal hyperplasia presenting in the breast of a prepubertal child.

    PubMed

    Abdelrahman, Tarig; Young, Philippa; Kozyar, Olexandra; Davies, Eleri; Dojcinov, Stefan; Mansel, Robert E

    2015-01-01

    Large benign lesions of the breasts are rare in children. We present a case of a 35 cm mass, weighing 2.7 kg in a 13-year-old girl with small developing breasts. Despite the enormity of the lesion, the patient managed to keep it concealed from her parents for 8 months. While initially suspicious of sarcoma a diagnosis of pseudoangiomatous stromal hyperplasia was suggested radiologically and confirmed histologically. Excision with reduction mammoplasty was performed, care taken not to disrupt the remaining breast tissue to facilitate future breast development. 18 months on, the cosmetic appearance of the breasts is good, with healthy underlying breast tissue developing. To the best of our knowledge this case is the largest documented breast tumour of this type in a patient of this age and illustrates the challenge of treating such tumours in the developing breast. PMID:26002664

  8. Tumours of the upper alimentary tract.

    PubMed

    Head, K W

    1976-01-01

    Tumours of the oropharynx of domestic animals are common in most parts of the world, but squamous cell carcinoma of the upper alimentary tract shows differences in prevalence in different geographical areas and occurs at different sites in the various species. Oral tumours of the melanogenic system are more common in dogs than in man. The following main histological categories, which broadly correspond to those used in the classification of tumours of man, are described: papilloma; squamous cell carcinoma; salivary gland tumours; malignant melanoma; tumours of soft (mesenchymal) tissues; tumours of the facial bones; tumours of haematopoietic and related tissues; and odontogenic tumours and jaw cysts. Papilloma, squamous cell carcinoma, malignant melanoma, fibroma, and fibrosarcoma account for about 80% of the tumours that occur in the upper alimentary tract of domestic animals. PMID:1086147

  9. Oncoprotein stability after tumour resection.

    PubMed Central

    Ong, G.; Gullick, W.; Sikora, K.

    1990-01-01

    The means by which oncogenes and their products activate malignant transformation are currently under intense investigation. However, published papers on experiments using human tumour material do not always report in detail their methods of collection or storage of the specimens. In order to assess the stability of oncogene encoded proteins following collection or storage of human tumour biopsies, we have examined the rate of decay of the c-myc, neu and EGF-receptor proteins. Solid tumours, containing amplified copies of each oncogene, were established in nude mice and the stability of the oncogene protein in portions of each tumour, left in phosphate buffered saline at room temperature for varying time intervals, was examined by immunoblotting. Intact EGF-receptor and neu oncoproteins were present even after 24 h under these conditions while the c-myc protein was apparently rapidly degraded after 20 min. These data demonstrate that oncogene products decay at different rates after tumour resection and that collection of human biopsies should take this into account in order to provide the basis for consistent measurements of protein expression. Images Figure 1 Figure 2 Figure 3 PMID:2139576

  10. Role of ERRF, a Novel ER-Related Nuclear Factor, in the Growth Control of ER-Positive Human Breast Cancer Cells

    PubMed Central

    Su, Dan; Fu, Xiaoying; Fan, Songqing; Wu, Xiao; Wang, Xin-Xin; Fu, Liya; Dong, Xue-Yuan; Ni, Jianping Jenny; Fu, Li; Zhu, Zhengmao; Dong, Jin-Tang

    2012-01-01

    Whereas estrogen–estrogen receptor α (ER) signaling plays an important role in breast cancer growth, it is also necessary for the differentiation of normal breast epithelial cells. How this functional conversion occurs, however, remains unknown. Based on a genome-wide sequencing study that identified mutations in several breast cancer genes, we examined some of the genes for mutations, expression levels, and functional effects on cell proliferation and tumorigenesis. We present the data for C1orf64 or ER-related factor (ERRF) from 31 cell lines and 367 primary breast cancer tumors. Whereas mutation of ERRF was infrequent (1 of 79 or 1.3%), its expression was up-regulated in breast cancer, and the up-regulation was more common in lower-stage tumors. In addition, increased ERRF expression was significantly associated with ER and/or progesterone receptor (PR) positivity, which was still valid in human epidermal growth factor receptor 2 (HER2)–negative tumors. In ER-positive tumors, ERRF expression was inversely correlated with HER2 status. Furthermore, higher ERRF protein expression was significantly associated with better disease-free survival and overall survival, particularly in ER- and/or PR-positive and HER2-negative tumors (luminal A subtype). Functionally, knockdown of ERRF in two ER-positive breast cancer cell lines, T-47D and MDA-MB-361, suppressed cell growth in vitro and tumorigenesis in xenograft models. These results suggest that ERRF plays a role in estrogen-ER–mediated growth of breast cancer cells and could, thus, be a potential therapeutic target. PMID:22341523

  11. Feasibility Evaluation of Radioimmunoguided Surgery of Breast Cancer

    PubMed Central

    Ravi, Ananth; Reilly, Raymond M.; Holloway, Claire M. B.; Caldwell, Curtis B.

    2012-01-01

    Breast-conserving surgery involves completely excising the tumour while limiting the amount of normal tissue removed, which is technically challenging to achieve, especially given the limited intraoperative guidance available to the surgeon. This study evaluates the feasibility of radioimmunoguided surgery (RIGS) to guide the detection and delineation of tumours intraoperatively. The 3D point-response function of a commercial gamma-ray-detecting probe (GDP) was determined as a function of radionuclide (131I, 111In, 99mTc), energy-window threshold, and collimator length (0.0–3.0-cm). This function was used to calculate the minimum detectable tumour volumes (MDTVs) and the minimum tumour-to-background activity concentration ratio (T:B) for effective delineation of a breast tumour model. The GDP had larger MDTVs and a higher minimum required T:B for tumour delineation with 131I than with 111In or 99mTc. It was shown that for 111In there was a benefit to using a collimator length of 0.5-cm. For the model used, the minimum required T:B required for effective tumour delineation was 5.2 ± 0.4. RIGS has the potential to significantly improve the accuracy of breast-conserving surgery; however, before these benefits can be realized, novel radiopharmaceuticals need to be developed that have a higher specificity for cancerous tissue in vivo than what is currently available. PMID:22518303

  12. Microfluidic processor allows rapid HER2 immunohistochemistry of breast carcinomas and significantly reduces ambiguous (2+) read-outs

    PubMed Central

    Ciftlik, Ata Tuna; Lehr, Hans-Anton; Gijs, Martin A. M.

    2013-01-01

    Biomarker analysis is playing an essential role in cancer diagnosis, prognosis, and prediction. Quantitative assessment of immunohistochemical biomarker expression on tumor tissues is of clinical relevance when deciding targeted treatments for cancer patients. Here, we report a microfluidic tissue processor that permits accurate quantification of the expression of biomarkers on tissue sections, enabled by the ultra-rapid and uniform fluidic exchange of the device. An important clinical biomarker for invasive breast cancer is human epidermal growth factor receptor 2 [(HER2), also known as neu], a transmembrane tyrosine kinase that connotes adverse prognostic information for the patients concerned and serves as a target for personalized treatment using the humanized antibody trastuzumab. Unfortunately, when using state-of-the-art methods, the intensity of an immunohistochemical signal is not proportional to the extent of biomarker expression, causing ambiguous outcomes. Using our device, we performed tests on 76 invasive breast carcinoma cases expressing various levels of HER2. We eliminated more than 90% of the ambiguous results (n = 27), correctly assigning cases to the amplification status as assessed by in situ hybridization controls, whereas the concordance for HER2-negative (n = 31) and -positive (n = 18) cases was 100%. Our results demonstrate the clinical potential of microfluidics for accurate biomarker expression analysis. We anticipate our technique will be a diagnostic tool that will provide better and more reliable data, onto which future treatment regimes can be based. PMID:23479638

  13. Appropriate use of tumour biomarkers for treatment with innovative drugs: A retrospective study

    PubMed Central

    MASSA, ILARIA; NANNI, ORIANA; GUIDOBONI, MASSIMO; FRASSINETI, GIOVANNI LUCA; ROCCA, ANDREA; BURGIO, MARCO ANGELO; VALMORRI, LINDA; MARRI, MATTIA; PIANCASTELLI, ALESSANDRA; FAEDI, MARINA; LEONI, MAURIZIO; TAMBERI, STEFANO; ALTINI, MATTIA; AMADORI, DINO

    2016-01-01

    Performing randomised clinical trials to address the clinical usefulness of predictive and prognostic tumour markers is a complex process for several reasons, and observational experiences may thus play an important role. The present study performed an observational retrospective analysis in Area Vasta Romagna, Italy, collecting information on tumour marker determination in 760 consecutive patients who started a new line of anticancer therapy between January and June 2010. The determination of well-known biomarkers was requested for all gastrointestinal stromal tumour (GIST) patients (n=13) and for almost all breast cancer patients (n=369), and targeted therapies were consequently prescribed. Conversely, Kirsten rat sarcoma viral oncogene homolog (KRAS) determination in colon cancer patients (n=177) was requested in ~50% of advanced cases, while epidermal growth factor receptor (EGFR) determination was required in slightly more than 30% of the same patients. EGFR and KRAS determinations were requested in only 15% and 7.5% of non-small cell lung cancer (NSCLC) patients (n=201), respectively. There would appear to be greater appropriateness of tumour marker determination for breast cancer and GISTs than for colon cancer and NSCLC. Resources can be further optimised by standardising tumour marker determinations in terms of the timing of requests and the consequent use of the results for tailored treatment planning. PMID:26870292

  14. Development of three-dimensional radiotherapy techniques in breast cancer

    NASA Astrophysics Data System (ADS)

    Coles, Charlotte E.

