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Sample records for her2-overexpressing metastatic breast

  1. PTEN expression as a predictor for the response to trastuzumab-based therapy in Her-2 overexpressing metastatic breast cancer

    PubMed Central

    Tan, Yen Y.; Fuchs, Eva-Maria; Hudelist, Gernot; Köstler, Wolfgang J.; Reiner, Angelika; Leser, Carmen; Salama, Mohamed; Attems, Johannes; Deutschmann, Christine; Zielinski, Christoph C.; Singer, Christian F.

    2017-01-01

    Background Even though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40–50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN). This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients. Methods Between 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS) and overall survival (OS) with a median follow-up of 60 months. Results Eighty patients were PTEN positive (69.6%) and 35 patients PTEN negative (30.4%). We found a significant association of the expression of PTEN and p53 (p = 0.041), while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018), while there was no significant correlation with PFS or OS. Conclusion In Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS. PMID:28253285

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

    PubMed

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

    2008-09-01

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

  3. The effects of bufadienolides on HER2 overexpressing breast cancer cells.

    PubMed

    Wang, Tianjiao; Mu, Lin; Jin, Haifeng; Zhang, Peng; Wang, Yueyue; Ma, Xiaochi; Pan, Jinjin; Miao, Jian; Yuan, Yuhui

    2016-06-01

    HER2 is a proto-oncogene frequently amplified in human breast cancer, its overexpression is correlated with tamoxifen resistance and decreased recurrence-free survival. Arenobufagin and bufalin are homogeneous bufadienolides of cardiac glycosides agents. In this research, we studied the effects of arenobufagin and bufalin on cellular survival and proliferation of HER2 overexpressing breast cancer cells and the mechanism under the results including the direct effect on HER2 downstream pathways. Our results showed that arenobufagin and bufalin could significantly inhibit the proliferation and survival of HER2 overexpressing breast cancer cells, along with the declination of SRC-1, SRC-3, nuclear transcription factor E2F1, phosphorylated AKT, and ERK. And the combination of each bufadienolide in low dose with tamoxifen could significantly enhance the inhibitory effect of tamoxifen on HER2 overexpressing breast cancer cells. All above suggest that arenobufagin and bufalin may be potential therapy adjuvants for HER2 overexpressing breast cancer therapy.

  4. PGC-1β regulates HER2-overexpressing breast cancer cells proliferation by metabolic and redox pathways.

    PubMed

    Victorino, Vanessa Jacob; Barroso, W A; Assunção, A K M; Cury, V; Jeremias, I C; Petroni, R; Chausse, B; Ariga, S K; Herrera, A C S A; Panis, C; Lima, T M; Souza, H P

    2016-05-01

    Breast cancer is a prevalent neoplastic disease among women worldwide which treatments still present several side effects and resistance. Considering that cancer cells present derangements in their energetic homeostasis, and that peroxisome proliferator-activated receptor- gamma coactivator 1 (PGC-1) is crucial for cellular metabolism and redox signaling, the main objective of this study was to investigate whether there is a relationship between PGC-1 expression, the proliferation of breast cancer cells and the mechanisms involved. We initially assessed PGC-1β expression in complementary DNA (cDNA) from breast tumor of patients bearing luminal A, luminal B, and HER2-overexpressed and triple negative tumors. Our data showed that PGC-1β expression is increased in patients bearing HER2-overexpressing tumors as compared to others subtypes. Using quantitative PCR and immunoblotting, we showed that breast cancer cells with HER2-amplification (SKBR-3) have greater expression of PGC-1β as compared to a non-tumorous breast cell (MCF-10A) and higher proliferation rate. PGC-1β expression was knocked down with short interfering RNA in HER2-overexpressing cells, and cells decreased proliferation. In these PGC-1β-inhibited cells, we found increased citrate synthase activity and no marked changes in mitochondrial respiration. Glycolytic pathway was decreased, characterized by lower intracellular lactate levels. In addition, after PGC-1β knockdown, SKBR-3 cells showed increased reactive oxygen species production, no changes in antioxidant activity, and decreased expression of ERRα, a modulator of metabolism. In conclusion, we show an association of HER2-overexpression and PGC-1β. PGC-1β knockdown impairs HER2-overexpressing cells proliferation acting on ERRα signaling, metabolism, and redox balance.

  5. HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells

    PubMed Central

    Wilson, Cindy A; Cajulis, Elaina E; Green, Jennifer L; Olsen, Taylor M; Chung, Young Ah; Damore, Michael A; Dering, Judy; Calzone, Frank J; Slamon, Dennis J

    2005-01-01

    Introduction Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-β) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-β1 on breast cancer cells in the presence or absence of overexpressed HER-2. Methods Cell proliferation assays were used to determine the effect of TGF-β on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-β1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-β signaling pathway was assessed using TGF-β1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. Results We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-β1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-β in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-β induced pro-invasive and pro-metastatic gene signature. Conclusion HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in

  6. Plumbagin Suppresses the Invasion of HER2-Overexpressing Breast Cancer Cells through Inhibition of IKKα-Mediated NF-κB Activation

    PubMed Central

    Kawiak, Anna; Domachowska, Anna

    2016-01-01

    HER2-overexpressing breast cancers account for about 30% of breast cancer occurrences and have been correlated with increased tumor aggressiveness and invasiveness. The nuclear factor-κB (NF-κB) is overexpressed in a subset of HER2-positive breast cancers and its upregulation has been associated with the metastatic potential of HER2-overexpressing tumors. The present study aimed at determining the potential of plumbagin, a naturally occurring naphthoquinone, to inhibit the invasion of HER2-overexpressing breast cancer cells and determine the involvement of NF-κB inhibition in plumbagin-mediated cell invasion suppression. In the present research we showed that plumbagin inhibited the transcriptional activity of NF-κB in HER2-positive breast cancer cells. The suppression of NF-κB activation corresponded with the inhibition of NF-κB p65 phosphorylation and downregulation of NF-κB-regulated matrix metalloproteinase 9 (MMP-9) expression. Plumbagin suppressed the invasion of HER2-overexpressing breast cancer cells and the inhibition of cell invasion was associated with the ability of plumbagin to inhibit NF-κB transcriptional activity. The silencing of NF-κB p65 increased the sensitivity of HER2-overexpressing breast cancer cells to plumbagin-induced cell invasion inhibition. NF-κB inhibition was associated with IκB kinase α (IKKα) activity suppression and inhibition of IκBα phosphorylation and degradation. The knockdown of IKKα resulted in increased sensitivity of HER2-positive cells to plumbagin-induced suppression of NF-κB transcriptional activity and expression of MMP-9. In conclusion, plumbagin inhibits the invasion of HER2-overexpressing breast cancer cells through the inhibition of IKKα-mediated NF-κB activation and downregulation of NF-κB-regulated MMP-9 expression. PMID:27727280

  7. Therapeutic strategies and mechanisms of tumorigenesis of HER2-overexpressing breast cancer

    PubMed Central

    Emde, Anna; Köstler, Wolfgang J.; Yarden, Yosef

    2010-01-01

    1. Abstract The receptor tyrosine kinase HER2 is overexpressed in approximately 25% of breast cancers. HER2 acts as a signal amplifier for its siblings, namely three different transmembrane receptors that collectively bind with 11 distinct growth factors of the EGF family. Thus, overexpression of HER2 confers aggressive invasive growth in preclinical models and in patients. Specific therapies targeting HER2 include monoclonal antibodies, antibody-drug conjugates, small molecule tyrosine kinase inhibitors, as well as heat shock protein and sheddase inhibitors. Two of these drugs have shown impressive – yet mostly transient – efficacy in patients with HER2 overexpressing breast cancer. We highlight the biological roles of HER2 in breast cancer progression, and overview the available therapeutic armamentarium directed against this receptor-kinase molecule. Focusing on the mechanisms that confer resistance to individual HER2 targeting agents, we envisage therapeutic approaches to delay or overcome the evolvement of resistance in patients. PMID:20951604

  8. Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells.

    PubMed

    Ma, Jui-Wen; Hung, Chao-Ming; Lin, Ying-Chao; Ho, Chi-Tang; Kao, Jung-Yie; Way, Tzong-Der

    2016-09-13

    Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits HER-2 expression. This study compared the HER-2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These findings suggest the possible application of AE in the treatment of HER-2-positive breast cancer.

  9. Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells

    PubMed Central

    Ma, Jui-Wen; Hung, Chao-Ming; Lin, Ying-Chao; Ho, Chi-Tang; Kao, Jung-Yie; Way, Tzong-Der

    2016-01-01

    Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits HER-2 expression. This study compared the HER-2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These findings suggest the possible application of AE in the treatment of HER-2-positive breast cancer. PMID:27391337

  10. The clinical value of HER-2 overexpression and PIK3CA mutations in the older breast cancer population: a FOCUS study analysis.

    PubMed

    Engels, Charla C; Kiderlen, Mandy; Bastiaannet, Esther; van Eijk, Ronald; Mooyaart, Antien; Smit, Vincent T H B M; de Craen, Anton J M; Kuppen, Peter J K; Kroep, Judith R; van de Velde, Cornelis J H; Liefers, Gerrit Jan

    2016-04-01

    Studies to confirm the effect of acknowledged prognostic markers in older breast cancer patients are scarce. The aim of this study was to evaluate the prognostic value of HER-2 overexpression and PIK3CA mutations in older breast cancer patients. Female breast cancer patients aged 65 years or older, diagnosed between 1997 and 2004 in a geographical region in The Netherlands, with an invasive, non-metastatic tumour and tumour material available, were included in the study. The primary endpoint was relapse-free period and secondary endpoint was relative survival. Determinants were immunochemical HER-2 scores (0/1+, 2+ or 3+) and PIK3CA as a binary measure. Overall, 1698 patients were included, and 103 had a HER-2 score of 3+. HER-2 overexpression was associated with a higher recurrence risk (5 years recurrence risk 34 % vs. 12 %, adjusted p = 0.005), and a worse relative survival (10 years relative survival 48 % vs. 84 % for HER-2 negative; p = 0.004). PIK3CA mutations had no significant prognostic effect. We showed, in older breast cancer patients, that HER-2 overexpression was significantly associated with a worse outcome, but PIK3CA mutations had no prognostic effect. These results imply that older patients with HER-2 overexpressing breast cancer might benefit from additional targeted anti-HER-2 therapy.

  11. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer

    PubMed Central

    Harder, J; Ihorst, G; Heinemann, V; Hofheinz, R; Moehler, M; Buechler, P; Kloeppel, G; Röcken, C; Bitzer, M; Boeck, S; Endlicher, E; Reinacher-Schick, A; Schmoor, C; Geissler, M

    2012-01-01

    Background: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. Methods: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. Results: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. Conclusion: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer. PMID:22374460

  12. Inhibition of phosphatidylcholine-specific phospholipase C downregulates HER2 overexpression on plasma membrane of breast cancer cells

    PubMed Central

    2010-01-01

    Introduction Overexpression on plasma membrane of human epidermal growth factor receptor 2 (HER2) is reported in 25% to 30% of breast cancers. Heterodimer formation with cognate members of the epidermal growth factor receptor (EGFR) family, such as HER3 and EGFR, activates abnormal cell-signalling cascades responsible for tumorigenesis and further transcriptional HER2 gene upregulation. Targeting the molecular mechanisms controlling HER2 overexpression and recycling may effectively deactivate this feedback-amplification loop. We recently showed that inactivation of phosphatidylcholine-specific phospholipase C (PC-PLC) may exert a pivotal role in selectively modulating the expression on the membrane of specific receptors or proteins relevant to cell function. In the present study, we investigated the capability of PC-PLC inhibition to target the molecular mechanisms controlling HER2 overexpression on the membrane of breast cancer cells by altering the rates of its endocytosis and lysosomal degradation. Methods Localization on the membrane and interaction of PC-PLC with HER2, EGFR, and HER3 were investigated on HER2-overexpressing and HER2-low breast cancer cell lines, by using confocal laser scanning microscopy, flow cytometry, cell-surface biotinylation, isolation of lipid rafts, and immunoprecipitation experiments. The effects of the PC-PLC inhibitor tricyclodecan-9-yl-potassium xanthate (D609) on HER2 expression on the membrane and on the levels of overall HER2, HER2-HER3, and HER2-EGFR contents were monitored in the HER2-overexpressing SKBr3 cells, after either transient or continuous receptor engagement with anti-HER2 monoclonal antibodies, including trastuzumab. Changes of HER2 expression and cell proliferation were examined in SKBr3, BT-474, and MDA-MB-453 cells continuously exposed to D609 alone or combined with trastuzumab. Results PC-PLC selectively accumulates on the plasma membrane of HER2-overexpressing cells, where it colocalizes and associates with

  13. Trastuzumab (Herceptin®): overcoming resistance in HER2-overexpressing breast cancer models.

    PubMed

    Albrecht, Huguette

    2010-11-01

    Evaluation of: Fujimoto-Ouchi K, Sekiguchi F, Yamamoto K et al.: Preclinical study of prolonged administration of trastuzumab as combination therapy after disease progression during trastuzumab monotherapy. Cancer Chemother. Pharmacol. 66, 269-276 (2010). Trastuzumab, a humanized antibody targeted against human epidermal receptor (HER)2, is used in combination with chemotherapy to treat patients with breast cancers overexpressing HER2. Despite initial clinical responses, disease progresses in a significant proportion of patients treated with trastuzumab and chemotherapy. Evidence of resistance to trastuzumab has not deterred a widespread clinical practice in the treatment of metastatic breast cancer - at least before lapatinib entered the clinic - which consists of continued administration of trastuzumab in combination with another chemotherapeutic drug. At present, it is not known if patients benefit from this practice. The present preclinical study demonstrates that, in the MDA-MB-361 and KPL-4 HER2(+) breast cancer models, induced resistance to trastuzumab monotherapy can be overcome by a combination of trastuzumab and granulocyte colony stimulating factor or chemotherapy. The response to trastuzumab and granulocyte colony stimulating factor appears to involve the host's immune system and antibody-dependent cellular cytotoxicity. The mechanisms underlying the response to trastuzumab and chemotherapy remain unclear.

  14. Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain.

    PubMed

    Koumarianou, Anna; Kontopoulou, Christina; Kouloulias, Vassilis; Tsionou, Christina

    2016-01-01

    Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases.

  15. Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain

    PubMed Central

    Koumarianou, Anna; Kontopoulou, Christina; Kouloulias, Vassilis; Tsionou, Christina

    2016-01-01

    Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases. PMID:27195161

  16. Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation.

    PubMed

    Chiang, Chun-Te; Way, Tzong-Der; Tsai, Shang-Jie; Lin, Jen-Kun

    2007-12-22

    Fatty acid synthase (FAS) expression is markedly elevated in HER2-overexpressing breast cancer cells. In this study, diosgenin, a plant-derived steroid, was found to be effective in suppressing FAS expression in HER2-overexpressing breast cancer cells. Diosgenin preferentially inhibited proliferation and induced apoptosis in HER2-overexpressing cancer cells. Furthermore, diosgenin inhibited the phosphorylation of Akt and mTOR, and enhanced phosphorylation of JNK. The use of pharmacological inhibitors revealed that the modulation of Akt, mTOR and JNK phosphorylation was required for diosgenin-induced FAS suppression. Finally, we showed that diosgenin could enhance paclitaxel-induced cytotoxicity in HER2-overexpressing cancer cells. These results suggested that diosgenin has the potential to advance as chemopreventive or chemotherapeutic agent for cancers that overexpress HER2.