    Radiotherapy following conservation surgery decreases local relapse and death from breast cancer. Currently, the challenge is to minimise the morbidity caused by this treatment without losing efficacy. Despite many advances in radiation techniques in other sites of the body, the majority of breast cancer patients are still planned and treated using 2-dimensional simple radiotherapy techniques. In addition, breast irradiation currently consumes 30% of the UK's radiotherapy workload. Therefore, any change to more complex treatment should be of proven benefit. The primary objective of this research is to develop and evaluate novel radiotherapy techniques to decrease irradiation of normal structures and improve localisation of the tumour bed. I have developed a forward-planned intensity modulated (IMRT) breast radiotherapy technique, which has shown improved dosimetry results compared to standard breast radiotherapy. Subsequently, I have developed and implemented a phase III randomised controlled breast IMRT trial. This National Cancer Research Network adopted trial will answer an important question regarding the clinical benefit of breast IMRT. It will provide DNA samples linked with high quality clinical outcome data, for a national translational radiogenomics study investigating variation in normal tissue toxicity. Thus, patients with significant late normal tissue side effects despite good dose homogeneity will provide the best model for finding differences due to underlying genetics. I evaluated a novel technique using high definition free-hand 3-dimensional (3D) ultrasound in a phantom study, and the results suggested that this is an accurate and reproducible method for tumour bed localisation. I then compared recognised methods of tumour bed localisation with the 3D ultrasound method in a clinical study. The 3D ultrasound technique appeared to accurately represent the shape and spatial position of the tumour cavity. This tumour bed localisation research

  15. Canine Mammary Mixed Tumours: A Review

    PubMed Central

    Dantas Cassali, Geovanni; Cavalheiro Bertagnolli, Angélica; Ferreira, Enio; Araújo Damasceno, Karine; de Oliveira Gamba, Conrado; Bonolo de Campos, Cecília

    2012-01-01

    Mammary mixed tumours are the most frequent neoplasias in female dogs. In humans, mixed tumours are frequently found in the salivary glands and are known as pleomorphic adenomas. In addition to their histomorphologic similarities, mixed tumours and pleomorphic adenomas have the potential to become malignant and give rise to carcinomas in mixed tumours and carcinomas ex-pleomorphic adenoma, respectively. The factors associated with malignant transformation are still poorly known in the case of canine mixed tumours. However, this form of neoplasia tends to be associated with a better prognosis than other malignant histological types. This paper discusses the main features associated with female canine mammary mixed tumours. PMID:23193497

  16. Pitfalls in colour photography of choroidal tumours

    PubMed Central

    Schalenbourg, A; Zografos, L

    2013-01-01

    Colour imaging of fundus tumours has been transformed by the development of digital and confocal scanning laser photography. These advances provide numerous benefits, such as panoramic images, increased contrast, non-contact wide-angle imaging, non-mydriatic photography, and simultaneous angiography. False tumour colour representation can, however, cause serious diagnostic errors. Large choroidal tumours can be totally invisible on angiography. Pseudogrowth can occur because of artefacts caused by different methods of fundus illumination, movement of reference blood vessels, and flattening of Bruch's membrane and sclera when tumour regression occurs. Awareness of these pitfalls should prevent the clinician from misdiagnosing tumours and wrongfully concluding that a tumour has grown. PMID:23238442

  17. Arrowhead approach for malignancies in the lower hemisphere of the breast

    PubMed Central

    2016-01-01

    Breast conservation treatment (BCT) is the preferred modality of treatment for early breast cancer. However, a moderate proportion of women will develop deformity and those with tumours in the lower hemisphere of the breast pose a particular challenge. Here, a technique is described which allows acceptable cosmetic outcome in women with small or medium-sized breasts without the use of therapeutic mammoplasty or volume replacement with flaps. PMID:26855913

  18. Arrowhead approach for malignancies in the lower hemisphere of the breast.

    PubMed

    Tan, Mona Poh-Choo

    2016-02-01

    Breast conservation treatment (BCT) is the preferred modality of treatment for early breast cancer. However, a moderate proportion of women will develop deformity and those with tumours in the lower hemisphere of the breast pose a particular challenge. Here, a technique is described which allows acceptable cosmetic outcome in women with small or medium-sized breasts without the use of therapeutic mammoplasty or volume replacement with flaps. PMID:26855913

  19. Dense Breasts

    MedlinePlus

    ... woman’s breasts. It is most commonly determined using mammography, a diagnostic test that uses low dose x- ... woman’s breasts, which is most commonly determined through mammography. The breast is made up of glandular, connective, ...

  20. Breast lump

    MedlinePlus

    Breast mass ... males and females of all ages have normal breast tissue. This tissue responds to hormone changes. Because of this, lumps can come and go. Breast lumps may appear at any age: Both male ...

  1. Breast Cancer

    MedlinePlus

    Breast cancer affects one in eight women during their lives. Breast cancer kills more women in the United States ... cancer. No one knows why some women get breast cancer, but there are a number of risk ...

  2. Breast Diseases

    MedlinePlus

    Most women experience breast changes at some time. Your age, hormone levels, and medicines you take may cause lumps, bumps, and discharges (fluids that are not breast milk). If you have a breast lump, pain, ...

  3. Breast ultrasound

    MedlinePlus

    ... JavaScript. Breast ultrasound is a test that uses sound waves to examine the breasts. How the Test is ... to the left or right. The device sends sound waves to the breast tissue. The sound waves help ...

  4. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

    PubMed Central

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko

    2016-01-01

    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  5. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan.

    PubMed

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-Ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko

    2016-01-01

    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal-regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  6. Remodelling of extracellular matrix due to solid stress accumulation during tumour growth

    PubMed Central

    Pirentis, Athanassios P.; Polydorou, Christiana; Papageorgis, Panagiotis; Voutouri, Chrysovalantis; Mpekris, Fotios; Stylianopoulos, Triantafyllos

    2015-01-01

    Solid stresses emerge as the expanding tumour displaces and deforms the surrounding normal tissue, and also as a result of intratumoural component interplay. Among other things, solid stresses are known to induce extensive extracellular matrix synthesis and reorganization. In the present study, we developed a mathematical model of tumour growth that distinguishes the contribution to stress generation by collagenous and non-collagenous tumour structural components, and also investigates collagen fibre remodelling exclusively due to solid stress. To this end, we initially conducted in vivo experiments using an orthotopic mouse model for breast cancer to monitor primary tumour growth and derive the mechanical properties of the tumour. Subsequently, we fitted the mathematical model to experimental data to determine values of the model parameters. According to the model, intratumoural solid stress is compressive, whereas extratumoural stress in the tumour vicinity is compressive in the radial direction and tensile in the periphery. Furthermore, collagen fibres engaged in stress generation only in the peritumoural region, and not in the interior where they were slackened due to the compressive stress state. Peritumoural fibres were driven away from the radial direction, tended to realign tangent to the tumour-host interface, and were also significantly stretched by tensile circumferential stresses. By means of this remodelling, the model predicts that the tumour is enveloped by a progressively thickening capsule of collagen fibres. This prediction is consistent with long-standing observations of tumour encapsulation and histologic sections that we performed, and it further corroborates the expansive growth hypothesis for the capsule formation. PMID:26194953

  7. Anti-tumour activity of oncolytic Western Reserve vaccinia viruses in canine tumour cell lines, xenografts, and fresh tumour biopsies.

    PubMed

    Autio, K; Knuuttila, A; Kipar, A; Ahonen, M; Parviainen, S; Diaconu, I; Kanerva, A; Hakonen, T; Vähä-Koskela, M; Hemminki, A

    2014-10-10

    Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours. PMID:25302859

  8. 2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography after breast conserving surgery: Correlation with molecular markers of breast cancer

    PubMed Central

    Ozguven, Salih; Inanir, Sabahat; Turoglu, Halil Turgut; Erdil, Tanju Yusuf; Ugurlu, Mustafa Umit; Gulluoglu, Bahadir

    2016-01-01

    Aim: To investigate the role of 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) early after breast-conserving surgery (BCS) in patients with breast cancer (BC) and whether we can determine which molecular biomarkers of breast carcinoma put the patients at risk. Materials and Methods: This retrospective study involved 88 patients with histologically proven T1 or T2 BC, who were treated with BCS and underwent 18F-FDG PET/CT study. The correlation between biological markers (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 [HER2], and Ki-67) of the primary tumor and 18F-FDG PET/CT findings was analyzed. Results: 18F-FDG PET/CT demonstrated the presence of BC disease (locoregional disease [LRD], distant metastases, or contralateral BC) in 26 of 88 patients (29.5%). Regarding immunohistochemical profiles, BC expressing high levels of Ki-67 were associated with an increased percentage of LRD, which was the major recurrence pattern on 18F-FDG PET/CT. Although the BC disease was observed more commonly in patients with HER2 positivity compared to those of HER2 negative, the difference did not reach statistical significance. The patients with T2 tumor or a higher histopathological grade had a higher percentage of BC disease. Conclusions: This study demonstrated that patients with early stage BC treated with BCS have a remarkable risk of the presence of BC even early after surgery, and there was a clinically important relationship between 18F-FDG PET/CT findings and biological markers of BC. These findings suggest that high-risk molecular biomarkers (Ki-67, HER2) can be taken into account in the decision-making the process for both preoperative imaging and planning of the surgical approach. PMID:27385883

  9. Tailored nanoparticles for tumour therapy.

    PubMed

    Jiang, Pei-Shin; Drake, Philip; Cho, Hui-Ju; Kao, Chao-Hung; Lee, Kun-Feng; Kuo, Chien-Hung; Lin, Xi-Zhang; Lin, Yuh-Jiuan

    2012-06-01

    Gd doped iron-oxide nanoparticles were developed for use in tumour therapy via magnetic fluid hyperthermia (MFH). The effect of the Gd3+ dopant on the particle size and magnetic properties was investigated. The final particle composition varied from Gd0.01Fe2.99O4 to Gd0.04Fe2.96O4 as determined by Inductively coupled plasma atomic emission spectroscopy (ICP-AES). TEM image analysis showed the average magnetic core diameters to be 12 nm and 33 nm for the lowest and highest Gd levels respectively. The specific power adsorption rate (SAR) determined with a field strength of 246 Oe and 52 kHz had a maximum of 38Wg(-1) [Fe] for the Gd0.03Fe2.97O4 sample. This value is about 4 times higher than the reported SAR values for Fe3O4. The potential for in vivo tumour therapy was investigated using a mouse model. The mouse models treated with Gd0.02Fe2.98O4 displayed much slower tumour growth after the first treatment cycle, the tumour had increased its mass by 25% after 7 days post treatment compared to a 79% mass increase over the same period for those models treated with standard iron-oxide or saline solution. After a second treatment cycle the mouse treated with Gd0.02Fe2.98O4 showed complete tumour regression with no tumour found for at least 5 days post treatment. PMID:22905580

  10. 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

  11. Brown tumour of the jaw

    PubMed Central

    Nair, Preeti P; Gharote, Harshkant P; Thomas, Shaji; R, Guruprasad; Singh, Neha

    2011-01-01

    Brown tumours are classic bony lesions that arise as a result of the effect of parathyroid hormone on bone tissue in some patients with hyperparathyroidism. They are erosive bony lesions caused by rapid osteolysis and peritrabecular fibrosis, resulting in a local destructive phenomenon. Facial skeleton is involved in about 2% of all cases of which the mandible is frequently affected. A 35-year-old female who was diagnosed with osteomalacia and brown tumour in posterior mandible as the sign of secondary hyperparathyroidism secondary to vitamin D deficiency is presented. PMID:22669885

  12. A rare urinary bladder tumour

    PubMed Central

    Haddad-Lacle, Judella Edwina Maria; Haddad, Charles Joseph; Villas, Bruce

    2014-01-01

    This case report describes a 54-year-old man who presented to his primary care physician with low back pain. During his workup, an incidental finding of a bladder mass was diagnosed. He underwent transurethral resection of the bladder tumour and the resulting pathology was consistent with extra nodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Presentation of MALT lymphoma in the urinary bladder is rare. This malignancy is more commonly found in the stomach. The prognosis for this rare tumour is excellent. Our patient showed no sign of recurrence with transurethral excision and radiation alone. PMID:24835803

  13. Second non-breast primary cancer following adjuvant therapy for early breast cancer: A report from the International Breast Cancer Study Group

    PubMed Central

    Gianni, Lorenzo; Gelber, Shari; Ravaioli, Alberto; Price, Karen N.; Panzini, Ilaria; Fantini, Manuela; Castiglione-Gertsch, Monica; Pagani, Olivia; Simoncini, Edda; Gelber, Richard D.; Coates, Alan S.; Goldhirsch, Aron

    2009-01-01

    The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for five years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of eight years and endocrine therapy (toremifene or tamoxifen) versus chemoendocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemoendocrine therapy compared with endocrine therapy. PMID:19062268

  14. PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers

    PubMed Central

    Stanley, Jennifer; Klepczyk, Lisa; Keene, Kimberly; Wei, Shi; Li, Yufeng; Forero, Andres; Grizzle, William; Wielgos, Monica; Brazelton, Jason; LoBuglio, Albert F.; Yang, Eddy S.

    2015-01-01

    Purpose Previous studies have shown that basal breast cancers, which may have an inherent “BRCAness” phenotype and sensitivity to inhibitors of poly (ADP-Ribose) polymerase (PARP), express elevated levels of PARP1. Our lab recently reported that HER2+ breast cancers also exhibit sensitivity to PARP inhibitors (PARPi) by attenuating the NF-kB pathway. In this study, we assessed PARP1 and phospho-p65, a marker of activated NF-kB levels in human breast cancer tissues. Methods PARP1 and PARP2 copy number, mRNA, and protein expression was assessed by interrogating the PAM-50 defined breast cancer patient set from the TCGA using the cBioPortal. PARP1 and phospho-p65 immunohistochemistry and correlation to clinical parameters was conducted using 307 primary breast cancer specimens (132 basal, 82 luminal, 93 HER2+) through univariate and multivariate analyses. Results In the PAM50 breast cancer data set, PARP1 and 2 expression was altered in 24/58 (41%) HER2+, 32/81 (40%) basal, and 75/324 (23%) luminal A/B breast cancer patients. This correlated with a statistically significant increase in PARP1 protein levels in HER2+ and basal but not luminal breast cancers (p=0.003, p=0.027, p=0.289, respectively). No change in PARP2 protein level was observed. Interestingly, using breast cancer specimens from 307 patients, HER2 positivity correlated with elevated PARP1 expression (p<0.0001) and was three times more likely than HER2 negative breast cancers to exhibit high PARP1 levels. No significant differences were noted between race, ER status, or PR status for PARP1 expression. Additionally, we found a significant correlation between HER2 status and phospho-p65 expression (p<0.0001). Lastly, a direct correlation between PARP1 and phospho-p65 (p<0.0001) was noted. Conclusions These results indicate a potential connection between HER2, PARP1, and phospho-p65. Furthermore, these data suggest that the PARPi sensitivity we previously observed in HER2+ breast cancer cells may be due

  15. Tumour spectrum in the FAMMM syndrome.

    PubMed Central

    Lynch, H. T.; Fusaro, R. M.; Pester, J.; Oosterhuis, J. A.; Went, L. N.; Rumke, P.; Neering, H.; Lynch, J. F.

    1981-01-01

    The Familial Atypical Multiple Mole-Melanoma Syndrome (FAMMM) is characterized by an autosomal dominantly inherited susceptibility to multiple atypical naevi. Patients with this hereditary phenotype show a strong susceptibility to cutaneous malignant melanoma (CMM). Our investigation of an extended Dutch kindred showing the FAMMM phenotype revealed a proband with bilateral intraocular malignant melanoma (IOM) and multiple CMM. The family revealed an array of tumours which included carcinoma of the lung, skin, larynx, and breast in addition to CMM and IOM, which were transmitted vertically through 3 generations. There was male-to-male transmission, and the number of affected males and females was about the same, which was consistent with an autosomal dominant inheritance. Thus the FAMMM syndrome not only indicates a potential for CMM, but a susceptibility to other systemic cancers as well. These observations, though limited to a single kindred, merit a painstaking evaluation of cancer of all anatomical sites in other kindreds showing the FAMMM syndrome. Such studies could yield clues to cancer aetiology, pathogenesis, and control. Images Fig. 2 Fig. 3 Fig. 4 PMID:7295511

  16. Significance of immunohistochemistry in breast cancer

    PubMed Central

    Zaha, Dana Carmen

    2014-01-01

    The biological characteristics of the tumour are used to estimate prognosis and select appropriate systemic therapy for patients with (breast) cancer. The advent of molecular technology has incorporated new biomarkers along with immunohistochemical and serum biomarkers. Immunohistochemical markers are often used to guide treatment decisions, to classify breast cancer into subtypes that are biologically distinct and behave differently, and both as prognostic and predictive factors. Steroid hormone receptors, markers of tumour proliferation, and factors involved in angiogenesis and apoptosis are of scientific interest. In this review we will provide information on the immunohistochemical markers used in the management of breast cancer patients using available data from the literature. We consider the utility of established immunohistochemical markers, and discuss the challenges involved in integrating novel molecular markers into clinical practice. PMID:25114853

  17. Frequent expression of PD-L1 on circulating breast cancer cells.

    PubMed

    Mazel, Martine; Jacot, William; Pantel, Klaus; Bartkowiak, Kai; Topart, Delphine; Cayrefourcq, Laure; Rossille, Delphine; Maudelonde, Thierry; Fest, Thierry; Alix-Panabières, Catherine

    2015-11-01

    Immune checkpoint regulators such as PD-L1 have become exciting new therapeutic targets leading to long lasting remissions in patients with advanced malignancies. However, in view of the remarkable costs and the toxicity profiles of these therapies, predictive biomarkers able to discriminate responders from non-responders are urgently needed. In the present paper, we provide evidence that PD-L1 is frequently expressed on metastatic cells circulating in the blood of hormone receptor-positive, HER2-negative breast cancer patients. We performed western blot, flow cytometry and immunocytochemical analyses to demonstrate the specificity of the PDL1 antibody used in our study and established immunoscores for PDL1 expression on single tumor cells. We then selected sixteen patients with circulating tumor cells (CTCs) using the CellSearch(®) system and found PD-L1((+)) CTCs in 11 patients (68.8%). The fraction of PD-L1((+)) CTCs varied from 0.2 to 100% in individual patients. This is the first report demonstrating the expression of PD-L1 on CTCs. The established CTC/PD-L1 assay can be used for liquid biopsy in future clinical trials for stratification and monitoring of cancer patients undergoing immune checkpoint blockade. PMID:26093818

  18. Estrogen Receptor Expression Is Associated with DNA Repair Capacity in Breast Cancer

    PubMed Central

    Matta, Jaime; Morales, Luisa; Ortiz, Carmen; Adams, Damian; Vargas, Wanda; Casbas, Patricia; Dutil, Julie; Echenique, Miguel; Suárez, Erick

    2016-01-01

    Estrogen-receptor-positive (ER+) tumors employ complex signaling that engages in crosstalk with multiple pathways through genomic and non-genomic regulation. A greater understanding of these pathways is important for developing improved biomarkers that can better determine treatment choices, risk of recurrence and cancer progression. Deficiencies in DNA repair capacity (DRC) is a hallmark of breast cancer (BC); therefore, in this work we tested whether ER signaling influences DRC. We analyzed the association between ER positivity (% receptor activation) and DRC in 270 BC patients, then further stratified our analysis by HER2 receptor status. Our results show that among HER2 negative, the likelihood of having low DRC values among ER- women is 1.92 (95% CI: 1.03, 3.57) times the likelihood of having low DRC values among ER+ women, even adjusting for different potential confounders (p<0.05); however, a contrary pattern was observed among HER2 positives women. In conclusion, there is an association between DRC levels and ER status, and this association is modified by HER2 receptor status. Adding a DNA repair capacity test to hormone receptor testing may provide new information on defective DNA repair phenotypes, which could better stratify BC patients who have ER+ tumors. ER+/HER2- tumors are heterogeneous, incompletely defined, and clinically challenging to treat; the addition of a DRC test could better characterize and classify these patients as well as help clinicians select optimal therapies, which could improve outcomes and reduce recurrences. PMID:27032101

  19. Tumours of the soft (mesenchymal) tissues.

    PubMed

    Weiss, E

    1974-01-01

    This is a classification of tumours of fibrous tissue, fat, muscle, blood and lymph vessels, and mast cells, irrespective of the region of the body in which they arise. Tumours of fibrous tissue are divided into fibroma, fibrosarcoma (including "canine haemangiopericytoma"), other sarcomas, equine sarcoid, and various tumour-like lesions. The histological appearance of the tumours is described and illustrated with photographs. PMID:4371740

  20. Of humans and canines: Immunohistochemical analysis of PCNA, Bcl-2, p53, cytokeratin and ER in mammary tumours.

    PubMed

    Kumaraguruparan, R; Prathiba, D; Nagini, S

    2006-10-01

    Mammary tumours are the most common neoplasms in humans and canines. Human and canine mammary tumours share several important epidemiological, clinicopathological and biochemical features. Development of mammary tumours involves accumulation of mutant cells caused by excessive proliferation and insufficient apoptosis or dysregulation of cellular differentiation. The present study was therefore designed to investigate the expression of proliferation, differentiation, and apoptosis associated proteins together with expression of estrogen receptors (ER) in both human and canine mammary tumours. Thirty breast cancer patients categorized as pre- and postmenopausal, and 30 mammary gland tumours obtained from bitches were included in this study. The expression of proliferating cell nuclear antigen (PCNA), Bcl-2, p53, cytokeratin and ER in tumour tissues and adjacent tissues were investigated using immunohistochemical staining. While the expression of PCNA, Bcl-2, p53 and ER was significantly increased, expression of cytokeratin was significantly lower in both human as well as canine mammary tumours compared to corresponding adjacent tissues. The magnitude of the changes was however more pronounced in premenopausal patients compared to postmenopausal patients. The changes in proliferation, apoptosis and differentiation associated proteins in human and canine mammary tumours validate use of the canine model to understand the molecular mechanisms of mammary carcinogenesis. PMID:16740286

  1. Canine Mammary Tumours Are Affected by Frequent Copy Number Aberrations, including Amplification of MYC and Loss of PTEN

    PubMed Central

    Borge, Kaja S.; Nord, Silje; Van Loo, Peter; Lingjærde, Ole C.; Gunnes, Gjermund; Alnæs, Grethe I. G.; Solvang, Hiroko K.; Lüders, Torben; Kristensen, Vessela N.; Børresen-Dale, Anne-Lise; Lingaas, Frode

    2015-01-01

    Background Copy number aberrations frequently occur during the development of many cancers. Such events affect dosage of involved genes and may cause further genomic instability and progression of cancer. In this survey, canine SNP microarrays were used to study 117 canine mammary tumours from 69 dogs. Results We found a high occurrence of copy number aberrations in canine mammary tumours, losses being more frequent than gains. Increased frequency of aberrations and loss of heterozygosity were positively correlated with increased malignancy in terms of histopathological diagnosis. One of the most highly recurrently amplified regions harbored the MYC gene. PTEN was located to a frequently lost region and also homozygously deleted in five tumours. Thus, deregulation of these genes due to copy number aberrations appears to be an important event in canine mammary tumour development. Other potential contributors to canine mammary tumour pathogenesis are COL9A3, INPP5A, CYP2E1 and RB1. The present study also shows that a more detailed analysis of chromosomal aberrations associated with histopathological parameters may aid in identifying specific genes associated with canine mammary tumour progression. Conclusions The high frequency of copy number aberrations is a prominent feature of canine mammary tumours as seen in other canine and human cancers. Our findings share several features with corresponding studies in human breast tumours and strengthen the dog as a suitable model organism for this disease. PMID:25955013

  2. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

    PubMed Central

    Chauhan, Vikash P.; Martin, John D.; Liu, Hao; Lacorre, Delphine A.; Jain, Saloni R.; Kozin, Sergey V.; Stylianopoulos, Triantafyllos; Mousa, Ahmed S.; Han, Xiaoxing; Adstamongkonkul, Pichet; Popović, Zoran; Huang, Peigen; Bawendi, Moungi G.; Boucher, Yves; Jain, Rakesh K.