  17. 64Cu-DOTA-Trastuzumab PET Imaging in Women with HER2-Overexpressing Breast Cancer

    DTIC Science & Technology

    2013-10-01

    Trastuzumab PET Joanne E. Mortimer1, James R. Bading2, David M. Colcher2, Peter S. Conti3, Paul H. Frankel4, Mary I. Carroll1, Shan Tong2, Erasmus Poku2...do you mean “board-certified”? [AQ7] When solely Curies are given, please also provide Becquerel equivalents. [AQ8] Please provide a manufacturer for...women with advanced breast cancer. Joanne E. Mortimer, David Colcher, Paul Frankel, Andrew Raubitschek, Mary Carroll, Peter Conti, Shan Tong, Kofi

  18. Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression.

    PubMed

    Stewart, Jonathan; James, Jacqueline; McCluggage, Glenn W; McQuaid, Stephen; Arthur, Kenneth; Boyle, David; Mullan, Paul; McArt, Darragh; Yan, Benedict; Irwin, Gareth; Harkin, D Paul; Zhengdeng, Lei; Ong, Chee-Wee; Yu, Jia; Virshup, David M; Salto-Tellez, Manuel

    2015-03-01

    The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P=0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2.

  19. HER-2 overexpression is not associated with increased ipsilateral breast tumor recurrence in DCIS treated with breast-conserving surgery followed by radiotherapy.

    PubMed

    Noh, Jae Myoung; Lee, Jihae; Choi, Doo Ho; Cho, Eun Yoon; Huh, Seung Jae; Park, Won; Nam, Seok Jin; Lee, Jeong Eon; Kil, Won-Ho

    2013-10-01

    We evaluated the clinical implications of human epidermal growth factor receptor (HER)-2 overexpression after adjuvant radiotherapy (RT) for ductal carcinoma in situ (DCIS). We reviewed 215 patients with DCIS who underwent breast-conserving surgery followed by RT. The association between HER-2 overexpression and ipsilateral breast tumor recurrence (IBTR) was evaluated. HER-2 overexpression was associated with comedo-type architecture, high nuclear grade, and negative hormonal receptors. The median follow-up duration was 75 months. Sixteen patients experienced IBTR; seven as DCIS recurrence and nine as invasive recurrence. The IBTR rate was 11.4% at 10 years. There was no significant difference in IBTR according to HER-2 expression (P = 0.1764), neither in invasive nor DCIS recurrence. Time to recurrence was shorter in HER-2 positive tumors (P = 0.0697). Adjuvant RT seems to counteract the negative effect of HER-2 overexpression in DCIS, while time to recurrence was relatively shorter. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2.

    PubMed

    Hanker, Ariella B; Garrett, Joan T; Estrada, Mónica Valeria; Moore, Preston D; Ericsson, Paula González; Koch, James P; Langley, Emma; Singh, Sharat; Kim, Phillip S; Frampton, Garrett M; Sanford, Eric; Owens, Philip; Becker, Jennifer; Groseclose, M Reid; Castellino, Stephen; Joensuu, Heikki; Huober, Jens; Brase, Jan C; Majjaj, Samira; Brohée, Sylvain; Venet, David; Brown, David; Baselga, José; Piccart, Martine; Sotiriou, Christos; Arteaga, Carlos L

    2017-08-01

    Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2(+)) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design: HER2(+) BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2(+) early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2(+) early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323-34. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

    PubMed Central

    Park, Y H; Park, M J; Ji, S H; Yi, S Y; Lim, D H; Nam, D H; Lee, J-I; Park, W; Choi, D H; Huh, S J; Ahn, J S; Kang, W K; Park, K; Im, Y-H

    2009-01-01

    In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM. PMID:19240719

  2. Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients.

    PubMed

    Park, Y H; Park, M J; Ji, S H; Yi, S Y; Lim, D H; Nam, D H; Lee, J-I; Park, W; Choi, D H; Huh, S J; Ahn, J S; Kang, W K; Park, K; Im, Y-H

    2009-03-24

    In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM.

  3. Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases.

    PubMed

    Kanojia, Deepak; Balyasnikova, Irina V; Morshed, Ramin A; Frank, Richard T; Yu, Dou; Zhang, Lingjiao; Spencer, Drew A; Kim, Julius W; Han, Yu; Yu, Dihua; Ahmed, Atique U; Aboody, Karen S; Lesniak, Maciej S

    2015-10-01

    The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that intracranial injection of HER2Ab-NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off-target side effects. Our results establish HER2Ab-NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation.

  4. Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells.

    PubMed

    Liu, Phillip C C; Liu, Xiangdong; Li, Yanlong; Covington, Maryanne; Wynn, Richard; Huber, Reid; Hillman, Milton; Yang, Gengjie; Ellis, Dawn; Marando, Cindy; Katiyar, Kamna; Bradley, Jodi; Abremski, Kenneth; Stow, Mark; Rupar, Mark; Zhuo, Jincong; Li, Yun-Long; Lin, Qiyan; Burns, David; Xu, Meizhong; Zhang, Colin; Qian, Ding-Quan; He, Chunhong; Sharief, Vaqar; Weng, Lingkai; Agrios, Costas; Shi, Eric; Metcalf, Brian; Newton, Robert; Friedman, Steven; Yao, Wenqing; Scherle, Peggy; Hollis, Gregory; Burn, Timothy C

    2006-06-01

    Overexpression and activating mutations of ErbB family members have been implicated in the development and progression of a variety of tumor types. Cleavage of the HER2 receptor by an as yet unidentified ectodomain sheddase has been shown to liberate the HER2 extracellular domain (ECD) leaving a fragment with constitutive kinase activity that can provide ligand-independent growth and survival signals to the cell. This process is clinically relevant since HER2 ECD serum levels in metastatic breast cancer patients are associated with a poorer prognosis. Thus, inhibition of the HER2 sheddase may provide a novel therapeutic approach for breast cancer. We describe the use of transcriptional profiling, pharmacological and in vitro approaches to identify the major source of HER2 sheddase activity. Real-time PCR was used to identify those ADAM family members which were expressed in HER2 shedding cell lines. siRNAs that selectively inhibited ADAM10 expression reduced HER2 shedding. In addition, we profiled over 1000 small molecules for in vitro inhibition of a panel of ADAM and MMP proteins; a positive correlation was observed only between ADAM10 inhibition and reduction of HER2 ECD shedding in a cell based assay. Finally, in vitro studies demonstrate that in combination with low doses of Herceptin, selective ADAM10 inhibitors decrease proliferation in HER2 overexpressing cell lines while inhibitors, that do not inhibit ADAM10, have no impact. These results are consistent with ADAM10 being a major determinant of HER2 shedding, the inhibition of which, may provide a novel therapeutic approach for treating a variety of cancers with active HER2 signaling.

  5. Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells.

    PubMed

    Mai, Zhiming; Blackburn, George L; Zhou, Jin-Rong

    2007-07-01

    Although tamoxifen (TAM) is used for the front-line treatment and prevention of estrogen receptor-positive (ER+) breast tumors, nearly 40% of estrogen-dependent breast tumors do not respond to TAM treatment. Moreover, the positive response is usually of short duration, and most tumors eventually develop TAM-resistance. Overexpression of HER2 gene is associated with TAM-resistance of breast tumor, and suppression of HER2 expression enhances the TAM activity. Soy isoflavone genistein has been shown to have anti-cancer activities and suppress expression of HER2 and ERalpha. The objective of this study was to test the hypothesis that genistein may sensitize the response of ER+ and HER2-overexpressing breast cancer cells to TAM treatment. The combination treatment of TAM and genistein inhibited the growth of ER+/HER2-overexpressing BT-474 human breast cancer cells in a synergistic manner in vitro. Determination of cellular markers indicated that this synergistic inhibitory effect might be contributed in part from combined effects on cell-cycle arrest at G(1) phase and on induction of apoptosis. Further determination of the molecular markers showed that TAM and genistein combination synergistically induced BT-474 cell apoptosis in part by synergistic downregulation of the expression of survivin, one of the apoptotic effectors, and downregulation of EGFR, HER2, and ERalpha expression. Our research may provide a novel approach for the prevention and/or treatment of TAM insensitive/resistant human breast cancer, and warrants further in vivo studies to verify the efficacy of genistein and TAM combination on the growth of ER+/HER2-overexpressing breast tumors and to elucidate the in vivo mechanisms of synergistic actions. (c) 2007 Wiley-Liss, Inc.

  6. Genistein Sensitizes Inhibitory Effect of Tamoxifen on the Growth of Estrogen Receptor-Positive and HER2-Overexpressing Human Breast Cancer Cells

    PubMed Central

    Mai, Zhiming; Blackburn, George L.; Zhou, Jin-Rong

    2009-01-01

    Although tamoxifen (TAM) is used for the front-line treatment and prevention of estrogen receptor-positive (ER+) breast tumors, nearly 40% of estrogen-dependent breast tumors do not respond to TAM treatment. Moreover, the positive response is usually of short duration, and most tumors eventually develop TAM-resistance. Overexpression of HER2 gene is associated with TAM-resistance of breast tumor, and suppression of HER2 expression enhances the TAM activity. Soy isoflavone genistein has been shown to have anti-cancer activities and suppress expression of HER2 and ERα. The objective of this study was to test the hypothesis that genistein may sensitize the response of ER+ and HER2-overexpressing breast cancer cells to TAM treatment. The combination treatment of TAM and genistein inhibited the growth of ER+/HER2-overexpressing BT-474 human breast cancer cells in a synergistic manner in vitro. Determination of cellular markers indicated that this synergistic inhibitory effect might be contributed in part from combined effects on cell-cycle arrest at G1 phase and on induction of apoptosis. Further determination of the molecular markers showed that TAM and genistein combination synergistically induced BT-474 cell apoptosis in part by synergistic downregulation of the expression of survivin, one of the apoptotic effectors, and downregulation of EGFR, HER2, and ERα expression. Our research may provide a novel approach for the prevention and/or treatment of TAM insensitive/resistant human breast cancer, and warrants further in vivo studies to verify the efficacy of genistein and TAM combination on the growth of ER+/HER2-overexpressing breast tumors and to elucidate the in vivo mechanisms of synergistic actions. PMID:17295235

  7. Functionalized immunostimulating complexes with protein A via lipid vinyl sulfones to deliver cancer drugs to trastuzumab-resistant HER2-overexpressing breast cancer cells

    PubMed Central

    Rodríguez-Serrano, Fernando; Mut-Salud, Nuria; Cruz-Bustos, Teresa; Gomez-Samblas, Mercedes; Carrasco, Esther; Garrido, Jose Manuel; López-Jaramillo, F Javier; Santoyo-Gonzalez, Francisco; Osuna, Antonio

    2016-01-01

    Background Around 20%–30% of breast cancers overexpress the proto-oncogene human epidermal growth receptor 2 (HER2), and they are characterized by being very invasive. Therefore, many current studies are focused on testing new therapies against tumors that overexpress this receptor. In particular, there exists major interest in new strategies to fight breast cancer resistant to trastuzumab (Tmab), a humanized antibody that binds specifically to HER2 interfering with its mitogenic signaling. Our team has previously developed immunostimulating complexes (ISCOMs) as nanocapsules functionalized with lipid vinyl sulfones, which can incorporate protein A and bind to G immunoglobulins that makes them very flexible nanocarriers. Methods and results The aim of this in vitro study was to synthesize and evaluate a drug delivery system based on protein A-functionalized ISCOMs to target HER2-overexpressing cells. We describe the preparation of ISCOMs, the loading with the drugs doxorubicin and paclitaxel, the binding of ISCOMs to alkyl vinyl sulfone-protein A, the coupling of Tmab, and the evaluation in both HER2-overexpressing breast cancer cells (HCC1954) and non-overexpressing cells (MCF-7) by flow cytometry and fluorescence microscopy. Results show that the uptake is dependent on the level of overexpression of HER2, and the analysis of the cell viability reveals that targeted drugs are selective toward HCC1954, whereas MCF-7 cells remain unaffected. Conclusion Protein A-functionalized ISCOMs are versatile carriers that can be coupled to antibodies that act as targeting agents to deliver drugs. When coupling to Tmab and loading with paclitaxel or doxorubicin, they become efficient vehicles for the selective delivery of the drug to Tmab-resistant HER2-overexpressing breast cancer cells. These nanoparticles may pave the way for the development of novel therapies for poor prognosis resistant patients. PMID:27698563

  8. Real world patterns of care in HER2-overexpressing breast cancer: Results of a survey of TEACH clinical trial investigators in 2011.

    PubMed

    Chavarri-Guerra, Y; St Louis, J; Bukowski, A; Soto-Perez-de-Celis, E; Liedke, P E R; Symecko, H; Moy, B; Higgins, M; Finkelstein, D M; Goss, P E

    2017-02-01

    HER2-overexpressing breast cancer (BC) is common among young patients and poses a public health burden. Adjuvant anti-HER2/neu therapy with trastuzumab reduces the risk of recurrence and improves survival. A web-based survey was sent to 386 physicians of the "TEACH" trial in 2011 to determine access to HER2/neu testing and treatment patterns for HER2-overexpressing BC. There were 151 responders (39%) from 28 countries. Ninety-seven percent reported HER2/neu expression is routinely measured in their institutions by immunohistochemistry (85%), FISH (80%) and other methods (16%). Twenty percent of responders from Asia reported that the test was not routinely available. Forty-eight percent of participants reported instances when adjuvant HER2-directed therapy was recommended to a patient who eventually did not receive it. Reasons for not receiving trastuzumab was cost (73%, p < 0.0001) in low- and middle-income countries and co-morbidities in high-income countries (43%, p = 0.003). This survey reflects the availability of HER2/neu testing and anti-HER2/neu therapy among physicians who participated in TEACH. A high proportion of women with HER2-overexpressing BC may not receive standard adjuvant therapy due to unavailability of the test and cost of therapy. Despite having some limitations, such as a possible selection bias of participating physicians, variable definitions of access to healthcare among respondents, and changes in trastuzumab availability since 2011, our results demonstrate that access to care and region of practice impact the implementation of cancer treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Characterization of the paclitaxel loaded chitosan graft Pluronic F127 copolymer micelles conjugate with a DNA aptamer targeting HER-2 overexpressing breast cancer cells

    NASA Astrophysics Data System (ADS)

    Thach Nguyen, Kim; Nguyen, Thu Ha; Do, Dinh Ho; Huan Le, Quang

    2017-03-01

    In this work we report the isolation of DNA aptamer that is specifically bound to a HER-2 overexpressing SK-BR-3 human breast cancer cell line, using SELEX strategy. Paclitaxel (PTX) loaded chitosan graft Pluronic F127 copolymer micelles conjugate with a DNA aptamer was synthesized and its structure was confirmed by TEM image. This binary mixed system consisting of DNA aptamer modified Pluronic F127 and chitosan could enhance PTX loading capacity and increase micelle stability. Morphology images confirmed the existence of PTX micelles, with an average size of approximately 86.22 ± 1.45 nm diameters. Drug release profile showed that the PTX conjugate maintained a sustained PTX release. From in vitro cell experiment it was shown that 89%–93%, 50%–58%, 55%–62%, 24%–28% and 2%–7% of the SK-BR-3, NS-VN-67, LH-VN-48, HT-VN-26 and NV-VN-31, respectively, were dead after 6–48 h. These results demonstrated a novel DNA aptamer-micelle assembly for efficient detection and a system for the delivery of PTX targeting specific HER-2 overexpressing. We have also successfully cultivated cancer tissues of explants from Vietnamese patients on a type I collagen substrate. The NS-VN-67, LH-VN-48, HT-VN-26 and NV-VN-31cell lines were used as cellular model sources for the study of chemotherapy drug in cancer.