    2013-01-01

    Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics. PMID:24084631

  3. Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation.

    PubMed

    Welte, Thomas; Kim, Ik Sun; Tian, Lin; Gao, Xia; Wang, Hai; Li, June; Holdman, Xue B; Herschkowitz, Jason I; Pond, Adam; Xie, Guorui; Kurley, Sarah; Nguyen, Tuan; Liao, Lan; Dobrolecki, Lacey E; Pang, Lan; Mo, Qianxing; Edwards, Dean P; Huang, Shixia; Xin, Li; Xu, Jianming; Li, Yi; Lewis, Michael T; Wang, Tian; Westbrook, Thomas F; Rosen, Jeffrey M; Zhang, Xiang H-F

    2016-06-01

    Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment. PMID:27183469

  4. Brain tumour mortality in immigrants.

    PubMed

    Neutel, C I; Quinn, A; Brancker, A

    1989-03-01

    All Canadian deaths due to malignant brain tumour for the years 1970-73 were identified and analysed for country of birth. The years 1970-73 were chosen since in later years country of birth was no longer available for each death. The brain tumour population consisted of 1551 male and 1058 female deaths and matched controls were chosen from deaths due to other causes. Americans who died of brain tumour in Canada had a standardized mortality ratio (SMR) of 1.0 compared to their fellow Americans in the USA. Italian, German, Dutch and British immigrants had SMR between 1.5 and 2.6 compared to rates in their home countries and between 1.24 and 2.09 when compared to Canadian rates. A series of graphs shows the increased risk for male immigrants quite dramatically, and indicates that for females the increases were less pronounced. Further analysis showed that the excess risk is confined to those who were born in Western Europe while their Canadian-born children experienced the same rates as all Canadians. Based on the limited information available, occupation could not be shown to play a role in establishing risk. An attempt was made to pinpoint the years of immigration which showed the greatest risk. It is concluded that the determination of risk of brain tumour has a strong environmental component. The possibilities for identification of this component are discussed. PMID:2722385

  5. Multiple cilia suppress tumour formation.

    PubMed

    Eberhart, Charles

    2016-04-01

    Primary cilia are cellular structures that have important functions in development and disease. The suppression of multiciliate differentiation of choroid plexus precursors, and maintenance of a single primary cilium by Notch1, is now shown to be involved in choroid plexus tumour formation. PMID:27027488

  6. Tumour vasculature--a potential therapeutic target.

    PubMed Central

    Baillie, C. T.; Winslet, M. C.; Bradley, N. J.

    1995-01-01

    The tumour vasculature is vital for the establishment, growth and metastasis of solid tumours. Its physiological properties limit the effectiveness of conventional anti-cancer strategies. Therapeutic approaches directed at the tumour vasculature are reviewed, suggesting the potential of anti-angiogenesis and the targeting of vascular proliferation antigens as cancer treatments. PMID:7543770

  7. Basal Subtype of Invasive Breast Cancer Is Associated With a Higher Risk of True Recurrence After Conventional Breast-Conserving Therapy

    SciTech Connect

    Hattangadi-Gluth, Jona A.; Wo, Jennifer Y.; Nguyen, Paul L.; Sreedhara, Meera; Freer, Phoebe E.; Georgian-Smith, Dianne; Bellon, Jennifer R.; Wong, Julia S.; Harris, Jay R.

    2012-03-01

    Purpose: To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1-T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT). Methods and Materials: From Jan 1998 to Dec 2003, 1,223 women with pT1-T2N0-3 IBC were treated with BCT (lumpectomy plus whole-breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic cancer subtypes were approximated by determining estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor-2-positive (HER-2+) expression, classified as luminal A (ER+ or PR+ and HER-2 negative [HER-2-]), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER- and PR- and HER-2+), and basal (ER- and PR- and HER-2- ) subtypes. Imaging, pathology, and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within 3 cm of the primary tumor. All others were defined as ELR. Results: At a median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence of 1.6%), including 15 TR and 9 ELR patients. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR than luminal B (1.2%) and luminal A (0.2%) subtypes (p < 0.0001). On multivariate analysis, basal subtype (hazard ratio [HR], 4.8, p = 0.01), younger age at diagnosis (HR, 0.97; p = 0.05), and increasing tumor size (HR, 2.1; p = 0.04) were independent predictors of TR. Only younger age (HR, 0.95; p = 0.01) significantly predicted for ELR. Conclusions: Basal and HER-2 subtypes are significantly associated with higher rates of TR among women with pT1-T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal

  8. Management of early breast cancer in older women: from screening to treatment

    PubMed Central

    Elomrani, Fadwa; Zine, Maryem; Afif, Mohamed; L’annaz, Saad; Ouziane, Imane; Mrabti, Hind; Errihani, Hassan

    2015-01-01

    Background Breast cancer is a common condition. It is a leading cause of death among women, and its incidence increases with age. Aging of the population and improvement of the quality of life of elders make it a major public health issue. We reviewed the literature to try to determine the management of breast cancer in older women. Methods We conducted a narrative review by literature searches using key words “breast cancer”, “elderly and older”, and “women” in Pubmed, Scopus, and Google Scholar. The aim of this review is to summarize the management of early breast cancer in older women by discussing the controversies of screening in older women. Then, we try to define the optimal strategy for these women, either surgery alone or primary endocrine therapy. We also discuss the indications of lymph node dissection, and we evaluate the benefit of adjuvant radiotherapy, chemotherapy, and the anti HER2 treatment for these women. Results More than 50% of patients with breast cancer are 65 years or older, and around 30% are more than 70 years old. Most randomized trials did not include older women. Hence, the treatment of breast cancer in older patients is based on the management provided to younger women. Regardless of age, the treatment must aim for the best efficiency. Advanced age in itself should not be a limitation to treatment. There are no standard guidelines set for elderly patients. Surgical treatment for older patients evolved to avoid mastectomy, and conservative mammary surgery was proposed, similar to that used in younger patients. The proportion of elderly patients receiving adjuvant radiotherapy is increasing. The role of adjuvant radiotherapy in older patients with breast cancer was analyzed. Adjuvant chemotherapy is beneficial to women with hormone receptor-negative tumors. In those with hormone receptor-positive tumors, adjuvant chemotherapy in association to trastuzumab is beneficial for HER2-positive tumors, and for women with HER2

  9. Breast Cancer

    MedlinePlus

    ... are here Home > Types of Cancer > Breast Cancer Breast Cancer This is Cancer.Net’s Guide to Breast Cancer. Use the menu below to choose the Overview/ ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer Overview Statistics Medical Illustrations Risk Factors Screening Symptoms ...

  10. Breast Cancer

    MedlinePlus

    ... I found something when I did my breast self-exam. What should I do now? How often should I have mammograms? I have breast cancer. What are my treatment options? How often should I do breast self-exams? I have breast cancer. Is my daughter ...

  11. Transcription profiles of non-immortalized breast cancer cell lines

    PubMed Central

    Fernandez-Cobo, Mariana; Holland, James F; Pogo, Beatriz GT

    2006-01-01

    Background Searches for differentially expressed genes in tumours have made extensive use of array technology. Most samples have been obtained from tumour biopsies or from established tumour-derived cell lines. Here we compare cultures of non-immortalized breast cancer cells, normal non-immortalized breast cells and immortalized normal and breast cancer cells to identify which elements of a defined set of well-known cancer-related genes are differentially expressed. Methods Cultures of cells from pleural effusions or ascitic fluids from breast cancer patients (MSSMs) were used in addition to commercially-available normal breast epithelial cells (HMECs), established breast cancer cell lines (T-est) and established normal breast cells (N-est). The Atlas Human Cancer 1.2 cDNA expression array was employed. The data obtained were analysed using widely-available statistical and clustering software and further validated through real-time PCR. Results According to Significance Analysis of Microarray (SAM) and AtlasImage software, 48 genes differed at least 2-fold in adjusted intensities between HMECs and MSSMs (p < 0.01). Some of these genes have already been directly linked with breast cancer, metastasis and malignant progression, whilst others encode receptors linked to signal transduction pathways or are otherwise related to cell proliferation. Fifty genes showed at least a 2.5-fold difference between MSSMs and T-est cells according to AtlasImage, 2-fold according to SAM. Most of these classified as genes related to metabolism and cell communication. Conclusion The expression profiles of 1176 genes were determined in finite life-span cultures of metastatic breast cancer cells and of normal breast cells. Significant differences were detected between the finite life-span breast cancer cell cultures and the established breast cancer cell lines. These data suggest caution in extrapolating information from established lines for application to clinical cancer research. PMID

  12. Denosumab in breast cancer treatment.

    PubMed

    Drooger, Jan C; van der Padt, Annemieke; Sleijfer, Stefan; Jager, Agnes

    2013-10-01

    The bone is the most common site to which breast cancer metastasises. Recently, denosumab, a fully human monoclonal antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL) has been developed as a new targeted bone therapy. In a large randomized phase III study with a head-to-head comparison of denosumab to zoledronic acid in patients with bone metastases of breast cancer, denosumab significantly delayed the time to first skeletal related event. In the adjuvant setting denosumab significantly increased bone mineral density compared to placebo in a phase III study in patients treated with aromatase inhibitors. Preclinical data suggest an effect of denosumab on tumour growth and even on carcinogenesis. This review describes the current indications for denosumab in the various settings of breast cancer treatment, with special attention for efficacy, short and long term toxicity and other relevant issues for clinical practice. Furthermore possible and necessary future research questions are proposed. PMID:23545361

  13. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer

    PubMed Central

    Wolff, Antonio C.; Hammond, M. Elizabeth H.; Hicks, David G.; Dowsett, Mitch; McShane, Lisa M.; Allison, Kimberly H.; Allred, Donald C.; Bartlett, John M.S.; Bilous, Michael; Fitzgibbons, Patrick; Hanna, Wedad; Jenkins, Robert B.; Mangu, Pamela B.; Paik, Soonmyung; Perez, Edith A.; Press, Michael F.; Spears, Patricia A.; Vance, Gail H.; Viale, Giuseppe; Hayes, Daniel F.