  10. Activation of an IL-6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2 Overexpressing Breast Cancers by Expanding the Cancer Stem Cell Population

    PubMed Central

    Korkaya, Hasan; Kim, Gwang-il; Davis, April; Malik, Fayaz; Henry, N. Lynn; Ithimakin, Suthinee; Quraishi, Ahmed A.; Tawakkol, Nader; D’Angelo, Rosemarie; Paulson, Amanda; Chung, Susan; Luther, Tahra; Paholak, Hayley S.; Liu, Suling; Hassan, Khaled; Zen, Qin; Clouthier, Shawn G.; Wicha, Max S.

    2012-01-01

    Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL-6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL-6 than parental cells. An IL-6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL-6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance. PMID:22819326

  11. Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells.

    PubMed

    Wu, Yanyuan; Ginther, Charles; Kim, Juri; Mosher, Nicole; Chung, Seyung; Slamon, Dennis; Vadgama, Jaydutt V

    2012-12-01

    To understand the mechanisms leading to trastuzumab resistance in HER2-overexpressing breast tumors, we created trastuzumab-insensitive cell lines (SKBR3/100-8 and BT474/100-2). The cell lines maintain HER2 receptor overexpression and show increase in EGF receptor (EGFR). Upon trastuzumab treatment, SKBR3/100-8 and BT474/100-2 cell lines displayed increased growth rate and invasiveness. The trastuzumab resistance in SKBR3/100-8 and BT474/100-2 was accompanied with activation of the Wnt/β-catenin signaling pathway. Further investigation found that Wnt3 overexpression played a key role toward the development of trastuzumab resistance. The expression of Wnt3 in trastuzumab-resistant cells increased nuclear expression of β-catenin and transactivated expression of EGFR. The increased Wnt3 in the trastuzumab-resistant cells also promoted a partial EMT-like transition (epithelial-to-mesenchymal transition); increased N-cadherin, Twist, Slug; and decreased E-cadherin. Knockdown of Wnt3 by siRNA restored cytoplasmic expression of β-catenin and decreased EGFR expression in trastuzumab-resistant cells. Furthermore, the EMT markers were decreased, E-cadherin was increased, and the cell invasiveness was inhibited in response to the Wnt3 downregulation. Conversely, SKBR3 cells which had been stably transfected with full-length Wnt3 exhibited EMT-like transition. The Wnt3 transfectants, SKBR3/Wnt3-7 and SKBR3/Wnt3-9, showed a significant decrease in E-cadherin and increase in N-cadherin, Twist, and Slug. The cells were less sensitive to trastuzumab than parental SKBR3 and vector-transfected cells. In summary, our data suggest that Wnt3 overexpression activates Wnt/β-catenin signaling pathway that leads to transactivation of EGFR and promotes EMT-like transition. This could be an important mechanism leading to trastuzumab resistance in HER2-overexpressing breast cancer cells.

  12. Dissecting GRB7-mediated signals for proliferation and migration in HER2 overexpressing breast tumor cells: GTP-ase rules

    PubMed Central

    Pradip, De; Bouzyk, Mark; Dey, Nandini; Leyland-Jones, Brian

    2013-01-01

    Amplification of human Her2 and its aberrant signaling in 20-30% of early breast cancer patients is responsible for highly aggressive tumors with poor outcome. Grb7 is reported to be co-amplified with Her2. We report a concurrent high expression of mRNA (from FFPE tumor samples; mRNA correlation, Pearson r2= 0.806), and high levels of GRB7 protein (immunoblot) in HER2+ breast cancer cell lines. We demonstrated the signaling mechanism of HER2 and downstream effectors that contributes to proliferation and migration. Using HER2+ and trastuzumab-resistant breast cancer cell lines, we identified the interaction between GRB7 and HER2 in the control of HER2+ cell proliferation. Our co-IP data show that GRB7 recruits SHC into the HER2-GRB7 signaling complex. This complex formation leads to activation of RAS-GTP. We also observed that following integrin engagement, GRB7 is phosphorylated at tyrosine in a p-FAK (Y397) dependent manner. This FAK-GRB7 complex leads to downstream activation of RAC1-GTP (responsible for migration) probably through the recruitment of VAV2. Our CO-IP data demonstrate that GRB7 directly binds with VAV2 following fibronectin engagement in HER2+ cells. To address whether GRB7 could serve as a pathway specific therapeutic target, we used siRNA to suppress GRB7 expression. Knockdown of GRB7 expression in the HER2+ breast cancer cell lines decreases RAS activation, cell proliferation, 2D and 3D colony formation and also blocked integrin-mediated RAC1 activation along with integrin-directed cell migration. These findings dissected the HER2-mediated signaling cascade into (1) HER2+ cell proliferation (HER2-GRB7-SHC-RAS) and (2) HER2+ cell migration (alpha5 beta1/alpha4 beta1-FAK-GRB7-VAV2-RAC1). Our data clearly demonstrate that a coupling of GRB7 with HER2 is required for the proliferative and migratory signals in HER2+ breast tumor cells. PMID:23593540

  13. Immunoliposome encapsulation increases cytotoxic activity and selectivity of curcumin and resveratrol against HER2 overexpressing human breast cancer cells.

    PubMed

    Catania, Angela; Barrajón-Catalán, Enrique; Nicolosi, Silvia; Cicirata, Federico; Micol, Vicente

    2013-08-01

    Natural compounds have been studied as a source of countless bioactive compounds with diverse activities. Among them, many dietary phytochemicals have been thoroughly studied for their cytotoxic or apoptotic effects in several cellular models in order to explain their anticancer capacity. Curcumin and resveratrol are two natural compounds with a large body of evidence showing their cytotoxic activity against a wide variety of cancer cells; however, their poor absorption, bioavailability, and low selectivity have limited their clinical use. With the aim of improving bioavailability and selectivity, the antiproliferative effects of free-, liposomed-, and immunoliposomed-curcumin and/or resveratrol formulations have been compared in two human breast cancer cell lines with different HER2 expression levels. The results demonstrate that when HER2-targeted immunoliposomes are coupled to trastuzumab there is a dramatic increase in the antiproliferative effects of curcumin and resveratrol in HER2 positive human breast cancer cells in comparison to regular liposomed or free forms, indicating an increase of its therapeutic effect. The enhancement of the cytotoxic effects was also correlated to the uptake of curcumin at intracellular level, as shown by using ImageStream technique. The striking efficacy of the immunoliposomed formulation containing both resveratrol and curcumin suggests a multitargeted mechanism of action that deserves further study. These findings show the potential of HER2-targeted nanovesicles to develop new drug delivery systems for cancer therapy based on these compounds and justify further preclinical trials.

  14. Polymeric micelles as a diagnostic tool for image-guided drug delivery and radiotherapy of HER2 overexpressing breast cancer

    NASA Astrophysics Data System (ADS)

    Hoang, Nu Bryan

    Block copolymer micelles have emerged as a viable formulation strategy with several drugs relying on this technology in clinical evaluation. To date, information on the tumor penetration and intratumoral distribution of block copolymer micelles (BCM) has been quite limited. Thus, there is impetus to develop a radiolabeled formulation that can be used to gain invaluable insight into the intratumoral distribution of the BCMs. This information could then be used to direct formulation strategies as a means to optimize treatment outcomes. This thesis describes the synthesis and characterization of a targeted block copolymer micelle system based on poly(ethylene glycol)-block -poly(epsilon-caprolactone) labeled with the radionuclide Indium-111 (111In). The incorporation of the imageable component, 111In permits pursuit of image-guided drug delivery for real-time monitoring of tumor localization and intratumoral distribution. Intracellular trafficking of drugs and therapies such as Auger electron emitting radionuclides to perinuclear and nuclear regions of cells is critical to realizing their full therapeutic potential. HER2 specific antibodies (trastuzumab fab fragments) and nuclear localization signal peptides were conjugated to the surface of the BCMs to direct uptake in HER2 expressing cells and subsequent localization in the cell nucleus. Cell uptake was HER2 density dependent, confirming receptor-mediated internalization of the BCMs. Importantly, conjugation of NLS resulted in a significant increase in nuclear uptake of the radionuclide 111In. Successful nuclear targeting was shown to improve the antiproliferative effect of the Auger electrons. In addition, a significant radiation enhancement effect was observed by concurrent delivery of low-dose MTX and 111In in all breast cancer cell lines evaluated. Imaging enabled the accurate quantification of the specific tumor uptake of the micelles and visualization of their degree of tumor penetration in relation to

  15. Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells.

    PubMed

    Carpenter, R L; Paw, I; Dewhirst, M W; Lo, H-W

    2015-01-29

    Epithelial-mesenchymal transition (EMT) is an essential step for tumor progression, although the mechanisms driving EMT are still not fully understood. In an effort to investigate these mechanisms, we observed that heregulin (HRG)-mediated activation of HER2, or HER2 overexpression, resulted in EMT, which is accompanied with increased expression of a known EMT regulator Slug, but not TWIST or Snail. We then investigated how HER2 induced Slug expression and found, for the first time, that there are four consensus HSF sequence-binding elements (HSEs), the binding sites for heat shock factor-1 (HSF-1), located in the Slug promoter. HSF-1 bound to and transactivated the Slug promoter independent of heat shock, leading to Slug expression in breast cancer cells. Mutation of the putative HSEs ablated Slug transcriptional activation induced by HRG or HSF-1 overexpression. Knockdown of HSF-1 expression by siRNA reduced Slug expression and HRG-induced EMT. The positive association between HSF-1 and Slug was confirmed by immunohistochemical staining of a cohort of 100 invasive breast carcinoma specimens. While investigating how HER2 activated HSF-1 independent of heat shock, we observed that HER2 activation resulted in concurrent phosphorylation of Akt and HSF-1. We then observed, also for the first time, that Akt directly interacted with HSF-1 and phosphorylated HSF-1 at S326. Inhibition of Akt using siRNA, dominant-negative Akt mutant, or small molecule inhibitors prevented HRG-induced HSF-1 activation and Slug expression. Conversely, constitutively active Akt induced HSF-1 phosphorylation and Slug expression. HSF-1 knockdown reduced the ability of Akt to induce Slug expression, indicating an essential role that HSF-1 plays in Akt-induced Slug upregulation. Altogether, our study uncovered the existence of a novel Akt-HSF-1 signaling axis that leads to Slug upregulation and EMT, and potentially contributes to progression of HER2-positive breast cancer.

  16. Apigenin induces caspase-dependent apoptosis by inhibiting signal transducer and activator of transcription 3 signaling in HER2-overexpressing SKBR3 breast cancer cells.

    PubMed

    Seo, Hye-Sook; Ku, Jin Mo; Choi, Han-Seok; Woo, Jong-Kyu; Jang, Bo-Hyoung; Go, Hoyeon; Shin, Yong Cheol; Ko, Seong-Gyu

    2015-08-01

    Phytoestrogens have been demonstrated to inhibit tumor induction; however, their molecular mechanisms of action have remained elusive. The present study aimed to investigate the effects of a phytoestrogen, apigenin, on proliferation and apoptosis of the human epidermal growth factor receptor 2 (HER2)-expressing breast cancer cell line SKBR3. Proliferation assay, MTT assay, fluorescence-activated cell sorting analysis, western blot analysis, immunocytochemistry, reverse transcription-polymerase chain reaction and ELISA assay were used in the present study. The results of the present study indicated that apigenin inhibited the proliferation of SKBR3 cells in a dose-and time-dependent manner. This inhibition of growth was accompanied by an increase in the sub-G0/G1 apoptotic population. Furthermore, apigenin enhanced the expression levels of cleaved caspase-8 and -3, and induced the cleavage of poly(adenosine diphosphate ribose) polymerase in SKBR3 cells, confirming that apigenin promotes apoptosis via a caspase-dependent pathway. Apigenin additionally reduced the expression of phosphorylated (p)-janus kinase 2 and p-signal transducer and activator of transcription 3 (STAT3), inhibited CoCl2-induced vascular endothelial growth factor (VEGF) secretion and decreased the nuclear localization of STAT3. The STAT3 inhibitor S31-201 decreased the cellular proliferation rate and reduced the expression of p-STAT3 and VEGF. Therefore, these results suggested that apigenin induced apoptosis via the inhibition of STAT3 signaling in SKBR3 cells. In conclusion, the results of the present study indicated that apigenin may be a potentially useful compound for the prevention or treatment of HER2-overexpressing breast cancer.

  17. Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overexpressing breast cancer cells.

    PubMed

    Seo, Hye-Sook; Choi, Han-Seok; Kim, Soon-Re; Choi, Youn Kyung; Woo, Sang-Mi; Shin, Incheol; Woo, Jong-Kyu; Park, Sang-Yoon; Shin, Yong Cheol; Ko, Seong-Gyu; Ko, Seong-Kyu

    2012-07-01

    Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are still unknown. This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of sub G(0)/G(1) apoptotic fractions. Overexpression of HER2 did not confer resistance to apigenin in MCF-7 cells. Apigenin-induced extrinsic apoptosis pathway up-regulating the levels of cleaved caspase-8, and inducing the cleavage of poly (ADP-ribose) polymerase, whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein. Moreover, apigenin reduced the tyrosine phosphorylation of HER2 (phospho-HER2 level) in MCF-7 HER2 cells, and up-regulated the levels of p53, phospho-p53 and p21 in MCF-7 vec and MCF-7 HER2 cells. This suggests that apigenin induces apoptosis through p53-dependent pathway. Apigenin also reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in MCF-7 vec and MCF-7 HER2 cells. Apigenin decreased the phosphorylation level of IκBα in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFκB signaling pathway in MCF-7 vec and MCF-7 HER2 cells. Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer.

  18. Quercetin induces caspase-dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in HER2-overexpressing BT-474 breast cancer cells.

    PubMed

    Seo, Hye-Sook; Ku, Jin Mo; Choi, Han-Seok; Choi, Youn Kyung; Woo, Jong-Kyu; Kim, Minsoo; Kim, Ilhwan; Na, Chang Hyeok; Hur, Hansol; Jang, Bo-Hyoung; Shin, Yong Cheol; Ko, Seong-Gyu

    2016-07-01

    Flavonoids are assumed to exert beneficial effects in different types of cancers at high concentrations. Yet, their molecular mechanisms of action remain unknown. The present study aimed to examine the effect of quercetin on proliferation and apoptosis in HER2-expressing breast cancer cells. The anti-proliferative effects of quercetin were examined by proliferation, MTT and clonogenic survival assays. The effect of quercetin on expression of apoptotic molecules was determined by western blotting. Luciferase reporter assay was performed to measure signal transducer and activator of transcription 3 (STAT3) transcriptional activity. ELISA assay was performed to measure intracellular MMP-9 levels. Immunocytochemistry was performed to evaluate the nuclear STAT3 level. The results revealed that quercetin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Quercetin also inhibited clonogenic survival (anchorage-dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Quercetin induced caspase-dependent extrinsic apoptosis upregulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly(ADP‑ribose) polymerase (PARP). In contrast, quercetin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease the mitochondrial membrane potential and did not affect the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Quercetin reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in the BT-474 cells. Quercetin inhibited MMP-9 secretion and decreased the nuclear translocation of STAT3. Our study indicates that quercetin induces apoptosis at concentrations >20 µM through inhibition of STAT3 signaling and could serve as a useful compound to prevent or treat HER2

  19. Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer.