    2014-01-01

    Purpose To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. Methods ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. Results The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. Recommendations The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. PMID:24099077

  14. Animal models of tumour-associated epilepsy.

    PubMed

    Kirschstein, Timo; Köhling, Rüdiger

    2016-02-15

    Brain tumours cause a sizeable proportion of epilepsies in adulthood, and actually can be etiologically responsible also for childhood epilepsies. Conversely, seizures are often first clinical signs of a brain tumour. Nevertheless, several issues of brain-tumour associated seizures and epilepsies are far from understood, or clarified regarding clinical consensus. These include both the specific mechanisms of epileptogenesis related to different tumour types, the possible relationship between malignancy and seizure emergence, the interaction between tumour mass and surrounding neuronal networks, and - not least - the best treatment options depending on different tumour types. To investigate these issues, experimental models of tumour-induced epilepsies are necessary. This review concentrates on the description of currently used models, focusing on methodological aspects. It highlights advantages and shortcomings of these models, and identifies future experimental challenges. PMID:26092434

  15. Perfusion analyses in advanced breast carcinoma during hyperthermia.

    PubMed

    Lagendijk, J J; Hofman, P; Schipper, J

    1988-01-01

    Blood flow in tumours and healthy tissue determines the ability of obtaining satisfactory temperature distributions in clinical hyperthermia, as well as the success of hyperthermia and radiation treatment. During the hyperthermia treatment, diagnostic data related to tissue blood flow can be determined by analysing the relationship between the amount of power absorbed in the tissue and the resulting temperature rise. The interpretation of the perfusion data (PERF) is highly complicated by the lack of an adequate theory to describe the heat transport in vascularized tissues. In vascularized breast tissues about 10 times as much power is needed to maintain therapeutic temperatures as is necessary in a stationary breast phantom. This large difference in maintenance power levels indicates the extreme importance of blood flow in tissue heat transport. PERF has been determined in 23 patients with advanced breast tumours. In this series (a) perfusion typically did not change during the stationary part of the individual hyperthermic sessions, (b) minimum tumour PERF was not related to tumour volume, and (c) there was no relation between tumour PERF and the ability to heat tumours. PERF can both increase and decrease after successful hyperthermia. PMID:3292667

  16. Stratification and therapeutic potential of PML in metastatic breast cancer

    PubMed Central

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D.; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R.; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M.; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H.; Scaltriti, Maurizio; Lawrie, Charles H.; Aransay, Ana M.; Iovanna, Juan L.; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; dM Vivanco, Maria; Matheu, Ander; Gomis, Roger R.; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  17. Stratification and therapeutic potential of PML in metastatic breast cancer.

    PubMed

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H; Scaltriti, Maurizio; Lawrie, Charles H; Aransay, Ana M; Iovanna, Juan L; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; Vivanco, Maria dM; Matheu, Ander; Gomis, Roger R; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  18. Selective anticancer activity of hirsutine against HER2‑positive breast cancer cells by inducing DNA damage.

    PubMed

    Lou, Chenghua; Yokoyama, Satoru; Saiki, Ikuo; Hayakawa, Yoshihiro

    2015-04-01

    Hirsutine is one of the major alkaloids isolated from plants of the Uncaria genus and is known for its cardioprotective, anti‑hypertensive and anti-arrhythmic activities. We recently reported that hirsutine is an anti-metastatic phytochemical by targeting NF-κB activation in a murine breast cancer model. In the present study, we further examined the clinical utility of hirsutine against human breast cancer. Among six distinct human breast cancer cell lines, hirsutine showed strong cytotoxicity against HER2-positive/p53-mutated MDA-MB‑453 and BT474 cell lines. Conversely, HER2-negative/p53 wild‑type MCF-7 and ZR-75-1 cell lines showed resistance against hirsutine-induced cytotoxicity. Hirsutine induced apoptotic cell death in the MDA-MB-453 cells, but not in the MCF-7 cells, through activation of caspases. Furthermore, hirsutine induced the DNA damage response in the MDA-MB-453 cells, but not in the MCF-7 cells, as highlighted by the upregulation of γH2AX expression. Along with the induction of the DNA damage response, the suppression of HER2, NF-κB and Akt pathways and the activation of the p38 MAPK pathway in the MDA-MB-453 cells were observed. Considering that there was no difference between MDA-MB-453 and MCF-7 cells in regards to irinotecan‑induced DNA damage response, our present results indicate the selective anticancer activity of hirsutine in HER2-positive breast cancer by inducing a DNA damage response. PMID:25672479

  19. Non-Pegylated Liposomal Doxorubicin-Cyclophosphamide in Sequential Regimens with Taxanes as Neoadjuvant Chemotherapy in Breast Cancer Patients

    PubMed Central

    Vici, Patrizia; Pizzuti, Laura; Gamucci, Teresa; Sergi, Domenico; Conti, Francesca; Zampa, Germano; Del Medico, Pietro; De Vita, Roy; Pozzi, Marcello; Botti, Claudio; Di Filippo, Simona; Tomao, Federica; Sperduti, Isabella; Di Lauro, Luigi

    2014-01-01

    Purpose: Chemotherapy regimens containing anthracyclines and taxanes represent the landmark of neoadjuvant systemic therapy of breast cancer. In advanced breast cancer patients liposomal anthracyclines (LA) have shown similar efficacy and less cardiac toxicity when compared to conventional anthracyclines. We performed this retrospective analysis in order to evaluate the efficacy and tolerability of neoadjuvant regimens including LA outside of clinical trials in routine clinical practice. Methods: Fifty operable or locally advanced, HER2 negative, breast cancer patients were retrospectively identified in 5 Italian cancer centres. Nineteen patients had received 4 cycles of non-pegylated liposomal doxorubicin (NPLD) and cyclophosphamide, followed by 4 cycles of docetaxel, every 3 weeks. In 25 patients the reverse sequence was employed, and a third subgroup of 6 patients received 4 cycles of NPLD/cyclophosphamide every 3 weeks followed by 4 cycles of weekly carboplatin and paclitaxel. Results: We observed 10 pathological complete responses (pCR) (20.0%, 95%CI, 9% to 31%), and 35 (70%, 95%CI, 57.3% to 82.7%) partial responses (pPR), whereas no patients progressed onto therapy. In the small subset of triple negative tumors the pCR rate was 37.5%, and in tumors expressing ER and/or PgR it was 16.7%. A pCR rate of 26.5% was observed in tumors with high Ki-67, whereas in tumors with low Ki-67 only one (6.2%) pCR was observed (p=0.14). Treatments were well tolerated. The most common toxicities were myelosuppression and palmar-plantar erytrodysesthesia; 4 asymptomatic and transient LVEF decrease have been recorded, without any case of clinical cardiotoxicity. Conclusions: NPLD-cyclophosphamide and taxanes sequential regimens were proven effective and well tolerated in breast cancer patients with contra-indication to conventional anthracyclines undergoing neoadjuvant chemotherapy, even outside of clinical trials in everyday clinical practice. PMID:24847380

  20. The Primary Implantation of Human Tumours to the Hamster Cheek Pouch

    PubMed Central

    Williams, Dorothy E.; Evans, D. M. D.; Blamey, R. W.

    1971-01-01

    The hamster cheek pouch is an immunologically privileged site. The present study is of simple implantation of human tumours direct from operative specimen to cheek pouch, in particular to determine whether tumour type influences the rate of successful implant. All implants were studied 10 or 20 days later. The use of cortisone significantly improved the number of implants growing. Carcinomas of the cervix were found to show growth in 55% of implants, in animals conditioned with cortisone. Growth from tumours of the uterine body, or from colorectal carcinomas, occurred in 25-30% of implants. Breast cancer gave poor results. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5 PMID:5144526

  1. The induction of human peripheral blood lymphoid colonies by conditioned media from human tumour cell lines.

    PubMed Central

    Vesole, D H; Moore, G E

    1980-01-01

    Conditioned medium (CM) from 29 human tumour cell lines and 3 malignant pleural fluids were tested for their ability to stimulate lymphoid colony formation in semi-solid agar; 9 of 14 malignant melanomas, 3 of 6 colonic carcinomas, 2 of 5 ovarian carcinomas, 3 of 4 breast carcinomas and 1 of 3 pleural fluids from breast cancer patients contained colony-stimulating activity (CSA) for human peripheral blood lymphoid cells (PBL) in semi-solid agar. Conditioned media also stimulated PBL proliferation in liquid medium; these effects were dose dependent. With the exception of one pleural fluid, extensive dialysis of CM did not significantly increase colony formation; CM from two tumour cell lines demonstrated a significant decrease in the induction of colony formation after dialysis. PMID:6970165

  2. Medical image segmentation to estimate HER2 gene status in breast cancer

    NASA Astrophysics Data System (ADS)

    Palacios-Navarro, Guillermo; Acirón-Pomar, José Manuel; Vilchez-Sorribas, Enrique; Zambrano, Eddie Galarza

    2016-02-01

    This work deals with the estimation of HER2 Gene status in breast tumour images treated with in situ hybridization techniques (ISH). We propose a simple algorithm to obtain the amplification factor of HER2 gene. The obtained results are very close to those obtained by specialists in a manual way. The developed algorithm is based on colour image segmentation and has been included in a software application tool for breast tumour analysis. The developed tool focus on the estimation of the seriousness of tumours, facilitating the work of pathologists and contributing to a better diagnosis.

  3. [Phylloides tumors of the breast. A rare disease picture with a predominantly favorable prognosis].

    PubMed

    Schönbach, F; Fischer, H P

    1986-10-01

    The phyllodes tumours, a group of rare (0.3%) neoplasms of the breast, consisting predominantly of mesenchymal tissue, are presented by an own case. A certain distinction between benign and malignant types can not always be obtained. The tumours are characterized by a high rate of local recurrences, but their prognosis is better than that of breast carcinomas, even in case of malignity. Metastasizing tumours mostly spread by an hematogenic pathway. The therapeutic access is surgical by complete local excision with a margin of security. Other oncological therapies failed to be successful. PMID:3024930

  4. Involvement of chemokine receptors in breast cancer metastasis

    NASA Astrophysics Data System (ADS)

    Müller, Anja; Homey, Bernhard; Soto, Hortensia; Ge, Nianfeng; Catron, Daniel; Buchanan, Matthew E.; McClanahan, Terri; Murphy, Erin; Yuan, Wei; Wagner, Stephan N.; Barrera, Jose Luis; Mohar, Alejandro; Verástegui, Emma; Zlotnik, Albert

    2001-03-01

    Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

  5. [Cystosarcoma phylloides of the breast--2 case reports].

    PubMed

    Böhme, M; Löttge, M; Cuno-Klausenitz, S

    1995-01-01

    Two cases of Cystosarcomata phylloides (C. ph.) in the breast were reported. In the first one after excision of the palpaple tumour mass the histological examination revealed a fibroadenoma with signs of C. ph. in the excision margins. The reported high rate of local recurrence also in cases of benign tumour type and/or in situ remained tumour structures (stromal hyperplasia) gave the reason for a second operation procedure, an enlarged quadrantectomy. In the second case sarcomatic degenerated areas and a high rate of atypical mitotic figures were found (> 20 mitosis/10 HPF). Therefore an ablative surgery was recommended. PMID:7778359

  6. The AURORA initiative for metastatic breast cancer.

    PubMed

    Zardavas, D; Maetens, M; Irrthum, A; Goulioti, T; Engelen, K; Fumagalli, D; Salgado, R; Aftimos, P; Saini, K S; Sotiriou, C; Campbell, P; Dinh, P; von Minckwitz, G; Gelber, R D; Dowsett, M; Di Leo, A; Cameron, D; Baselga, J; Gnant, M; Goldhirsch, A; Norton, L; Piccart, M

    2014-11-11

    Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients. PMID:25225904

  7. The AURORA initiative for metastatic breast cancer

    PubMed Central

    Zardavas, D; Maetens, M; Irrthum, A; Goulioti, T; Engelen, K; Fumagalli, D; Salgado, R; Aftimos, P; Saini, K S; Sotiriou, C; Campbell, P; Dinh, P; von Minckwitz, G; Gelber, R D; Dowsett, M; Di Leo, A; Cameron, D; Baselga, J; Gnant, M; Goldhirsch, A; Norton, L; Piccart, M

    2014-01-01

    Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as ‘exceptional responders' or as ‘rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients. PMID:25225904

  8. Haemangioleiomyomatous tumour of the lung.

    PubMed Central

    Soorae, A S; Bharucha, H

    1980-01-01

    A case of haemangioleiomyomatous tumour of the lung, occurring as a peripheral, solitary nodule in an asymptomatic 54-year-old man is presented. The tumour was well-demarcated and microscopically it was characterised by the presence of vascular spaces with endothelial, pericytic, and, predominantly, smooth muscle proliferation. Islands of cartilage and slit-like spaces lined by bronchial epithelium make this a hamartomatous lesion of a quite distinctive and unusual variety, which does not fit any of the well-recognised patterns of hamartomas previously described. The long-term prognosis after limited excision is considered to be favourable. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:7358861

  9. Comparison of Clinicopathological Features and Treatments between Young (≤40 Years) and Older (>40 Years) Female Breast Cancer Patients in West China: A Retrospective, Epidemiological, Multicenter, Case Only Study.