    PubMed

    Park, John W; Melisko, Michelle E; Esserman, Laura J; Jones, Lori A; Wollan, Jami Breen; Sims, Robert

    2007-08-20

    Lapuleucel-T (APC8024), an autologous active cellular immunotherapy, was prepared from peripheral-blood mononuclear cells, including antigen-presenting cells, that were activated in vitro with recombinant fusion protein BA7072. This antigen construct consisted of sequences from intracellular and extracellular domains of human epidermal growth factor receptor 2 (HER-2) linked to granulocyte-macrophage colony-stimulating factor. We conducted a phase I study to evaluate the safety and immunologic activity of lapuleucel-T in patients with HER-2-overexpressing metastatic breast cancer. Metastatic breast cancer patients whose tumors overexpressed or amplified HER-2 were eligible. Patients underwent leukapheresis and subsequent lapuleucel-T infusion 2 days later at weeks 0, 2, and 4. Patients who achieved a partial response (PR) or had stable disease (SD) lasting through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment. End points included safety, immunologic activity, and antitumor activity. Nineteen patients were enrolled; 18 patients received treatment. Therapy was well tolerated, with no grade 3 or 4 adverse events associated with the treatment. Significant cellular immune responses specific for the immunizing antigen and HER-2 sequences were induced after treatment, as measured by lymphocyte proliferation and interferon gamma enzyme-linked immunospot assay. One patient experienced a PR lasting 6 months. Three additional patients had SD lasting more than 1 year. Autologous active cellular immunotherapy with lapuleucel-T was feasible, safe, and well tolerated. The treatment stimulated significant immune responses, which were enhanced after boost infusions. Lapuleucel-T therapy was associated with tumor response or extended disease stabilization in some patients and warrants further investigation.

  20. Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: new insights into de novo resistance to trastuzumab (Herceptin).

    PubMed

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Martin-Castilló, Begoña; Pérez-Martínez, Maria Carmen; Cufí, Silvia; Del Barco, Sonia; Bernado, Luis; Brunet, Joan; López-Bonet, Eugeni; Menendez, Javíer A

    2010-09-01

    Pioneering clinical studies in de novo refractoriness to the anti-HER2 monoclonal antibody trastuzumab have suggested that HER2 gene-amplification can take place also in a basal-like molecular background to generate basal/HER2+ tumors intrinsically resistant to trastuzumab. Here, we first investigated the unique histogenesis of the basal/HER2+ phenotype in breast carcinomas. The presence of basal CK5/CK6 cytokeratin expression in HER2+ tumors revealed a significant overlap in the histological features of HER2+/CK5/6+ and basal-like breast carcinomas. Basal/HER2+ tumors were typically poorly differentiated, high-grade invasive ductal carcinomas with large geographic necrosis, pushing margins of invasion, syncytial arrangement of tumor cells, ribbon- or festoon-like architecture, squamous metaplasia, stromal lymphocytic infiltrates, high mitotic index and strong p53 positivity. Secondly, we performed low-scale proteomic approaches in JIMT-1 cells, a unique model of HER2-gene amplified trastuzumab-resistant breast carcinoma with a basal-like phenotype, to develop biomarker signatures that may differentiate trastuzumab-responsive from non-responsive tumors. When applying antibody-based array technology to the extracellular milieu of trastuzumab-refractory JIMT-1 and trastuzumab-sensitive SKBR3 cell cultures, JIMT-1 cells were found to secrete higher amounts of several growth factors including amphiregulin, EGF, IGFBP-6, PDGF-AA, neurotrophins, TGFbeta and VEGF. Semi-quantitative signaling node multi-target sandwich ELISAs revealed that JIMT-1 cells drastically overactivate RelA, the prosurvival subunit of NF-kappaB as compared to trastuzumab-sensitive luminal/HER2+ SKBR3 cells. When simultaneously assessing the activation status of 42 receptor tyrosine kinases (RTK) using a human phospho-RTK array, JIMT-1 cells were found to constitutively display hyperactivation of the insulin-like growth factor-I receptor (IGF-1R). High-content immunofluorescence imaging revealed

  1. A Pilot Study of Dose-Dense Paclitaxel With Trastuzumab and Lapatinib for Node-negative HER2-Overexpressed Breast Cancer

    PubMed Central

    Iyengar, Neil M.; Fornier, Monica N.; Sugarman, Steven M.; Theodoulou, Maria; Troso-Sandoval, Tiffany A.; D’Andrea, Gabriella M.; Drullinsky, Pamela R.; Gajria, Devika; Goldfarb, Shari B.; Comen, Elizabeth A.; Lake, Diana E.; Modi, Shanu; Traina, Tiffany A.; Lacouture, Mario E.; Chen, Melanie F.; Patil, Sujata; Baselga, José; Norton, Larry; Hudis, Clifford A.; Dang, Chau T.

    2016-01-01

    Treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer with dual anti-HER2 therapy has been shown to improve outcomes. In the present pilot phase II study, patients with early-stage HER2-positive breast cancer received adjuvant treatment with dose-dense paclitaxel, trastuzumab, and lapatinib. However, this combination was not feasible because of unexpected toxicity. Background Dual anti-HER2 therapy is effective for HER2-amplified breast cancer. Weekly paclitaxel, trastuzumab, and full-dose lapatinib (PTL) is not feasible because of grade 3 diarrhea. We conducted a phase II feasibility study of dose-dense (DD; every other week) PTL (ClinicalTrials.gov identifier, NCT01827163). Patients and Methods Eligible patients had HER2-positive breast cancer, tumor size ≤ 3 cm, and negative nodes. Treatment included paclitaxel (175 mg/m2 × 4, every 2 weeks with pegfilgrastim), trastuzumab (4 mg/kg load and then 2 mg/kg weekly), and lapatinib (1000 mg daily). After paclitaxel × 4, trastuzumab (6 mg/kg every 3 weeks) plus lapatinib were continued for 1 year. The primary endpoint was feasibility, defined as (1) > 80% of patients completing PTL without a dose delay or reduction, (2) grade 3 diarrhea rate < 20%, and (3) cardiac event rate < 4%. Results From May 2013 to November 2013, we enrolled 20 of 55 planned patients. The median age was 49 years (range, 34–74 years). One patient had immediate paclitaxel hypersensitivity and was deemed inevaluable. Only 13 of 19 evaluable patients (68%) completed PTL without a dose delay or reduction or unacceptable toxicities. Only 3 of 19 (16%) had grade 3 diarrhea. Rash was frequent, with all grades in 18 of 19 (95%) and grade 3 in 2 of 19 (11%). The study was stopped early because of excess toxicity. Conclusion The discontinuation rate during DD PTL was high, owing, in part, to an unexpectedly high incidence of rash. The trial was halted, because the initial discontinuation rate from overall toxicity made

  2. Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells.

    PubMed

    Seo, Hye-Sook; Jo, Jae Kyung; Ku, Jin Mo; Choi, Han-Seok; Choi, Youn Kyung; Woo, Jong-Kyu; Kim, Hyo In; Kang, Soo-Yeon; Lee, Kang Min; Nam, Koong Won; Park, Namkyu; Jang, Bo-Hyoung; Shin, Yong Cheol; Ko, Seong-Gyu

    2015-10-23

    Phytoestrogen intake is known to be beneficial to decrease breast cancer incidence and progression. But its molecular mechanisms of action are still unknown. The present study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Apigenin also inhibited clonogenic survival (anchorage-dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Apigenin-induced extrinsic a caspase-dependent apoptosis up-regulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly (ADP-ribose) polymerase (PARP). Whereas, apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential without affecting the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Apigenin reduced the expression of phospho-JAK1, phospho-JAK2 and phospho-STAT3 and decreased signal transducer and activator of transcription 3 (STAT3) dependent luciferase reporter gene activity in BT-474 cells. Apigenin inhibited CoCl2-induced VEGF secretion and decreased the nuclear translocation of STAT3. Our study indicates that apigenin induces apoptosis through inhibition of STAT3 signalling and could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer.

  3. Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2.

    PubMed

    Rexer, Brent N; Ghosh, Ritwik; Narasanna, Archana; Estrada, Mónica Valeria; Chakrabarty, Anindita; Song, Youngchul; Engelman, Jeffrey A; Arteaga, Carlos L

    2013-10-01

    Mutations in receptor tyrosine kinase (RTK) genes can confer resistance to receptor-targeted therapies. A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib. We studied the mechanisms of HER2-T798M-induced resistance to identify potential strategies to overcome that resistance. HER2-T798M was stably expressed in BT474 and MCF10A cells. Mutant cells and xenografts were evaluated for effects of the mutation on proliferation, signaling, and tumor growth after treatment with combinations of inhibitors targeting the EGFR/HER2/HER3/PI3K axis. A low 3% allelic frequency of the T798M mutant shifted 10-fold the IC50 of lapatinib. In mutant-expressing cells, lapatinib did not block basal phosphorylation of HER2, HER3, AKT, and ERK1/2. In vitro kinase assays showed increased autocatalytic activity of HER2-T798M. HER3 association with PI3K p85 was increased in mutant-expressing cells. BT474-T798M cells were also resistant to the HER2 antibody trastuzumab. These cells were sensitive to the pan-PI3K inhibitors BKM120 and XL147 and the irreversible HER2/EGFR TKI afatinib but not the MEK1/2 inhibitor CI-1040, suggesting continued dependence of the mutant cells on ErbB receptors and downstream PI3K signaling. BT474-T798M cells showed increased expression of the EGFR ligands EGF, TGFα, amphiregulin, and HB-EGF. Addition of the EGFR neutralizing antibody cetuximab or lapatinib restored trastuzumab sensitivity of BT474-T798M cells and xenografts, suggesting that increased EGFR ligand production was causally associated with drug resistance. Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene-amplified breast cancer cells harboring T798M mutant alleles. ©2013 AACR.

  4. Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells

    PubMed Central

    Seo, Hye-Sook; Jo, Jae Kyung; Ku, Jin Mo; Choi, Han-Seok; Choi, Youn Kyung; Woo, Jong-Kyu; in Kim, Hyo; Kang, Soo-yeon; Lee, Kang min; Nam, Koong Won; Park, Namkyu; Jang, Bo-Hyoung; Shin, Yong Cheol; Ko, Seong-Gyu

    2015-01-01

    Phytoestrogen intake is known to be beneficial to decrease breast cancer incidence and progression. But its molecular mechanisms of action are still unknown. The present study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Apigenin also inhibited clonogenic survival (anchorage-dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Apigenin-induced extrinsic a caspase-dependent apoptosis up-regulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly (ADP-ribose) polymerase (PARP). Whereas, apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential without affecting the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Apigenin reduced the expression of phospho-JAK1, phospho-JAK2 and phospho-STAT3 and decreased signal transducer and activator of transcription 3 (STAT3) dependent luciferase reporter gene activity in BT-474 cells. Apigenin inhibited CoCl2-induced VEGF secretion and decreased the nuclear translocation of STAT3. Our study indicates that apigenin induces apoptosis through inhibition of STAT3 signalling and could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer. PMID:26500281

  5. A phase 2 randomized trial to evaluate the impact of a supervised exercise program on cardiotoxicity at 3 months in patients with HER2 overexpressing breast cancer undergoing adjuvant treatment by trastuzumab: design of the CARDAPAC study.

    PubMed

    Jacquinot, Quentin; Meneveau, Nathalie; Chatot, Marion; Bonnetain, Franck; Degano, Bruno; Bouhaddi, Malika; Dumoulin, Gilles; Vernerey, Dewi; Pivot, Xavier; Mougin, Fabienne

    2017-06-19

    The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer is a poor prognosis. Trastuzumab improves overall survival but is associated with cardiotoxicity, especially a decline in left ventricular ejection fraction (LVEF). In addition, chemotherapy and radiotherapy increase fatigue and pain, decrease physical capacity and health-related quality of life. To date, no study has evaluated the benefits of physical activity on the side effects of treatment in patients with HER2 positive breast cancer. The aim of this study is to evaluate the impact of 3 months' exercise intervention on myocardial function and in particular on the rate of cardiotoxicity. This multicenter, randomized clinical trial will include 112 patients treated by adjuvant trastuzumab for HER2 positive breast cancer to investigate the effects of a 3 months' supervised exercise program (intermittent exercise, combining moderate and high intensities; 55 minutes duration, 3 times per week), on the rate of cardiotoxicity [defined by either a decrease of the LVEF under 50% or an absolute drop of LVEF of 10%] between baseline and at 3 months and on strength, aerobic capacity, metabolic, inflammatory and hormonal parameters. Health-related quality of life, fatigue, pain and level of physical activity will also be assessed. Participants are randomly allocated to one of the two groups ("training group" vs "standard oncological care"). Performance-based and self-reported outcomes are assessed at baseline, at the end of supervised exercise program and at six months follow-up. Although physical exercise is recommended to reduce the side effects of adjuvant treatments in breast cancer patients, no randomized study has been conducted to assess the benefits of a physical training program in patients with HER2 overexpressing breast cancer. Cardiac toxicity of trastuzumab may be minimized with an exercise program combining high and moderate intensities. This type of program may be safe

  6. Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer.

    PubMed

    Li, Wei-Ming; Chiang, Chih-Sheng; Huang, Wei-Chen; Su, Chia-Wei; Chiang, Min-Yu; Chen, Jian-Yi; Chen, San-Yuan

    2015-12-28

    We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers.

  7. Targeting GPR110 in HER2-Overexpressing Breast Cancers

    DTIC Science & Technology

    2015-10-01

    reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions...Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204... Research and Materiel Command Fort Detrick, Maryland 21702-5012 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT

  8. Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma

    PubMed Central

    De Silva, Nadeera; Schulz, Laura; Paterson, Anna; Qain, Wendi; Secrier, Maria; Godfrey, Edmund; Cheow, Heok; O'Donovan, Maria; Lao-Sirieix, Pierre; Jobanputra, Minesh; Hochhauser, Daniel; Fitzgerald, Rebecca; Ford, Hugo

    2015-01-01

    Background: Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. Methods: Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/− Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. Results: The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. Conclusions: Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo. PMID:26484410

  9. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function

    PubMed Central

    Garrett, Joan T.; Sutton, Cammie R.; Kuba, María Gabriela; Cook, Rebecca S .; Arteaga, Carlos L.