    PubMed

    Wang, Ke; Ren, Yu; Li, Hongyuan; Zheng, Ke; Jiang, Jun; Zou, Tianning; Ma, Binlin; Li, Hui; Liu, Qilun; Ou, Jianghua; Wang, Ling; Wei, Wei; He, Jianjun; Ren, Guosheng

    2016-01-01

    The incidence of young cases of breast cancer is higher in China compared to the western world. We aimed to explore differences in risk factors, clinicopathological features and treatment modes of young female breast cancer compared to older patients in West China. We collected clinical information from 12,209 female breast cancer patients in West China, including risk factors, clinicopathological features and treatment modes, from January 2010 to December 2012. Chi-square tests and the multivariate logistic regression analysis were applied for statistical analysis. There were 2,682 young (≤40 years) cases and 9,527 older cases at the time of breast cancer diagnosis. Young patients had a greater tumor diameter at diagnosis, and a higher probability of axillary lymph node and distant metastasis (P < 0.05). The progesterone receptor positive expression rate, estrogen receptor/progesterone receptor double positive expression rate, and human epidermal growth factor receptor 2 (HER2) negative expression rate was higher in young patients compared to older patients (P < 0.05). For young patients, the age at menarche was earlier, they had lower marriage rates, fewer pregnancies and births, and a lower breastfeeding rate (P < 0.05). A higher proportion of young patients underwent advanced operations, neoadjuvant and adjuvant chemotherapy, radiotherapy, and endocrine therapy compared to older patients (P < 0.05). We found significant differences in the clinicopathological features, risk factors and treatment modes between young (≤40 years) and older (>40 years) female breast cancer patients in West China. As some of these results differ from those found in the western female population, it is likely that the mechanism of tumorigenesis of young female breast cancer patients in West China may differ from that in western developed countries. Further investigation into the regional differences in breast cancer tumorigenesis is warranted. PMID:27031236

  10. Comparison of Clinicopathological Features and Treatments between Young (≤40 Years) and Older (>40 Years) Female Breast Cancer Patients in West China: A Retrospective, Epidemiological, Multicenter, Case Only Study

    PubMed Central

    Li, Hongyuan; Zheng, Ke; Jiang, Jun; Zou, Tianning; Ma, Binlin; Li, Hui; Liu, Qilun; Ou, Jianghua; Wang, Ling; Wei, Wei; He, Jianjun; Ren, Guosheng

    2016-01-01

    The incidence of young cases of breast cancer is higher in China compared to the western world. We aimed to explore differences in risk factors, clinicopathological features and treatment modes of young female breast cancer compared to older patients in West China. We collected clinical information from 12,209 female breast cancer patients in West China, including risk factors, clinicopathological features and treatment modes, from January 2010 to December 2012. Chi-square tests and the multivariate logistic regression analysis were applied for statistical analysis. There were 2,682 young (≤40 years) cases and 9,527 older cases at the time of breast cancer diagnosis. Young patients had a greater tumor diameter at diagnosis, and a higher probability of axillary lymph node and distant metastasis (P < 0.05). The progesterone receptor positive expression rate, estrogen receptor/progesterone receptor double positive expression rate, and human epidermal growth factor receptor 2 (HER2) negative expression rate was higher in young patients compared to older patients (P < 0.05). For young patients, the age at menarche was earlier, they had lower marriage rates, fewer pregnancies and births, and a lower breastfeeding rate (P < 0.05). A higher proportion of young patients underwent advanced operations, neoadjuvant and adjuvant chemotherapy, radiotherapy, and endocrine therapy compared to older patients (P < 0.05). We found significant differences in the clinicopathological features, risk factors and treatment modes between young (≤40 years) and older (>40 years) female breast cancer patients in West China. As some of these results differ from those found in the western female population, it is likely that the mechanism of tumorigenesis of young female breast cancer patients in West China may differ from that in western developed countries. Further investigation into the regional differences in breast cancer tumorigenesis is warranted. PMID:27031236

  11. [On the possibility to determine genetic identity of the tissues with malignant tumours imbedded in paraffin blocks].

    PubMed

    Pigolkin, Yu I; Dolzhansky, O V; Korostylev, S A; Pal'tseva, E M; Fedorov, D N

    2016-01-01

    The results of analysis of the literature data were used to develop the forensic medical criteria for the assessment of the suitability of paraffin blocks containing the imbedded malignant tumours for the genetic identification of the tissues. The forensic medical criteria and the algorithm for the preliminary characteristic of the material of interest were proposed to avoid the potential errors. It is not recommended to use gastrointestinal carcinomas, breast tumours, and poorly differentiated ovarian tumours. Also unsuitable is the material formerly exposed to radio- and chemotherapeutic agents or paraffin blocks stored during more than 5-7 years. In the doubtful cases, immunohistochemical studies must be carried out to confirm microsatellite instability. Moreover, the tumour genotype and DNA composition from the patients' blood should be confirmed. PMID:27239766

  12. From High-Throughput Microarray-Based Screening to Clinical Application: The Development of a Second Generation Multigene Test for Breast Cancer Prognosis

    PubMed Central

    Brase, Jan C.; Kronenwett, Ralf; Petry, Christoph; Denkert, Carsten; Schmidt, Marcus

    2013-01-01

    Several multigene tests have been developed for breast cancer patients to predict the individual risk of recurrence. Most of the first generation tests rely on proliferation-associated genes and are commonly carried out in central reference laboratories. Here, we describe the development of a second generation multigene assay, the EndoPredict test, a prognostic multigene expression test for estrogen receptor (ER) positive, human epidermal growth factor receptor (HER2) negative (ER+/HER2−) breast cancer patients. The EndoPredict gene signature was initially established in a large high-throughput microarray-based screening study. The key steps for biomarker identification are discussed in detail, in comparison to the establishment of other multigene signatures. After biomarker selection, genes and algorithms were transferred to a diagnostic platform (reverse transcription quantitative PCR (RT-qPCR)) to allow for assaying formalin-fixed, paraffin-embedded (FFPE) samples. A comprehensive analytical validation was performed and a prospective proficiency testing study with seven pathological laboratories finally proved that EndoPredict can be reliably used in the decentralized setting. Three independent large clinical validation studies (n = 2,257) demonstrated that EndoPredict offers independent prognostic information beyond current clinicopathological parameters and clinical guidelines. The review article summarizes several important steps that should be considered for the development process of a second generation multigene test and offers a means for transferring a microarray signature from the research laboratory to clinical practice.

  13. Parotid gland metastasis of a breast cancer.

    PubMed

    Perez-Fidalgo, J A; Chirivella, I; Laforga, J; Colio, J M; Blanes, M D; Baydal, R; Roselló, S; De-la-Morena, E; Lluch, A

    2007-04-01

    Parotid gland metastases from malignant tumors are extremely rare. A 61-year-old woman was diagnosed with an early breast cancer with no expression of oestrogen and progesterone receptors. Five years later the patient presented a tumour in parotid gland. After total parotidectomy, microscopic analysis of the gland demonstrated an invasive duct carcinoma (IDC) with positive expression of oestrogen receptor. The patient was treated with chemotherapy followed by complementary local radiotherapy. Diagnosis of a metastasic tumour in parotid gland poses a challenge. In our case an immunohistochemical study of oestrogen receptor was fundamental to establish a diagnosis. PMID:17462982

  14. A robust screening method for dietary agents that activate tumour-suppressor microRNAs

    PubMed Central

    Hagiwara, Keitaro; Gailhouste, Luc; Yasukawa, Ken; Kosaka, Nobuyoshi; Ochiya, Takahiro

    2015-01-01

    Certain dietary agents, such as natural products, have been reported to show anti-cancer effects. However, the underlying mechanisms of these substances in human cancer remain unclear. We recently found that resveratrol exerts an anti-cancer effect by upregulating tumour-suppressor microRNAs (miRNAs). In the current study, we aimed to identify new dietary products that have the ability to activate tumour-suppressor miRNAs and that therefore may serve as novel tools for the prevention and treatment of human cancers. We describe the generation and use of an original screening system based on a luciferase-based reporter vector for monitoring miR-200c tumour-suppressor activity. By screening a library containing 139 natural substances, three natural compounds — enoxolone, magnolol and palmatine chloride — were identified as being capable of inducing miR-200c expression in breast cancer cells at 10 μM. Moreover, these molecules suppressed the invasiveness of breast cancer cells in vitro. Next, we identified a molecular pathway by which the increased expression of miR-200c induced by natural substances led to ZEB1 inhibition and E-cadherin induction. These results indicate that our method is a valuable tool for a fast identification of natural molecules that exhibit tumour-suppressor activity in human cancer through miRNA activation. PMID:26423775

  15. Immunological Characterization of Whole Tumour Lysate-Loaded Dendritic Cells for Cancer Immunotherapy

    PubMed Central

    Ottobrini, Luisa; Biasin, Mara; Borelli, Manuela; Lucignani, Giovanni; Trabattoni, Daria; Clerici, Mario

    2016-01-01

    Introduction Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies. Matherials & Methods We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC), as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras). Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation. Results Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN-γ but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines. Conclusion Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer. PMID:26795765

  16. Hypoxia-mediated tumour targeting.

    PubMed

    Binley, K; Askham, Z; Martin, L; Spearman, H; Day, D; Kingsman, S; Naylor, S

    2003-04-01

    Hypoxia is a common physiological feature of tumours. It activates a signalling cascade that culminates in the stabilization of the HIF-1 transcription factor and activation of genes that possess a hypoxia response element (HRE). We have used an optimized hypoxia responsive promoter (OBHRE) to investigate hypoxia-targeted gene expression in vivo in the context of an adenovirus vector. The OBHRE promoter showed limited activity in the liver or spleen such that expression was 1000-fold lower than that driven by the strong CMV/IE promoter. However, in the context of the tumour microenvironment, the OBHRE promoter achieved expression levels comparable to that of the CMV/IE promoter. Next, we showed that an adenovirus expressing the human cytochrome P450 (CYP2B6) regulated by the OBHRE promoter delays tumour growth in response to the prodrug cyclophosphamide (CPA). Finally, we exploited the hepatotropism of adenovirus to investigate whether the OBHRE promoter could mitigate the hepatotoxicity of a recombinant adenovirus expressing thymidine kinase (TK) in the context of the prodrug ganciclovir (GCV). High-dose Ad.CMVTK/GCV treatment caused significant liver necrosis whereas the same dose of Ad.HRETK was well tolerated. These in vivo data demonstrate that hypoxia-targeted gene expression via the OBHRE promoter can be used to increase the therapeutic window of cytotoxic cancer gene therapy. PMID:12646859

  17. Is clinical breast examination important for breast cancer detection?

    PubMed Central

    Provencher, L.; Hogue, J.C.; Desbiens, C.; Poirier, B.; Poirier, E.; Boudreau, D.; Joyal, M.; Diorio, C.; Duchesne, N.; Chiquette, J.

    2016-01-01

    Background Screening clinical breast examination (cbe) is controversial; the use of cbe is declining not only as a screening tool, but also as a diagnostic tool. In the present study, we aimed to assess the value of cbe in breast cancer detection in a tertiary care centre for breast diseases. Methods This retrospective study of all breast cancers diagnosed between July 1999 and December 2010 at our centre categorized cases according to the mean of detection (cbe, mammography, or both). A cbe was considered “abnormal” in the presence of a mass, nipple discharge, skin or nipple retraction, edema, erythema, peau d’orange, or ulcers. Results During the study period, a complete dataset was available for 6333 treated primary breast cancers. Cancer types were ductal carcinoma in situ (15.3%), invasive ductal carcinoma (75.7%), invasive lobular carcinoma (9.0%), or others (2.2%). Of the 6333 cancers, 36.5% (n = 2312) were detected by mammography alone, 54.8% (n = 3470) by mammography and cbe, and 8.7% (n = 551) by physician-performed cbe alone (or 5.3% if considering ultrasonography). Invasive tumours diagnosed by cbe alone were more often triple-negative, her2-positive, node-positive, and larger than those diagnosed by mammography alone (p < 0.05). Conclusions A significant number of cancers would have been missed if cbe had not been performed. Compared with cancers detected by mammography alone, those detected by cbe had more aggressive features. Clinical breast examination is a very low-cost test that could improve the detection of breast cancer and could prompt breast ultrasonography in the case of a negative mammogram. PMID:27536182

  18. Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy.

    PubMed

    Walker, J; Martin, C; Callaghan, R

    2004-03-01

    Resistance to cancer chemotherapy involves both altered drug activity at the designated target and modified intra-tumour pharmacokinetic properties (e.g. uptake, metabolism). The membrane transporter P-glycoprotein (P-gp) plays a major role in pharmacokinetic resistance by preventing sufficient intracellular accumulation of several anticancer agents. Whilst inhibiting P-gp has great potential to restore chemotherapeutic effectiveness in blood-borne cancers, the situation in solid tumours is less clear. Therefore, the degree of resistance tumours pose to the cytotoxicity of vinblastine and doxorubicin was characterised using the multicellular tumour spheroid model. Tumour spheroids were generated from either drug-sensitive MCF7(WT) breast cancer cells or a resistant P-gp-expressing variant (NCI/ADR(Res)). Drug-induced cytotoxicity in tumour spheroids was measured using an outgrowth assay and compared with that observed in monolayer cultures. As anticipated, the 3-D organisation of MCF7(WT) in tumour spheroids was associated with a reduction in the potency of doxorubicin and vinblastine-i.e. the inherent multicellular resistance phenomenon. In contrast, tumour spheroids from NCI/ADR(Res) cells did not display multicellular resistance. However their constitutive expression of P-gp reduced the potency of both anticancer drugs. Moreover, the highly potent P-gp inhibitor, the anthranilic acid derivative, XR9576, was able to restore the cytotoxic efficacy of both drugs in tumour spheroids comprising NCI/ADR(Res) cells. The results suggest that inhibition of P-gp in solid tumours is achievable and that generation of potent inhibitors will provide a significant benefit towards restoration of chemotherapy in solid tissues. PMID:14962729

  19. Breast conservative surgery: is it appropriate for locally advanced breast cancer following downstaging by neoadjuvant chemotherapy? A pathological assessment.

    PubMed

    Moneer, M; El-Didi, M; Khaled, H

    1999-12-01

    The application of breast conserving surgery to down-staged cases with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy (NACT) is still a controversial issue with a variable incidence of locoregional failures. In this study, the response of LABC to NACT was assessed pathologically and the eligible candidates for breast conserving surgery were identified retrospectively. The efficacy of preoperative clinical examination and mammography in detecting these pathological changes were also evaluated. The study included 41 LABC cases. They received NACT (FAC) and were then subjected to a mastectomy. The cases were examined clinically and by mammography before starting treatment and immediately before surgery. Residual tumours in the mastectomy specimens were correlated with the pretreatment and preoperative clinical and mammographic findings in order to assess the efficacy of these tools for detection of NACT-induced changes. After 3 cycles of NACT, 78% of women showed an objective response. However, only 25% of them would have been eligible for breast conserving surgery. The remaining responders had an increased incidence of either multifocality and or peritumoural in situ carcinoma. Both clinical examination and mammography were inadequate for detection of these chemotherapy-induced changes and hence for selecting suitable candidates for breast conservation. This study has shown that tumour regression by NACT is probably induced by a process of tumour segmentation and is associated with an increased incidence of ductal in situ lesions in the original tumour bearing area. PMID:14731459

  20. Fertility sparing treatment in borderline ovarian tumours

    PubMed Central

    Alvarez, Rosa Maria; Vazquez-Vicente, Daniel

    2015-01-01

    Borderline ovarian tumours are low malignant potential tumours. They represent 10–15% of all epithelial ovarian malignancies. Patients with this type of tumour are younger at the time of diagnosis than patients with invasive ovarian cancer. Most of them are diagnosed in the early stages and have an excellent prognosis. It has been quite clearly established that the majority of borderline ovarian tumours should be managed with surgery alone. Because a high proportion of women with this malignancy are young and the prognosis is excellent, the preservation of fertility is an important issue in the management of these tumours. In this systemic review of the literature, we have evaluated in-depth oncological safety and reproductive outcomes in women with borderline ovarian tumours treated with fertility-sparing surgery, reviewing the indications, benefits, and disadvantages of each type of conservative surgery, as well as new alternative options to surgery to preserve fertility. PMID:25729420

  1. Fertility sparing treatment in borderline ovarian tumours.

    PubMed

    Alvarez, Rosa Maria; Vazquez-Vicente, Daniel

    2015-01-01

    Borderline ovarian tumours are low malignant potential tumours. They represent 10-15% of all epithelial ovarian malignancies. Patients with this type of tumour are younger at the time of diagnosis than patients with invasive ovarian cancer. Most of them are diagnosed in the early stages and have an excellent prognosis. It has been quite clearly established that the majority of borderline ovarian tumours should be managed with surgery alone. Because a high proportion of women with this malignancy are young and the prognosis is excellent, the preservation of fertility is an important issue in the management of these tumours. In this systemic review of the literature, we have evaluated in-depth oncological safety and reproductive outcomes in women with borderline ovarian tumours treated with fertility-sparing surgery, reviewing the indications, benefits, and disadvantages of each type of conservative surgery, as well as new alternative options to surgery to preserve fertility. PMID:25729420

  2. Intraoperative radiotherapy for breast cancer

    PubMed Central

    Williams, Norman R.; Pigott, Katharine H.; Brew-Graves, Chris

    2014-01-01

    Intra-operative radiotherapy (IORT) as a treatment for breast cancer is a relatively new technique that is designed to be a replacement for whole breast external beam radiotherapy (EBRT) in selected women suitable for breast-conserving therapy. This article reviews twelve reasons for the use of the technique, with a particular emphasis on targeted intra-operative radiotherapy (TARGIT) which uses X-rays generated from a portable device within the operating theatre immediately after the breast tumour (and surrounding margin of healthy tissue) has been removed. The delivery of a single fraction of radiotherapy directly to the tumour bed at the time of surgery, with the capability of adding EBRT at a later date if required (risk-adaptive technique) is discussed in light of recent results from a large multinational randomised controlled trial comparing TARGIT with EBRT. The technique avoids irradiation of normal tissues such as skin, heart, lungs, ribs and spine, and has been shown to improve cosmetic outcome when compared with EBRT. Beneficial aspects to both institutional and societal economics are discussed, together with evidence demonstrating excellent patient satisfaction and quality of life. There is a discussion of the published evidence regarding the use of IORT twice in the same breast (for new primary cancers) and in patients who would never be considered for EBRT because of their special circumstances (such as the frail, the elderly, or those with collagen vascular disease). Finally, there is a discussion of the role of the TARGIT Academy in developing and sustaining high standards in the use of the technique. PMID:25083504

  3. Breast cancer

    MedlinePlus

    ... of targeted therapy. It blocks certain hormones that fuel cancer growth. Cancer treatment can be local or ... breast cancer should not drink alcohol at all) Alternative Names Cancer - breast; Carcinoma - ductal; Carcinoma - lobular; DCIS; ...

  4. Breast Implants

    MedlinePlus

    ... Updated Safety Information (Consumer Article) FDA Provides Updated Safety Data on Silicone Gel-Filled Breast Implants (Press Announcement) [ARCHIVED] Breast Implant Guidance for Industry (2006) Post Approval Studies Webpage Freedom of Information ...

  5. Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted SiRNA Delivery to HER2+ Breast Cancer

    PubMed Central

    Ngamcherdtrakul, Worapol; Morry, Jingga; Gu, Shenda; Castro, David J.; Goodyear, Shaun M.; Sangvanich, Thanapon; Reda, Moataz M.; Lee, Richard; Mihelic, Samuel A.; Beckman, Brandon L.; Hu, Zhi; Gray, Joe W.; Yantasee, Wassana

    2015-01-01

    In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct has been engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2-nanoparticles produced apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2−) cells. One dose of the siHER2-nanoparticles reduced HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Multiple doses administered intravenously over 3 weeks significantly inhibited tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation. PMID:26097445

  6. 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

  7. Salivary expression of soluble HER2 in breast cancer patients with positive and negative HER2 status

    PubMed Central

    Laidi, Fatna; Bouziane, Amal; Lakhdar, Amina; Khabouze, Samira; Rhrab, Brahim; Zaoui, Fatima

    2014-01-01

    Background The aim of this study was to investigate the relationship between salivary concentration of the soluble fragment of the HER2 (human epidermal growth factor receptor) protein and its status in mammary tissues. Methods This case-control study was done in 27 breast cancer patients with no visible metastatic disease treated at the gynecology service, Maternity Souissi Hospital, Rabat, Morocco. Two groups were selected, ie, patients with positive and negative HER2 status in mammary tissue. The salivary HER2 protein concentration was assessed by enzyme-linked immunosorbent assay. The salivary HER2 concentration was compared between the HER2-positive and HER2-negative groups using the Mann-Whitney U test. A P-value <0.05 was considered to be statistically significant. Results No statistically significant difference in salivary HER2 protein expression was found between the case and control groups. There was also no significant difference in clinical characteristics according to positive and negative HER2 status (P>0.05), except for the progesterone hormone receptor which was statistically significant in both the case and control groups (P=0.047). Conclusion According to our data, salivary expression of the HER2 receptor may not be a reliable alternative to tissue assessment. PMID:25053886

  8. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells.