    2012-01-01

    Purpose Dual blockade of HER2 with trastuzumab with lapatinib or with pertuzumab is a superior treatment approach compared to single agent HER2 inhibitors. However, many HER2-overexpressing breast cancers still escape from this combinatorial approach. Inhibition of HER2 and downstream phosphatidylinositol-3 kinase (PI3K)/AKT causes a transcriptional and post-translational upregulation of HER3 which, in turn, counteracts the antitumor action of the HER2-directed therapies. We hypothesized that suppression of HER3 would synergize with dual blockade of HER2 in breast cancer cells sensitive and refractory to HER2 antagonists. Experimental Design Inhibition of HER2/HER3 in HER2+ breast cancer cell lines was evaluated by western blot. We analyzed drug-induced apoptosis and 2- and 3-dimensional growth in vitro. Growth inhibition of PI3K was examined in vivo in xenografts treated with combinations of trastuzumab, lapatinib, and the HER3 neutralizing monoclonal antibody U3-1287. Results Treatment with U3-1287 blocked the upregulation of total and phosphorylated HER3 that followed treatment with lapatinib and trastuzumab and, in turn, enhanced the anti-tumor action of the combination against trastuzumab-sensitive and -resistant cells. Mice bearing HER2+ xenografts treated with lapatinib, trastuzumab, and U3-1287 exhibited fewer recurrences and better survival compared to mice treated with lapatinib and trastuzumab. Conclusions Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3. Therapeutic inhibitors of HER3 should be considered as part of multi-drug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers. PMID:23224399

  10. PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma.

    PubMed

    Deguchi, Yasunori; Okabe, Hiroshi; Oshima, Nobu; Hisamori, Shigeo; Minamiguchi, Sachiko; Muto, Manabu; Sakai, Yoshiharu

    2017-05-01

    Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as "gastroesophageal adenocarcinoma"; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA. Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy. PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G1 cell cycle arrest were inhibited by PTEN knockdown through Akt activation in NCI-N87 and OE19 cells. PTEN knockdown impaired the antiproliferative effect of trastuzumab in OE19 xenograft models. A clinical response was observed in 50 % of PTEN-positive tumors (9 of 18) but in no tumors with PTEN loss (none of 5). PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.

  11. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

    PubMed

    Richman, Susan D; Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

    2016-03-01

    HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society

  12. Simvastatin inhibits tumor angiogenesis in HER2-overexpressing human colorectal cancer.

    PubMed

    Li, Gang; Zheng, Junhua; Xu, Bin; Ling, Jie; Qiu, Wei; Wang, Yongbing

    2017-01-01

    Overexpression of the HER2 oncogene contributes to tumor angiogenesis, which is an essential hallmark of cancer. Simvastatin has been reported to exhibit antitumor activities in several cancers; however, its roles and molecular mechanismsin the regulation of colorectal angiogenesis remain to be clarified. Here, we show that colon cancer cells express high levels of VEGF, total HER2 and phosphorylated HER2, and simvastatin apparently decreased their expression in HER2-overexpressing colon cancer cells. Simvastatin pretreatment reduced endothelial tube formation in vitro and microvessel density in vivo. Furthermore, simvastatin markedly inhibited tumor angiogenesis even in the presence of heregulin (HRG)-β1 (a HER2 co-activator) pretreatment in HER2+ tumor cells. Mechanistic investigation showed that simvastatin significantly abrogated HER2-induced tumor angiogenesis by inhibiting VEGF secretion. Together, these results provide a novel mechanism underlying the simvastatin-induced inhibition of tumor angiogenesis through regulating HER2/VEGF axis.

  13. Curing Metastatic Breast Cancer.

    PubMed

    Sledge, George W

    2016-01-01

    Metastatic breast cancer is generally considered incurable, and this colors doctor-patient interactions for patients with metastatic disease. Although true for most patients, there appear to be important exceptions, instances where long-term disease-free survival occurs. Although these instances are few in number, they suggest the possibility of cure. How will we move toward cure for a much larger population of patients with metastatic disease? This article outlines a potential research agenda that might move us toward that distant goal. Copyright © 2016 by American Society of Clinical Oncology.

  14. Increased risk of brain metastases in women with breast cancer and p16 expression in metastatic lymph-nodes.

    PubMed

    Furet, Elise; El Bouchtaoui, Morad; Feugeas, Jean-Paul; Miquel, Catherine; Leboeuf, Christophe; Beytout, Clémentine; Bertheau, Philippe; Le Rhun, Emilie; Bonneterre, Jacques; Janin, Anne; Bousquet, Guilhem

    2017-06-06

    Metastatic breast cancer is a leading cause of mortality in women, partly on account of brain metastases. However, the mechanisms by which cancer cells cross the blood-brain barrier remain undeciphered. Most molecular studies predicting metastatic risk have been performed on primary breast cancer samples. Here we studied metastatic lymph-nodes from patients with breast cancers to identify markers associated with the occurrence of brain metastases. Transcriptomic analyses identified CDKN2A/p16 as a gene potentially associated with brain metastases. Fifty-two patients with HER2-overexpressing or triple-negative breast carcinoma with lymph nodes and distant metastases were included in this study. Transcriptomic analyses were performed on laser-microdissected tumor cells from 28 metastatic lymph-nodes. Supervised analyses compared the transcriptomic profiles of women who developed brain metastases and those who did not. As a validation series, we studied metastatic lymph-nodes from 24 other patients.Immunohistochemistry investigations showed that p16 mean scores were significantly higher in patients with brain metastases than in patients without (7.4 vs. 1.7 respectively, p < 0.01). This result was confirmed on the validation series. Multivariate analyses showed that the p16 score was the only variable positively associated with the risk of brain metastases (p = 0.01).With the same threshold of 5 for p16 scores using a Cox model, overall survival was shorter in women with a p16 score over 5 in both series. The risk of brain metastases in women with HER2-overexpressing or triple-negative breast cancer could be better assessed by studying p16 protein expression on surgically removed axillary lymph-nodes.

  15. Increased risk of brain metastases in women with breast cancer and p16 expression in metastatic lymph-nodes

    PubMed Central

    Feugeas, Jean-Paul; Miquel, Catherine; Leboeuf, Christophe; Beytout, Clémentine; Bertheau, Philippe; Le Rhun, Emilie; Bonneterre, Jacques; Janin, Anne; Bousquet, Guilhem

    2017-01-01

    Purpose Metastatic breast cancer is a leading cause of mortality in women, partly on account of brain metastases. However, the mechanisms by which cancer cells cross the blood-brain barrier remain undeciphered. Most molecular studies predicting metastatic risk have been performed on primary breast cancer samples. Here we studied metastatic lymph-nodes from patients with breast cancers to identify markers associated with the occurrence of brain metastases. Results Transcriptomic analyses identified CDKN2A/p16 as a gene potentially associated with brain metastases. Materials and Methods Fifty-two patients with HER2-overexpressing or triple-negative breast carcinoma with lymph nodes and distant metastases were included in this study. Transcriptomic analyses were performed on laser-microdissected tumor cells from 28 metastatic lymph-nodes. Supervised analyses compared the transcriptomic profiles of women who developed brain metastases and those who did not. As a validation series, we studied metastatic lymph-nodes from 24 other patients. Immunohistochemistry investigations showed that p16 mean scores were significantly higher in patients with brain metastases than in patients without (7.4 vs. 1.7 respectively, p < 0.01). This result was confirmed on the validation series. Multivariate analyses showed that the p16 score was the only variable positively associated with the risk of brain metastases (p = 0.01). With the same threshold of 5 for p16 scores using a Cox model, overall survival was shorter in women with a p16 score over 5 in both series. Conclusions The risk of brain metastases in women with HER2-overexpressing or triple-negative breast cancer could be better assessed by studying p16 protein expression on surgically removed axillary lymph-nodes. PMID:28445153

  16. Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer?

    PubMed

    Arteaga, Carlos L

    2011-08-01

    Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer. ©2011 AACR.

  17. Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer?

    PubMed Central

    Arteaga, Carlos L.

    2011-01-01

    Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer. PMID:21670086

  18. 64Cu-DOTA-trastuzumab PET Imaging in Women with HER2 Overexpressing Breast Cancer

    DTIC Science & Technology

    2011-10-01

    for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection...James Bading , Ph.D.; Peter Conti, M.D., Ph.D. 5e. TASK NUMBER E-Mail: jmortimer@coh.org 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME...Supporting Data ……………………………………………………………………... 6 Annual Report 2011 Introduction: HER2 is a transmembrane protein in the epidermal growth

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

    PubMed

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

    2016-08-01

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

  20. Current approaches to the management of Her2-negative metastatic breast cancer

    PubMed Central

    2012-01-01

    While metastatic breast cancer (MBC) remains incurable, a vast array of active therapeutic agents has provided the opportunity for long-term disease control while maintaining quality of life and physical function. Optimal management of MBC balances a multitude of factors, including a woman's performance status, social support, symptoms, disease burden, prior therapies, and surrogates for tumor biology. Choosing the most appropriate initial therapy and subsequent sequence of treatments demands flexibility as goals and patient preferences may change. Knowledge of the estrogen receptor (ER), progesterone receptor (PR), and Her2 receptor status of the metastatic tumor has become critical to determining the optimal treatment strategy in the metastatic setting as targeted therapeutic approaches are developed. Patients with ER+ or PR+ breast cancer or both have a wide array of hormonal therapy options that can forestall the use of cytotoxic therapies, although rapidly progressive phenotypes and the emergence of resistance may ultimately lead to the need for chemotherapy in this setting. So-called 'triple-negative' breast cancer - lacking ER, PR, and Her2 overexpression - remains a major challenge. These tumors have an aggressive phenotype, and clear targets for therapy have not yet been established. Chemotherapy remains the mainstay of treatment in this group, but biologically based clinical trials of new agents are critical to developing a more effective set of therapies for this patient population. PMID:22429313

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

    SciTech Connect

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

    2007-02-01

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

  2. Breast Carcinoma in Young Women: No Evidence of Increasing Rates of Metastatic Breast Carcinoma in a Single Tertiary Center Review.

    PubMed

    Conlon, Niamh; Howard, Jane; Catalano, Jeffrey; Gallagher, Meighan; Tan, Lee K; Corben, Adriana D

    2016-05-01

    Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER-2 overexpression status for the period 2000-2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000-2003] to 8.7% [2008-2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER-2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER-2-positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12-year period 2000-2011 and no increase in the proportion of young patients presenting with metastatic disease. © 2016 Wiley Periodicals, Inc.

  3. Breast cancer (metastatic)

    PubMed Central

    2010-01-01

    Introduction Median survival from metastatic breast cancer is 12 months without treatment, but young people can survive up to 20 years with the disease, whereas in other metastatic cancers this would be considered unusual. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line hormonal treatment? What are the effects of second-line hormonal treatment in women who have not responded to tamoxifen? What are the effects of first-line chemotherapy? What are the effects of first-line chemotherapy in combination with a monoclonal antibody? What are the effects of second-line chemotherapy? What are the effects of treatments for bone metastases? What are the effects of treatments for spinal cord metastases? What are the effects of treatments for cerebral or choroidal metastases? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 77 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: first-line hormonal treatment using anti-oestrogens (tamoxifen), ovarian ablation, progestins, selective aromatase inhibitors, or combined gonadorelin analogues plus tamoxifen; second-line hormonal treatment using progestins or selective aromatase inhibitors; first-line non-taxane combination chemotherapy; first-line taxane-based combination chemotherapy; first-line high- versus low-dose standard chemotherapy

  4. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials

    PubMed Central

    Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

    2016-01-01

    Abstract HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti‐EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK–AKT pathway activation through HER2 up‐regulation. We assessed HER2‐amplification/overexpression in stage II–III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II–III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2‐amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression‐free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II–III tumours showed HER2 protein overexpression. Of the HER2‐overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II–III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2‐overexpression was associated with KRAS/BRAF wild‐type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II–III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II–III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2‐overexpressing cases experienced recurrence, but the difference was not significant. HER2‐amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II–III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2‐targeted therapy in patients with HER2‐amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John

  5. HER-2 overexpression/amplification in Barrett's oesophagus predicts early transition from dysplasia to adenocarcinoma: a clinico-pathologic study.

    PubMed

    Rossi, Elisa; Grisanti, Salvatore; Villanacci, Vincenzo; Della Casa, Domenico; Cengia, Paolo; Missale, Guido; Minelli, Luigi; Buglione, Michela; Cestari, Renzo; Bassotti, Gabrio

    2009-09-01

    Barrett's oesophagus (BO) is the primary precursor lesion for oesophageal adenocarcinoma (ADC). The natural history of metaplasia-dysplasia-carcinoma sequence remains largely unknown. HER2/neu oncogene results overexpressed/amplified in preneoplastic lesions and in ADC of the oesophagus and it has been associated with poor prognosis. Our aim was to evaluate the role of HER2 overexpression/amplification in predicting the conversion from precursor lesions to ADC. We retrospectively evaluated by univariate analysis of single variables clinical records and histological specimens of 21 patients with a confirmed diagnosis of BO and/or oesophageal dysplasia. Clinical variables included age, gender, alcohol and smoking intake, presence of symptoms (pyrosis, disphagia) and endoscopic features (length). HER2 status was studied by immunohistochemistry and fluorescence in situ hybridization (FISH) on paraffin-embedded tissue. The end-points were the occurrence of progression and the time-to-progression (TTP) from the initial histologic lesion to the worst pathological pattern. Median age at diagnosis was 63 years (range 37-84). BO median length was 4.5 cm. Progression occurred in 11 of 21 patients and median TTP was 24 months. HER2 was overexpressed/amplified in 8 of 21 (38%) patients. HER2 overexpression/ amplification and the presence of dysplasia were statistically associated with progression (P= 0.038). This study provides evidence for a possible role of HER2 in the transition from dysplasia to ADC of the oesophagus. This fact could help in identifying patients at high risk of malignant transformation.

  6. Megakaryocytes mimicking metastatic breast carcinoma.

    PubMed

    Hoda, Syed A; Resetkova, Erika; Yusuf, Yasmin; Cahan, Anthony; Rosen, Paul P

    2002-05-01

    False-positive diagnosis of lymph nodes occurs when a benign element in a lymph node, or in its capsule, is interpreted as metastatic carcinoma. This report describes a patient with breast carcinoma who had megakaryocytes in axillary sentinel lymph nodes mimicking metastatic carcinoma. The patient had no history of a hematologic disease, and we found no evidence of a concurrent hematopoietic disorder. The megakaryocytes were reactive for CD31, CD61, and von Willebrand factor, but not for cytokeratin (AE1/AE3). Megakaryocytes should be added to the list of benign histologic abnormalities that may simulate metastatic carcinoma in a sentinel lymph node.

  7. Cutaneous metastatic pigmented breast carcinoma.

    PubMed

    Gaitan-Gaona, Francisco; Said, Mirra C; Valdes-Rodriguez, Rodrigo

    2016-03-16

    A 66-year-old woman presented with a 3 cm black, ulcerated nodule located on the skin of the upper abdomen, just below the breast. The lesion was painful to the touch, but the patient reported no other associated symptoms and was otherwise healthy. A 4-mm punch biopsy of the affected skin was obtained and the histological diagnosis was cutaneous metastatic pigmented breast carcinoma.

  8. Outcome prediction values of soluble human epidermal growth factor receptor-2 extracellular domain in metastatic breast cancer.

    PubMed

    Shao, Xiying; Wang, Xian; Xu, Xiaohong; Feng, Jianguo; Han, Mark; Zhang, Han; Chen, Zhan-Hong; Wang, Sheng; Zang, Yi-Min; Huang, Ping; Jin, Hongchuan; Wang, Xiaojia

    2014-01-01

    HER-2 overexpression is an independent predictor for poor prognosis of breast cancer patients. Recently, extracellular domain of HER-2 (ECD) was found detectable in the serum of breast cancer patients. In this prospective study, we wonder whether ECD levels predict the clinical outcome of metastatic breast cancer patients. ECD were measured in 190 women with metastatic breast cancer. Chi-square test was performed to determine the relationship between ECD status and clinical outcomes. Kaplan-Meier curves were applied for survival analysis. Elevated ECD levels were significantly associated with short-term response to Herceptin treatment. The median PFS was significantly longer in ECD-Low patients. The patients who remained low ECD levels or achieved low ECD levels after treatments have significantly longer PFS than those whose levels remained high or converted from low to high. Overall, our results support the clinical utility of measuring serum HER2 ECD levels in patients with advanced breast cancer. Baseline and serial measurements of serum ECD levels are reliably predictive of clinical outcome of breast cancer patients.

  9. Inhibition of mTOR is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells

    PubMed Central

    Miller, Todd W.; Forbes, James T.; Shah, Chirayu; Wyatt, Shelby K.; Manning, H. Charles; Olivares, Maria G.; Sanchez, Violeta; Dugger, Teresa C.; Granja, Nara de Matos; Narasanna, Archana; Cook, Rebecca S.; Kennedy, J. Phillip; Lindsley, Craig W.; Arteaga, Carlos L.

    2009-01-01

    Purpose A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mTOR is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab. Experimental Design Immunocompetent mice bearing HER2-positive mammary tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the combination. Mice were imaged for tumor cell death using an optical Annexin-V probe and with [18F]FDG-PET. The signaling and growth effects of the mTOR inhibitor RAD001 on HER2+ cells treated with trastuzumab or lapatinib were evaluated. Results Treatment of mice with trastuzumab plus rapamycin was more effective than single-agent treatments, inducing complete regression of 26/26 tumors. The combination induced tumor cell death (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor cell proliferation as determined by phospho-S6 and Ki67 immunohistochemistry, respectively. In culture, the combination of RAD001 plus trastuzumab inhibited cell growth more effectively than either drug alone. Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 resulted in HER2-independent activation of mTOR and dampened the response to trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased phospho-S6 and growth in TSC2-expressing but not in TSC2-knockdown cells. Conclusions Inhibition of PI3K and mTOR are required for the growth inhibitory effect of HER2 antagonists. These findings collectively support the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2+ breast cancer. PMID:19934303

  10. HER2 overexpression reverses the relative resistance of EGFR-mutant H1975 cell line to gefitinib.

    PubMed

    Xu, Jing; Shen, Li; Zhang, Bi-Cheng; Xu, Wen-Hong; Ruan, Shu-Qin; Pan, Chi; Wei, Qi-Chun

    2016-12-01

    Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that has been demonstrated to be clinically useful for the treatment of patients with non-small cell lung cancer (NSCLC). However, ~50% of patients do not respond to EGFR TKI treatment through the emergence of mutations, such as T790M. Therefore, it is important to determine which patients are eligible for treatment with gefitinib. As a preferred dimerization partner for EGFR, the role of EGFR 2 (HER2) in mediating sensitivity to gefitinib is poorly understood. In the present study, full-length human HER2 cDNA was introduced to the NSCLC cell lines H1975 and H1299, which have a low endogenous expression level of HER2. In addition, it was observed in the present study that the H1975 cell line harbored the L858R and T790M mutations in the EGFR kinase domain. Western blot analysis and MTT assay were used to evaluate the TKI sensitivity of HER2 expression status, and the activation of HER3 and HER2 downstream effectors. The results indicated that the sensitivity of H1975 cells to gefitinib was restored by the overexpression of HER2, which stimulated HER2-driven signaling cascades accompanied by the activation of protein kinase B. By contrast, ectopic HER2 overexpression in H1299 cells did not significantly alter the sensitivity to gefitinib treatment. In conclusion, the current study results suggested that the relatively resistance of the H1975 cell line to gefitinib could be reversed by the overexpression of HER2. Therefore, the expression of HER2 could also be considered when evaluate the patients' potential response to gefitinib, particularly in the subgroup of lung cancer patients who harbor an EGFR mutation.

  11. Cost-Effectiveness of Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

    PubMed

    Durkee, Ben Y; Qian, Yushen; Pollom, Erqi L; King, Martin T; Dudley, Sara A; Shaffer, Jenny L; Chang, Daniel T; Gibbs, Iris C; Goldhaber-Fiebert, Jeremy D; Horst, Kathleen C

    2016-03-20

    The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study showed a 15.7-month survival benefit with the addition of pertuzumab to docetaxel and trastuzumab (THP) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2) -overexpressing metastatic breast cancer. We performed a cost-effectiveness analysis to assess the value of adding pertuzumab. We developed a decision-analytic Markov model to evaluate the cost effectiveness of docetaxel plus trastuzumab (TH) with or without pertuzumab in US patients with metastatic breast cancer. The model followed patients weekly over their remaining lifetimes. Health states included stable disease, progressing disease, hospice, and death. Transition probabilities were based on the CLEOPATRA study. Costs reflected the 2014 Medicare rates. Health state utilities were the same as those used in other recent cost-effectiveness studies of trastuzumab and pertuzumab. Outcomes included health benefits expressed as discounted quality-adjusted life-years (QALYs), costs in US dollars, and cost effectiveness expressed as an incremental cost-effectiveness ratio. One- and multiway deterministic and probabilistic sensitivity analyses explored the effects of specific assumptions. Modeled median survival was 39.4 months for TH and 56.9 months for THP. The addition of pertuzumab resulted in an additional 1.81 life-years gained, or 0.62 QALYs, at a cost of $472,668 per QALY gained. Deterministic sensitivity analysis showed that THP is unlikely to be cost effective even under the most favorable assumptions, and probabilistic sensitivity analysis predicted 0% chance of cost effectiveness at a willingness to pay of $100,000 per QALY gained. THP in patients with metastatic HER2-positive breast cancer is unlikely to be cost effective in the United States. © 2015 by American Society of Clinical Oncology.

  12. CD4+ Th1 HER2-Specific T Cells as a Novel Treatment for HER2-Overexpressing Breast Cancer

    DTIC Science & Technology

    2007-10-01

    involving adjuvants , GM- CSF was highly effective for use with our peptide vaccines. Second, we have thoroughly characterized the cytokine production by...neu-Tg mice were immunized with each peptide three times at a 50 μg vaccine dose (with CFA/IFA as adjuvant ) and then spleens were harvested. The...Since the type of vaccine adjuvant used in peptide immunization can also influence the magnitude and phenotype of the T cell responses, we next examined

  13. Heparanase Mechanisms in Brain - Metastatic Breast Cancer

    DTIC Science & Technology

    2012-04-01

    by 74%. These findings introduce a new concept that links microRNA mechanisms with brain metastatic breast cancer by downregulating HPSE, providing...the groundwork for heparanase-based therapeutics in patients with brain metastases, BMBC in particular. MicroRNA , Breast Cancer , Brain...by 74% (Figs. 4B-D). These findings introduce new concepts that links microRNA mechanisms with brain metastatic breast cancer by downregulating

  14. Assessment and prognostic analysis of EGFR mutations or/and HER2 overexpression in Uygur's Non-small Cell Lung Cancer.

    PubMed

    Shen, Hongli; Du, Guoli; Liu, Zhonghua; Bao, Jianling; Yu, Qin; Jia, Chunli; Liang, Xuelin; Shan, Li

    2015-01-01

    The epidermal growth factor receptor (EGFR) mutations and human epidermal growth factor receptor HER-2/neu (HER2) have been established roles in the signal transduction pathways leading to cell growth and differentiation. The present study focus on the significance of EGFR mutations combined with HER2 overexpression on survival outcomes in Non-small Cell Lung Cancer patients in Uygur population. A total of 111 consecutive Uygurods: A total of 111 consecutive Cell Lung Cancer under went lung Cell Lung biopsy or surgery at the Affiliated Tumor Hospital of Xin Jiang Medical University between March 2009 and January 2013 were included in this retrospective study. All the patients included had received gefitinib 250 mg once daily. The HER2 expression were evaluated by immunohistochemical staining with score of membranous staining being 0 = none, 1 = weak, 2 = 10-30% cells, 3≥30% cells stained, and Real-time PCR techniques were conducted to detect mutations of EGFR through 21 kinds of human EGFR gene mutation detection kits. A retrospective review of the medical records was analyzed to determine the correlation between the presence of EGFR mutations combined with HER2 overexpression and clinicopathological factors. The overall rate of EGFR mutation was 10.81% (n = 12), which mainly involved exons 19 (83.33%, n = 10), 21 (16.67%, n = 2). The overall rate of HER2 overexpression was 21.62% (n = 24). EGFR mutation combined with HER2 overexpression analysis was performed in 111 patients, with an overall rate of 5.41% (n = 6). Median progression-free survival and overall survival were significantly longer in the EGFR mutations group than in the wild type group (PFS: 10.0±1.5 versus 3.8±1.4 months, P = 0.000; OS: 27.3±2.9 versus 19.1±4.7 months, P = 0.000). The ORR in patients with HER2 overexpression was 29.17%, and 13.80% in those patients with HER2 negative, but no significant difference (P = 0.121). The median PFS and OS in HER2 positive group showed no significant

  15. Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer.

    PubMed

    McCormack, Paul L

    2013-09-01

    Pertuzumab (Perjeta®) is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor and reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors. Inhibition of HER2 signalling results in a reduction of tumour cell proliferation, invasiveness and survival. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumour activities; they act synergistically in inhibiting the growth of HER2-overexpressing breast cancer cell lines in vitro. The efficacy of intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) in combination with trastuzumab plus docetaxel in the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial. Pertuzumab in combination with trastuzumab and docetaxel significantly increased independently assessed median progression-free survival (primary endpoint), objective response rate and overall survival compared with placebo in combination with trastuzumab and docetaxel. Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the pivotal CLEOPATRA trial. Thus, pertuzumab is a valuable addition to the growing list of anti-HER2 targeted therapies for breast cancer.

  16. The maximum standardized uptake value of metastatic site in 18 F-FDG PET/CT predicts molecular subtypes and survival in metastatic breast cancer: An Izmir Oncology Group study.

    PubMed

    Cokmert, Suna; Tanriverdi, Ozgur; Karapolat, Inanc; Demir, Lutfiye; Bayoglu, Vedat; Can, Alper; Akyol, Murat; Yilmaz, Yasar; Oktay Tarhan, Mustafa

    2016-01-01

    The purpose of this study was to analyse the association between the 18F-2-deoxy-2-fluorodeoxyglucose maximum standardized uptake value (SUVmax) of metastatic sites and molecular subtypes and survival in metastatic breast cancer (MBC) patients. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) was performed in 176 MBC patients before any therapeutic intervention. The FDG uptakes of metastatic sites were evaluated using the SUVmax. Histopathological prognostic parameters, such as the tumor size, grade, lymph node involvement, lymphovascular invasion, estrogen (ER), progesterone receptors (PR), HER2 status and Ki67 were determined from the primary breast tumor tissue. The SUVmax of the metastatic sites was assessed in relation to the molecular subtypes and survival in univariate and multivariate analyses. Cox regression analysis was used to evaluate the associations between SUVmax measurements and overall survival (OS). The mean SUVmax of 176 tumors was 8.0. Among the subtypes 49 (28.8%) were luminal A, 51 (28.9%) luminal B, 35 (19.8%) HER2-overexpressing, and 41 (23.2%) triple- negative, and the corresponding means of SUVmax were 5.6, 7.4, 11.4, 11.0, respectively. A cut-off value of ≤8.4 yielded 80% sensitivity and 57.1% specificity with an area under the receiver operating characteristics curve (AUC) of 0.731 for predicting that a tumor was of the luminal A subtype. A cut-off value of SUVmax ≥10.05 yielded 62.9% sensitivity and 67.4% specificity with an AUC of 0.648 for predicting a HER2 overexpressing subtype. A cut-off value of SUVmax ≥9.25 yielded 61% sensitivity and 64.4% specificity with an AUC of 0.660 for predicting a triple-negative subtype. The SUVmax could not effectively differentiate patients with luminal B subtype. Cox regression analysis showed that in patients with MBC, a SUVmax ≤7.55 acted as an independent negative prognostic factor for OS (hazard ratio/HR = 1.552). The SUVmax of metastatic

  17. Promotion of Tumor-Initiating Cells in Primary and Recurrent Breast Tumors

    DTIC Science & Technology

    2013-07-01

    elucidating alternative therapeutic targets in this disease. Her2- overexpression was first shown to activate NF-kB over a decade ago ( Galang et al...leads to activation of NF-kB family members involved in the canonical pathway, specifically the p65/p50 heterodimeric complex ( Galang et al., 1996; Biswas...normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res 53: 627–635. Galang

  18. Associations between serum CA724 and HER2 overexpression among stage II–III resectable gastric cancer patients: an observational study

    PubMed Central

    Chen, Xin-Zu; Liu, Jian-Ping; He, Du; Liu, Yang; Liu, Kai; Chen, Xiao-Long; Mo, Xian-Ming; Zhou, Zong-Guang; Hu, Jian-Kun

    2016-01-01

    Objectives Associations between serum tumor biomarkers and human epidermal growth factor receptor 2 (HER2) overexpression among locally advanced gastric cancer patients were yet to be determined and therefore warranted investigation. Results A total of 318 patients were analyzed. The odds ratios of CA724 were 4.79 (95% CI 1.55–14.79) and 6.29 (1.40–28.19) in comparing the HER2 (2+/3+) and HER2 (3+) with the negative group, respectively (p < 0.05). A combination of the four biomarkers yielded slightly but not significantly greater areas under the curve (AUC = 0.83; 0.71–0.94) than that of serum CA724 alone (0.80; 0.68–0.91); however, an index generated from the combination had better diagnostic performance with 85.7% sensitivity, 80.4% specificity and 97.8% negative predictive value to predict the strong overexpression of HER2 (3+). CA199, CEA or CA125 alone was not associated with HER2 overexpression. Leave-one-out cross-validation found a consistent association between serum CA724 and HER2 (2+/3+) overexpression. Methods Patients undergoing radical gastrectomy from 8/2012 to 12/2013 and with pathological stage II–III gastric cancer were retrospectively analyzed. HER2 expression of the surgical samples was estimated using immunohistochemistry; serum CA724, CA199, CEA and CA125 were preoperatively tested. Internal validation was performed using the leave-one-out approach. Conclusions Serum CA724 is significantly associated with the overexpression of HER2 among locally advanced gastric cancer patients. The combination of CA724, CA199, CEA and CA125 is better than serum CA724 alone in predicting HER2 overexpression. External validation and further investigation of the biological mechanisms of these associations are required. PMID:27027339

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

    PubMed Central

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

    2016-01-01

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

  20. Metastatic Breast Cancer, Version 1.2012

    PubMed Central

    Carlson, Robert W.; Allred, D. Craig; Anderson, Benjamin O.; Burstein, Harold J.; Edge, Stephen B.; Farrar, William B.; Forero, Andres; Giordano, Sharon Hermes; Goldstein, Lori J.; Gradishar, William J.; Hayes, Daniel F.; Hudis, Clifford A.; Isakoff, Steven Jay; Ljung, Britt-Marie E.; Mankoff, David A.; Marcom, P. Kelly; Mayer, Ingrid A.; McCormick, Beryl; Pierce, Lori J.; Reed, Elizabeth C.; Smith, Mary Lou; Soliman, Hatem; Somlo, George; Theriault, Richard L.; Ward, John H.; Wolff, Antonio C.; Zellars, Richard; Kumar, Rashmi; Shead, Dorothy A.