    PubMed

    Galanzha, Ekaterina I; Shashkov, Evgeny V; Kelly, Thomas; Kim, Jin-Woo; Yang, Lily; Zharov, Vladimir P

    2009-12-01

    The spread of cancer cells between organs, a process known as metastasis, is the cause of most cancer deaths. Detecting circulating tumour cells -- a common marker for the development of metastasis -- is difficult because ex vivo methods are not sensitive enough owing to limited blood sample volume and in vivo diagnosis is time-consuming as large volumes of blood must be analysed. Here, we show a way to magnetically capture circulating tumour cells in the bloodstream of mice followed by rapid photoacoustic detection. Magnetic nanoparticles, which were functionalized to target a receptor commonly found in breast cancer cells, bound and captured circulating tumour cells under a magnet. To improve detection sensitivity and specificity, gold-plated carbon nanotubes conjugated with folic acid were used as a second contrast agent for photoacoustic imaging. By integrating in vivo multiplex targeting, magnetic enrichment, signal amplification and multicolour recognition, our approach allows circulating tumour cells to be concentrated from a large volume of blood in the vessels of tumour-bearing mice, and this could have potential for the early diagnosis of cancer and the prevention of metastasis in humans. PMID:19915570

  9. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells

    PubMed Central

    Galanzha, Ekaterina I.; Shashkov, Evgeny V.; Kelly, Thomas; Kim, Jin-Woo; Yang, Lily; Zharov, Vladimir P.

    2012-01-01

    The spread of cancer cells between organs, a process known as metastasis, is the cause of most cancer deaths1,2. Detecting circulating tumour cells—a common marker for the development of metastasis3,4—is difficult because ex vivo methods are not sensitive enough owing to limited blood sample volume and in vivo diagnosis is time-consuming as large volumes of blood must be analysed5–7. Here, we show a way to magnetically capture circulating tumour cells in the bloodstream of mice followed by rapid photoacoustic detection. Magnetic nanoparticles, which were functionalized to target a receptor commonly found in breast cancer cells, bound and captured circulating tumour cells under a magnet. To improve detection sensitivity and specificity, gold-plated carbon nanotubes conjugated with folic acid were used as a second contrast agent for photoacoustic imaging. By integrating in vivo multiplex targeting, magnetic enrichment, signal amplification and multicolour recognition, our approach allows circulating tumour cells to be concentrated from a large volume of blood in the vessels of tumour-bearing mice, and this could have potential for the early diagnosis of cancer and the prevention of metastasis in humans. PMID:19915570

  10. Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets

    NASA Astrophysics Data System (ADS)

    Yoon, Hyeun Joong; Kim, Tae Hyun; Zhang, Zhuo; Azizi, Ebrahim; Pham, Trinh M.; Paoletti, Costanza; Lin, Jules; Ramnath, Nithya; Wicha, Max S.; Hayes, Daniel F.; Simeone, Diane M.; Nagrath, Sunitha

    2013-10-01

    The spread of cancer throughout the body is driven by circulating tumour cells (CTCs). These cells detach from the primary tumour and move from the bloodstream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods for measuring and studying these cells in patient blood samples prevents the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs. However, the devices are reliant on three-dimensional structures, which limits further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolating CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalized graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at a low concentration of target cells (73 +/- 32.4% at 3-5 cells per ml blood).

  11. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells

    NASA Astrophysics Data System (ADS)

    Galanzha, Ekaterina I.; Shashkov, Evgeny V.; Kelly, Thomas; Kim, Jin-Woo; Yang, Lily; Zharov, Vladimir P.

    2009-12-01

    The spread of cancer cells between organs, a process known as metastasis, is the cause of most cancer deaths. Detecting circulating tumour cells-a common marker for the development of metastasis-is difficult because ex vivo methods are not sensitive enough owing to limited blood sample volume and in vivo diagnosis is time-consuming as large volumes of blood must be analysed. Here, we show a way to magnetically capture circulating tumour cells in the bloodstream of mice followed by rapid photoacoustic detection. Magnetic nanoparticles, which were functionalized to target a receptor commonly found in breast cancer cells, bound and captured circulating tumour cells under a magnet. To improve detection sensitivity and specificity, gold-plated carbon nanotubes conjugated with folic acid were used as a second contrast agent for photoacoustic imaging. By integrating in vivo multiplex targeting, magnetic enrichment, signal amplification and multicolour recognition, our approach allows circulating tumour cells to be concentrated from a large volume of blood in the vessels of tumour-bearing mice, and this could have potential for the early diagnosis of cancer and the prevention of metastasis in humans.

  12. A review of the ligands and related targeting strategies for active targeting of paclitaxel to tumours.

    PubMed

    Li, Juan; Wang, Fengshan; Sun, Deqing; Wang, Rongmei

    2016-08-01

    It has been 30 years since the discovery of the anti-tumour property of paclitaxel (PTX), which has been successfully applied in clinic for the treatment of carcinomas of the lungs, breast and ovarian. However, PTX is poorly soluble in water and has no targeting and selectivity to tumour tissue. Recent advances in active tumour targeting of PTX delivery vehicles have addressed some of the issues related to lack of solubility in water and non-specific toxicities associated with PTX. These PTX delivery vehicles are designed for active targeting to specific cancer cells by the addition of ligands for recognition by specific receptors/antigens on cancer cells. This article will focus on various ligands and related targeting strategies serving as potential tools for active targeting of PTX to tumour tissues, illustrating their use in different tumour models. This review also highlights the need of further studies on the discovery of receptors in different cells of specific organ and ligands with binding efficiency to these specific receptors. PMID:26878228

  13. Infracentimetric HER-2 positive breast tumours—review of the literature

    PubMed Central

    da Fonseca Reis Silva, Danilo; Ribeiro, Joana M

    2015-01-01

    Breast cancer is the most common malignant neoplasm in the world among women. As a result of the dissemination of population screening programmes, about half of non-metastatic breast cancers are now diagnosed at stage I. 10–15% of T1abN0 tumours over-express human epidermal growth factor (HER-2). These tumours have a globally excellent prognosis, however, treatment with chemotherapy and/or targeted therapy may further improve outcomes in selected cases. In this article, we will review studies with information on prognosis and benefit of adjuvant therapy for T1abN0 HER-2+ breast cancer. PMID:26635897

  14. Mammary gland-specific ablation of focal adhesion kinase reduces the incidence of p53-mediated mammary tumour formation

    PubMed Central

    van Miltenburg, M H A M; van Nimwegen, M J; Tijdens, I; Lalai, R; Kuiper, R; Klarenbeek, S; Schouten, P C; de Vries, A; Jonkers, J; van de Water, B

    2014-01-01

    Background: Elevated expression of focal adhesion kinase (FAK) occurs in numerous human cancers including colon-, cervix- and breast cancer. Although several studies have implicated FAK in mammary tumour formation induced by ectopic oncogene expression, evidence supporting a role for FAK in spontaneous mammary tumour development caused by loss of tumour suppressor genes such as p53 is lacking. Alterations in the tumour suppressor gene p53 have been implicated in over 50% of human breast cancers. Given that elevated FAK expression highly correlates with p53 mutation status in human breast cancer, we set out to investigate the importance of FAK in p53-mediated spontaneous mammary tumour development. Methods: To directly assess the role of FAK, we generated mice with conditional inactivation of FAK and p53. We generated female p53lox/lox/FAK+/+/WapCre, p53lox/lox/FAKflox/+/WapCre and p53lox/lox/FAKflox/−/WapCre mice, and mice with WapCre-mediated conditional expression of p53R270H, the mouse equivalent of human p53R273H hot spot mutation, together with conditional deletion of FAK, P53R270H/+/FAKlox/+/WapCre and p53R270H/+/FAKflox/−/WapCre mice. All mice were subjected to one pregnancy to induce WapCre-mediated deletion of p53 or expression of p53 R270H, and Fak genes flanked by two loxP sites, and subsequently followed the development of mammary tumours. Results: Using this approach, we show that FAK is important for p53-induced mammary tumour development. In addition, mice with the mammary gland-specific conditional expression of p53 point mutation R270H, the mouse equivalent to human R273H, in combination with conditional deletion of Fak showed reduced incidence of p53R270H-induced mammary tumours. In both models these effects of FAK were related to reduced proliferation in preneoplastic lesions in the mammary gland ductal structures. Conclusions: Mammary gland-specific ablation of FAK hampers p53-regulated spontaneous mammary tumour formation. Focal adhesion

  15. Malignant Leydig cell tumour of the testis.

    PubMed

    Powari, Manish; Kakkar, Nandita; Singh, S K; Rai, R S; Jogai, Sanjay

    2002-01-01

    A case of malignant Leydig cell tumour is presented. It is a rare primary malignant tumour of the testis and occurs exclusively in adults. The present case is of interest because it occurred at the young age of 25 years which is rare. Histologically it showed almost all features which suggest malignancy and also had metastases to the lungs and liver. The clinical details and pathology of this tumour are discussed. PMID:11803271

  16. Tumours of the liver and biliary system

    PubMed Central

    Ponomarkov, V.; Mackey, L. J.

    1976-01-01

    In this histological classification of liver and gall bladder tumours the tumour types largely correspond to those found in man. The most common tumours in this group are liver cell adenoma, hepatocellular carcinoma, and cholangiocarcinoma. ImagesFig. 5Fig. 6Fig. 7Fig. 8Fig. 13Fig. 14Fig. 1Fig. 2Fig. 3Fig. 4Fig. 9Fig. 10Fig. 11Fig. 12 PMID:1086149

  17. 6-thioguanine selectively kills BRCA2 defective tumours and overcomes PARP inhibitor resistance

    PubMed Central

    Issaeva, Natalia; Thomas, Huw D.; Djurenovic, Tatjana; Jaspers, Janneke E.; Stoimenov, Ivaylo; Kyle, Suzanne; Pedley, Nicholas; Gottipati, Ponnari; Zur, Rafal; Sleeth, Kate; Chatzakos, Vicky; Mulligan, Evan; Lundin, Cecilia; Gubanova, Evgenia; Kersbergen, Ariena; Harris, Adrian L; Sharma, Ricky A; Rottenberg, Sven; Curtin, Nicola J.; Helleday, Thomas

    2010-01-01

    Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors are tested for these tumours in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSBs) that we show are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumours in a xenograft model. Spontaneous BRCA1 defective mammary tumours gain resistance to PARP inhibitors through increased p-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1 defective PARP inhibitor resistant (PIR) tumours. We also show that 6TG can kill cells and tumours that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PIR BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is required for survival also to mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumours and suggest that 6TG may be effective in the treatment of advanced tumours that have developed resistance to PARP inhibitors or platinum-based chemotherapy. PMID:20631063

  18. Breast Cancer

    MedlinePlus

    Breast cancer affects one in eight women during their lives. No one knows why some women get breast cancer, but there are many risk factors. Risks that ... who have family members with breast or ovarian cancer may wish to be tested for the genes. ...