    2013-01-01

    These NCCN Guidelines Insights highlight the important updates/changes specific to the management of metastatic breast cancer in the 2012 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. These changes/updates include the issue of retesting of biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) on recurrent disease, new information regarding first-line combination endocrine therapy for metastatic disease, a new section on monitoring of patients with metastatic disease, and new information on endocrine therapy combined with an mTOR inhibitor as a subsequent therapeutic option. PMID:22773798

  1. [Role of surgery in metastatic breast cancer].

    PubMed

    Medina-Franco, Heriberto; Suárez-Bobadilla, Yoli Lizbeth

    2012-01-01

    Breast cancer is the most common malignant tumor in Mexican women and very often patients present with advanced stages. Patients with metastatic breast cancer have limited therapeutic options and the mainstay of treatment in this disease stage is systemic chemotherapy Traditionally, the role of surgery in this context is limited to symptom palliation. The increase in efficiency of chemotherapy drugs and the new endocrine and molecular targeted therapy has prolonged the life expectancy of this group of patients and has expanded surgical indications beyond palliation. Some recent institutional reports suggest increasing survival of patients who undergo resection of limited metastatic disease. On another hand, there are reports of survival benefit when the primary tumor is removed even in presence of metastatic disease. We conducted a systematic review of the literature with the objective to analyze the role of surgery in the multidisciplinary management of metastatic breast cancer in order to improve the prognosis of this increasing group of patients.

  2. 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.

  3. Inflammatory Breast Cancer from Metastatic Ovarian Cancer

    PubMed Central

    Achariyapota, Vuthinun; Chuangsuwanich, Tuenjai

    2016-01-01

    Metastases to the breast from tumors other than breast carcinomas are extremely rare and represent only 0.2–1.3% of all diagnosed malignant breast tumors. Furthermore, while the most common sites for advanced ovarian cancer metastases are the liver, lung, and pleura, metastasis to the breast from a primary ovarian cancer is uncommon and has only been reported in 0.03–0.6% of all breast cancers. Here we describe a case report of a 50-year-old female patient with a rare case of breast metastases from an advanced ovarian cancer, presenting as inflammatory breast cancer. Our observations emphasize the clinical importance of distinguishing between primary and metastatic breast cancer during diagnosis for the purpose of appropriate prognosis and treatment. PMID:27047697

  4. HER-2 overexpression/amplification in Barrett’s oesophagus predicts early transition from dysplasia to adenocarcinoma: a clinico-pathologic study

    PubMed Central

    Rossi, Elisa; Grisanti, Salvatore; Villanacci, Vincenzo; Casa, Domenico Della; Cengia, Paolo; Missale, Guido; Minelli, Luigi; Buglione, Michela; Cestari, Renzo; Bassotti, Gabrio

    2009-01-01

    Barrett’s oesophagus (BO) is the primary precursor lesion for oesophageal adenocarcinoma (ADC). The natural history of metaplasia-dysplasia-carcinoma sequence remains largely unknown. HER2/neu oncogene results overexpressed/amplified in preneoplastic lesions and in ADC of the oesophagus and it has been associated with poor prognosis. Our aim was to evaluate the role of HER2 overexpression/amplification in predicting the conversion from precursor lesions to ADC. We retrospectively evaluated by univariate analysis of single variables clinical records and histological specimens of 21 patients with a confirmed diagnosis of BO and/or oesophageal dysplasia. Clinical variables included age, gender, alcohol and smoking intake, presence of symptoms (pyrosis, disphagia) and endoscopic features (length). HER2 status was studied by immunohistochemistry and fluorescence in situ hybridization (FISH) on paraffin-embedded tissue. The end-points were the occurrence of progression and the time-to-progression (TTP) from the initial histologic lesion to the worst pathological pattern. Median age at diagnosis was 63 years (range 37–84). BO median length was 4.5 cm. Progression occurred in 11 of 21 patients and median TTP was 24 months. HER2 was overexpressed/amplified in 8 of 21 (38%) patients. HER2 overexpression/ amplification and the presence of dysplasia were statistically associated with progression (P= 0.038). This study provides evidence for a possible role of HER2 in the transition from dysplasia to ADC of the oesophagus. This fact could help in identifying patients at high risk of malignant transformation. PMID:19292734

  5. HER2-targeted recombinant protein immuno-caspase-6 effectively induces apoptosis in HER2-overexpressing GBM cells in vitro and in vivo.

    PubMed

    Zhang, Leiming; Ren, Junlin; Zhang, Hangyu; Cheng, Gang; Xu, Yanming; Yang, Shuangwu; Dong, Chao; Fang, Dandong; Zhang, Jianning; Yang, Angang

    2016-11-01

    Glioblastoma multiforme (GBM), which is associated with a high rate of morbidity and mortality, is among the most malignant and treatment-refractory neoplasms in human adults. As GBM is highly resistant to conventional therapies, immunotherapies are a promising treatment candidate. HER2 is an attractive target for GBM immunotherapy, as its expression is highly associated with various types of GBM. We previously reported that a novel HER2-targeted recombinant protein e23sFv-Fdt-casp6 has an antitumor effect on HER2-positive gastric cancer cells. In this study, we established a genetically modified Chinese hamster ovary cell line, which produced and secreted e23sFv-Fdt-casp6 proteins. Following specific binding to and internalization into HER2-overexpressing tumor cells, the e23sFv-Fdt-casp6 protein induced tumor cell apoptosis and inhibited the proliferation of HER2-overexpressing A172 and U251MG cells in vitro, but not in U87MG cells with undetectable HER2. The e23sFv-Fdt-casp6 gene was introduced into severe combined immunodeficient mice bearing human glioblastoma xenografts by using intramuscular injections of a liposome-encapsulated vector. The recombinant protein e23sFv-Fdt-casp6 specifically targeted tumor cells and induced apoptosis, thereby leading to potent inhibition of tumor growth and prolonged the survival time of tumor-bearing mice. We concluded that e23sFv‑Fdt‑casp6 represents a promising HER2-targeted treatment option for human gliomas.

  6. High Serum miR-19a Levels Are Associated with Inflammatory Breast Cancer and Are Predictive of Favorable Clinical Outcome in Patients with Metastatic HER2+ Inflammatory Breast Cancer

    PubMed Central

    Anfossi, Simone; Giordano, Antonio; Gao, Hui; Cohen, Evan N.; Tin, Sanda; Wu, Qiong; Garza, Raul J.; Debeb, Bisrat G.; Alvarez, Ricardo H.; Valero, Vicente; Hortobagyi, Gabriel N.; Calin, George A.; Ueno, Naoto T.; Woodward, Wendy A.; Reuben, James M.

    2014-01-01

    Introduction Altered serum microRNA (miRNA) levels may be correlated with a dysregulated expression pattern in parental tumor tissue and reflect the clinical evolution of disease. The overexpression of miR-21, miR-10b, and miR-19a is associated with the acquisition of malignant characteristics (increased tumor cell proliferation, migration, invasion, dissemination, and metastasis); thus, we determined their utility as serum biomarkers for aggressive breast cancer (HER2-overexpressed or -amplified [HER2+] and inflammatory breast cancer [IBC]). Experimental Design In this prospective study, we measured miR-21, miR-10b, and miR-19a levels using quantitative reverse transcriptase-polymerase chain reaction in the serum of 113 breast cancer patients and determined their association with clinicopathologic factors and clinical outcome. Thirty healthy donors with no history of cancer were enrolled as controls. Results Patients with non-metastatic HER2+ breast cancer had higher serum miR-21 median levels than patients with non-metastatic HER2− disease (p = 0.044); whereas patients with metastatic HER2+ breast cancer had higher serum miR-10b median levels than patients with metastatic HER2− disease (p = 0.0004). There were no significant differences in serum miR-19a median levels between HER2+ and HER2− groups, regardless of the presence of metastases. High serum miR-19a levels were associated with IBC (p = 0.039). Patients with metastatic IBC had significantly higher serum miR-19a median levels than patients with metastatic non-IBC (p = 0.019). Finally, high serum miR-19a levels were associated with longer progression-free survival time (10.3 vs. 3.2 months; p = 0.022) and longer overall survival time (median not reached vs. 11.2 months; p = 0.003) in patients with metastatic HER2+ IBC. Conclusion High levels of miR-21 and miR-10b were present in the serum of patients with non-metastatic and metastatic HER2+ breast cancer, respectively. High

  7. Clinically advanced and metastatic pure mucinous carcinoma of the breast: a comprehensive genomic profiling study.

    PubMed

    Ross, Jeffrey S; Gay, Laurie M; Nozad, Sahar; Wang, Kai; Ali, Siraj M; Boguniewicz, Ann; Khaira, Depinder; Johnson, Adrienne; Elvin, Julia A; Vergilio, Jo-Anne; Suh, James; Miller, Vincent A; Stephens, Philip J

    2016-01-01

    BC (23 %): ERBB2 amplification was found in 3 of 3 cases (100 %) that were HER2+ by IHC and/or FISH; 1 pmucBC was negative for HER2 overexpression by IHC, but positive for amplification by CGP; and 2 pmucBC harbored the ERBB2 substitutions D769Y and V777L (one sample also featured ERBB2 amplification). The enrichment of ERBB2 GA in metastatic pmucBC versus non-metastatic primary pmucBC was significant (p = 0.03). CRGA were also found in 20 additional genes including PIK3CA (5), BRCA1 (1), TSC2 (1), STK11 (1), AKT3 (1), and ESR1 (1). Metastatic pmucBC is a distinct form of breast cancer that features a relatively high frequency of CRGA, including a significant enrichment of FGFR1 alterations and a high frequency of ERBB2 alterations when compared with non-metastatic pmucBC. These findings suggest that CGP can identify a variety of known and emerging therapy targets that have the potential to improve outcomes for patients with clinically advanced and metastatic forms of this disease.

  8. Over-treatment in metastatic breast cancer.

    PubMed

    Senkus, Elżbieta; Łacko, Aleksandra

    2017-02-01

    Metastatic breast cancer is an incurable disease and the main goals of treatment are prolongation of survival and preservation/improvement of quality of life. Thus the main philosophy of treatment should be to use the least toxic methods, as long as they provide sufficient disease control. In ER-positive tumours this can be in many cases achieved by endocrine therapy; in HER2-positive cancers efficacy of backbone therapy can be enhanced by an anti-HER2 agent. In patients requiring chemotherapy, consecutive single agent regimen provide disease control of a duration at least comparable to multidrug regimen, at a cost of significantly lower toxicity and are a preferred strategy in the majority of cases. Available data demonstrate, however, that aggressive chemotherapy is still overused in many metastatic breast cancer patients. The objective of this manuscript is to critically review available data on treatment choices and sequence in metastatic breast cancer across all breast cancer subtypes in relation to possible overtreatment, including therapies which are not recommended by current guidelines or not even approved. Our aim is to provide guidance on applying these data to clinical practice, but also to describe various, often non-scientific factors influencing therapeutic decisions in an aim to identify areas requiring educational and possibly political actions.

  9. Theranostics Targeting Metastatic Breast Cancer

    DTIC Science & Technology

    2016-10-01

    competition for raw materials results in development of highly disordered and fenestrated (porated) blood vessels in tumor tissues separated by vascular basal...reached 50% saturation in 3 min82 on FR+ KB cells. Comparison of 2 and 3 was conducted in FR+ syngeneic M109 lung tumor model.81 Nearly identical ...efficacies of 8 and EC145 were identical .101 Phase I clinical trial of 8 for refractory and metastatic solid tumors began in 2009; in December 2010, the

  10. Integrating Molecular Mechanisms and Clinical Evidence in the Management of Trastuzumab Resistant or Refractory HER-2+ Metastatic Breast Cancer

    PubMed Central

    Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Yau, Thomas

    2011-01-01

    Human epidermal growth factor receptor (HER)-2+ breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2+ advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8–12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies. PMID:22020213

  11. Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism

    PubMed Central

    Sartorius, Carol A.; Hanna, Colton T.; Gril, Brunilde; Cruz, Hazel; Serkova, Natalie J.; Huber, Kendra M.; Kabos, Peter; Schedin, Troy B.; Borges, Virginia F.; Steeg, Patricia S.; Cittelly, Diana M.

    2015-01-01

    Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER−) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER−, progesterone receptor-negative (PR−) and normal HER2) tumors. Young age is an independent risk factor for development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of MRI detectable lesions by 56% as compared to estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated EGFR ligands Egf, Ereg, and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02 fold, P<0.01 compared to vehicle-control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. ShRNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes, and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER

  12. Metastatic breast cancer in patients with schizophrenia

    PubMed Central

    MEYER, AARON A.; HWANG, M.; FARASATPOUR, M.; JANARDHAN, R.; MARGENTHALER, J.A.; VIRGO, K.S.; JOHNSON, FRANK E.

    2013-01-01

    Breast cancer is a major health problem worldwide. The median survival duration for patients with metastatic breast cancer is two to three years. Approximately 1% of populations worldwide have schizophrenia. The manner in which schizophrenic patients fare when diagnosed with metastatic breast carcinoma (MBC) was evaluated. We queried the National Department of Veterans Affairs (DVA) datasets using computer codes for a pre-existing diagnosis of schizophrenia and a later diagnosis of breast carcinoma. Chart-based data concerning the identified subjects were then requested. Previously determined inclusion and exclusion criteria were applied to select evaluable patients from the medical records, prior to extracting demographic details and data concerning the treatment course in each subject. Ten patients had distant metastases at initial diagnosis, while seven developed MBC following prior curative-intent treatment. Two patients refused therapy. Ten did not comply with recommended management. Five harmed or threatened physicians, other caregivers or themselves. Schizophrenic patients with MBC often fail to understand the nature of their illnesses. Often they do not accept palliative treatment, while a number of them do not comply with therapy, once initiated. They often exhibit behaviors that are detrimental to themselves or others. Formal psychiatric consultation is therefore necessary in patients. Several detrimental behaviors may be predicted reliably by history alone. PMID:24649175

  13. HER2 mediated de novo production of TGFβ leads to SNAIL driven epithelial-to-mesenchymal transition and metastasis of breast cancer.

    PubMed

    Gupta, Parul; Srivastava, Sanjay K

    2014-12-01

    HER2 is an important determinant of poor prognosis in breast cancer patients. Studies indicate that HER2 positive tumors are mostly resistant to therapy and have high metastatic potential however, the underlying mechanisms remain unknown. In this study, MDA-MB-231 and MCF-7 breast cancer cells with their HER2 overexpressing syngeneic variants were used to delineate the role of HER2 in EMT and metastasis. Our results demonstrated that HER2 overexpression increased the invasive potential of cells. Our results also showed that HER2 overexpression lead to the production of TGFβ resulting in the activation of TGFβ/SMAD signaling. Furthermore, activation of SNAIL, SLUG and ZEB-1, the transcriptional repressors of E-cadherin and increased mesenchymal characteristics were observed in high HER2 cells. Interestingly, EMT by HER2 was mediated through TGFβ. Intravenous injection of high HER2 MDA-MB-231 (HH) cells in athymic nude mice showed early and substantial metastasis as compared to the parent cells establishing the direct role of HER2 in metastasis. Our results showed that inhibition of HER2 mediated EMT by cucurbitacin B a triterpenoid, resulted in the suppression of brain metastasis of breast cancer cells. Taken together, our results identify a novel mechanism of HER2 in promoting breast cancer metastasis through de novo synthesis of TGFβ leading to EMT, an initial and essential step of metastasis.

  14. Staging breast cancer, rehearsing metastatic disease.

    PubMed

    Sinding, Christina; Gray, Ross; Fitch, Margaret; Greenberg, Marlene

    2002-01-01

    Social science researchers have fruitfully used a range of conceptualizations of "performance": as a metaphor for social life, a way of vivifying research findings, and a form of scholarly representation. In this article, the researchers consider performance in its hermeneutic sense, as a way of generating meaning. The drama Handle With Care? Living With Metastatic Breast Cancer was created by a research team, a theater troupe, and women with breast cancer. The researchers employ an interpretive phenomenologicalframework to explore interviews with women with breast cancer involved in creating Handle With Care? The performative context in which the drama developed allowed certain illness meanings to emerge, intensify, and shift. The article also considers ethical dilemmas surfaced by this project.

  15. Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer

    ClinicalTrials.gov

    2017-03-28

    Hormone Receptor Positive Malignant Neoplasm of Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Metastatic Breast Cancer

  16. Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer

    ClinicalTrials.gov

    2017-08-28

    Breast Carcinoma Metastatic in the Bone; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  17. Management of patients with metastatic breast cancer.

    PubMed

    Cruz Jurado, J; Richart Aznar, P; García Mata, J; Fernández Martínez, R; Peláez Fernández, I; Sampedro Gimeno, T; Galve Calvo, E; Murillo Jaso, L; Polo Marqués, E; García Palomo, A

    2011-09-01

    Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Aromatase inhibitors (AI) have been extensively studied in this setting. This section summarizes the key data regarding the use of AI in advanced breast cancer. In postmenopausal women, AI are the first line of treatment for untreated patients, or those who had prior AI treatment and progress after 12 months of adjuvant therapy. A longer disease-free interval and absence of visceral disease is associated with a better response. If tumors recur in less than 12 months, it is recommended that tamoxifen (TAM) or the estrogen-receptor antagonist fulvestrant (FUL) treatment be initiated. In the second-line setting, the best option after progression is the administration of either FUL or TAM. In the third-line setting, reintroduction of AI is considered an acceptable option. In premenopausal women who have not received prior treatment or who have progressed after 12 months following adjuvant treatment, it is recommended to initiate therapy with a combination of TAM and a luteinizing hormone-releasing hormone (LHRH) analog. If there is treatment failure with the use of this combination, megestrol acetate or an LHRH agonist plus an AI may be reasonable alternatives. Intensive research is ongoing to understand the mechanisms of resistance to hormone therapy. In human epidermal growth factor receptor 2 positive-patients, combinations with HER2 antagonists are associated with significant clinical activity.

  18. The treatment of metastatic breast cancer.

    PubMed

    Greenberg, E J

    1991-01-01

    While metastatic breast cancer is not curable, it is treatable. Its treatment is associated with a relatively high rate of success, and patients are able to maintain a good quality of life for periods ranging from a few months to several years. This knowledge should encourage both the patient and the oncologist to maintain treatment as long as potentially effective therapeutic methods are available. Progress is ongoing both in the development of new forms of treatment and in new ways of using and combining already existing therapeutic modalities. There is still no established "best" or "only" first treatment of metastatic breast cancer. When secondary and later treatment is to be undertaken, the task of selecting the most appropriate treatment becomes even more complex. It is only through controlled clinical trials that useful therapeutic guidelines will develop. Treatment is a joint endeavor involving both the physician and the patient. Communication must remain open. In the final stages of the illness, treatment should be directed toward the relief of distressing symptoms and anxiety.

  19. Organtropic Metastatic Secretomes and Exosomes in Breast Cancer

    DTIC Science & Technology

    2014-10-01

    metastatic organ- tropism we are currently analyzing secretomes and extracellular miRNAs from lung (Lyden laboratory) and bone metastatic breast cancer...cells (Kang Laboratory). Task 1a: Identify differentially secreted miRNAs associated with bone- tropism of breast cancer cells (Months 1-36). Dr...Kang’s group is responsible for this task. Task 1b: Identify differentially secreted proteins and miRNAs associated with lung- tropism of breast

  20. 'Omic approaches to preventing or managing metastatic breast cancer

    PubMed Central

    2011-01-01

    Early detection of metastasis-prone breast cancers and characterization of residual metastatic cancers are important in efforts to improve management of breast cancer. Applications of genome-scale molecular analysis technologies are making these complementary approaches possible by revealing molecular features uniquely associated with metastatic disease. Assays that reveal these molecular features will facilitate development of anatomic, histological and blood-based strategies that may enable detection prior to metastatic spread. Knowledge of these features also will guide development of therapeutic strategies that can be applied when metastatic disease burden is low, thereby increasing the probability of a curative response. PMID:22216753

  1. 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

  2. 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

    2016-08-24

    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.

  3. Metastatic breast cancer presenting as a gallstone ileus.

    PubMed

    Sahebally, Shaheel M; Sehgal, Rishabh; Kelly, Justin; Faul, Peter N; Waldron, David

    2013-12-16

    Metastatic breast cancer to the small bowel (SB) presenting as gallstone ileus and resulting in SB obstruction has not been described previously. A 76-year-old woman with previous metastatic breast cancer to the axial spine and hips presented with abdominal pain and bilious vomiting. CT scanning revealed SB obstruction consistent with gallstone ileus. The patient underwent two segmental SB resections for distal ileal strictures mimicking what appeared to be macroscopic Crohn's disease. The entero-biliary fistula was undisturbed. Pathological analysis revealed the dual pathologies of gallstone ileus and metastatic carcinoma from a breast primary causing luminal SB obstruction. Improvements in staging and treatment modalities have contributed to the increased overall long-term survival for breast cancer, compelling clinicians to consider metastatic breast cancer as a differential diagnosis in women presenting with new onset of gastrointestinal symptoms in order that appropriate treatment be administered in a timely fashion.

  4. A Phase I-II Study of Combined Blockade of the ErbB Receptor Network with Trastuzumab and Gefitinib in Patients with HER2 (ErbB2)-Overexpressing Metastatic Breast Cancer

    PubMed Central

    Arteaga, Carlos L.; O’Neill, Anne; Moulder, Stacy L.; Pins, Michael; Sparano, Joseph A.; Sledge, George W.; Davidson, Nancy E.

    2010-01-01

    Purpose To determine the safety, and efficacy of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in combination with trastuzumab in patients with metastatic HER2-positive metastatic breast cancer. Experimental Design Patients with HER2-overexpressing breast cancer were treated with trastuzumab 2 mg/kg/week and gefitinib 250 to 500 mg/day. The primary end point of the study was to increase the proportion progression-free from 50% to 65% at 6 months in chemotherapy-naive patients and from 50% to 70% at 3 months in patients previously treated with chemotherapy in the metastatic setting. Results In the phase I study, all patients treated with gefitinib 500 mg/day developed grade 3 diarrhea. The phase II study was conducted using trastuzumab and gefitinib 250 mg/day. One patient achieved a complete response, 2 had a partial response, and 6 had stable disease for an overall response rate of 9% and a clinical benefit rate of 28% (9 of 32). Median time to progression (TTP) was 3 months (95% confidence interval, 2.3-4.1) in patients with no prior systemic therapy in the metastatic setting (n = 23). In patients treated with prior systemic therapy (n = 9), the median TTP of 5.3 months (95% confidence interval, 2.8-8.1). Overall median survival was 27 months. TTP was similar in EGFR-positive compared with EGFR-negative patients. Conclusions Gefitinib 250 mg/day was the maximal dose that can be safely administered with weekly trastuzumab. Interim analysis of the efficacy suggested that the combination was unlikely to result in clinical benefit compared with trastuzumab alone. These results do not support the use of this combination in patients with HER2-positive breast cancer. PMID:18829509

  5. Clinical Features of Male Breast Cancer: Experiences from Seven Institutions Over 20 Years.

    PubMed

    Hong, Ji Hyung; Ha, Kyung Sun; Jung, Yun Hwa; Won, Hye Sung; An, Ho Jung; Lee, Guk Jin; Kang, Donghoon; Park, Ji Chan; Park, Sarah; Byun, Jae Ho; Suh, Young Jin; Kim, Jeong Soo; Park, Woo Chan; Jung, Sang Seol; Park, Il Young; Chung, Su-Mi; Woo, In Sook

    2016-10-01

    Breast cancer treatment has progressed significantly over the past 20 years. However, knowledge regarding male breast cancer (MBC) is sparse because of its rarity. This study is an investigation of the clinicopathologic features, treatments, and clinical outcomes of MBC. Clinical records of 59 MBC patients diagnosed during 1995-2014 from seven institutions in Korea were reviewed retrospectively. Over a 20-year period, MBC patients accounted for 0.98% among total breast cancer patients, and increased every 5 years. The median age of MBC patientswas 66 years (range, 24 to 87 years). Forty-three patients (73%) complained of a palpable breast mass initially. The median symptom duration was 5 months (range, 1 to 36 months). Mastectomy was performed in 96% of the patients. The most frequent histology was infiltrating ductal carcinoma (75%). Ninety-one percent of tumors (38/43) were estrogen receptor-positive, and 28% (11/40) showed epidermal growth factor receptor 2 (HER-2) overexpression. After curative surgery, 42% of patients (19/45) received adjuvant chemotherapy; 77% (27/35) received hormone therapy. Five out of ten patients with HER-2 overexpressing tumors did not receive adjuvant anti-HER-2 therapy, while two out of four patients with HER-2 overexpressing tumors received palliative trastuzumab for recurrent and metastatic disease. Letrozole was used for one patient in the palliative setting. The median overall survival durations were 7.2 years (range, 0.6 to 17.0 years) in patients with localized disease and 2.9 years (range, 0.6 to 4.3 years) in those with recurrent or metastatic disease. Anti-HER-2 and hormonal therapy, except tamoxifen, have been underutilized in Korean MBC patients compared to female breast cancer patients. With the development of precision medicine, active treatment with targeted agents should be applied. Further investigation of the unique pathobiology of MBC is clinically warranted.

  6. Eribulin Improves Survival of Women with Metastatic Breast Cancer

    Cancer.gov

    Treatment with eribulin (Halaven™) improved overall survival in women with metastatic breast cancer whose disease progressed despite multiple rounds of prior chemotherapy, according to the results of a phase III clinical trial called EMBRACE.

  7. Ribociclib as First-Line Treatment for Metastatic Breast Cancer

    Cancer.gov

    A summary of interim results from a phase III trial testing ribociclib plus letrozole (Femara®) as a first-line treatment for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.

  8. Ileocaecal intussusception secondary to metastatic phyllodes tumour of the breast.

    PubMed

    Morcos, Basem B; Baker, Bilal; Hashem, Sameh A

    2010-09-01

    A patient with phyllodes tumour of the breast is discussed. During follow-up, she presented with intestinal obstruction caused by ileocaecal intussusception. The cause of the intussusception was metastatic phyllodes tumour, which is a unique presentation.

  9. Targeting Angiogenesis in Metastatic Breast Cancer

    PubMed Central

    Reddy, Sangeetha; Raffin, Michael

    2012-01-01

    Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC. PMID:22843553

  10. [Atypical metastatic breast localization in lung cancer].

    PubMed

    Serraille, A; Barazzutti, H; Greillier, L; Barlesi, F

    2015-11-01

    In the context of bronchial cancers, the most frequent sites for metastases to occur are the lung, bone, brain, liver and adrenal glands. However, metastasis to other sites does additionally occur and this might be influenced by the biological characteristics of the tumour. We report the case of a 54-year-old woman with a primary bronchial adenocarcinoma with an EML4-ALK translocation. During her treatment with crizotinib, the patient developed a lesion in her right breast. The initial pathological diagnosis was of an invasive ductal adenocarcinoma of the breast. However, an additional immuno-histochemical analysis revealed it to be a metastasis from her bronchial tumour. This case is an illustration that, in the context of a lung cancer with ALK rearrangement, synchronous or secondary lesions must be interpreted with caution. Specific biological analysis - ALK immunohistochemistry or FISH - must be performed to confirm a primary or metastatic origin for these lesions. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  11. 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

    2017-03-30

    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

  12. Targeting IKK in Basal-Like Breast Tumors as a Therapeutic Approach

    DTIC Science & Technology

    2010-06-01

    therapeutic targets in this disease. Her2- overexpression was first shown to activate NF-kB over a decade ago ( Galang et al., 1996), however, the role that NF...family members involved in the canonical pathway, specifically the p65/p50 heterodimeric complex ( Galang et al., 1996; Biswas et al., 2004). Given this...epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res 53: 627–635. Galang CK, Garcia-Ramirez J, Solski

  13. Breast cancer metastatic to the kidney with renal vein involvement.

    PubMed

    Nasu, Hatsuko; Miura, Katsutoshi; Baba, Megumi; Nagata, Masao; Yoshida, Masayuki; Ogura, Hiroyuki; Takehara, Yasuo; Sakahara, Harumi

    2015-02-01

    The common sites of breast cancer metastases include bones, lung, brain, and liver. Renal metastasis from the breast is rare. We report a case of breast cancer metastatic to the kidney with extension into the renal vein. A 40-year-old woman had undergone left mastectomy for breast cancer at the age of 38. A gastric tumor, which was later proved to be metastasis from breast cancer, was detected by endoscopy. Computed tomography performed for further examination of the gastric tumor revealed a large left renal tumor with extension into the left renal vein. It mimicked a primary renal tumor. Percutaneous biopsy of the renal tumor confirmed metastasis from breast cancer. Surgical intervention of the stomach and the kidney was avoided, and she was treated with systemic chemotherapy. Breast cancer metastatic to the kidney may present a solitary renal mass with extension into the renal vein, which mimics a primary renal tumor.

  14. Mammaglobin, a Valuable Diagnostic Marker for Metastatic Breast Carcinoma

    PubMed Central

    Wang, Zhiqiang; Spaulding, Betsy; Sienko, Anna; Liang, Yiaoming; Li, Hongbao; Nielsen, Gitte; Yub Gong, Gyung; Ro, Jae Y.; “Jim” Zhai, Qihui

    2009-01-01

    Identification of metastasis and occult micrometastases of breast cancer demands sensitive and specific diagnostic markers. In this study, we assessed the utility of a mouse monoclonal antibody to human mammaglobin for one such purpose. Immunohistochemical stains were performed on paraffin-embedded sections from a total of 284 cases, which consisted of primary breast invasive carcinomas (41 cases) with matched metastases to ipsilateral axillary lymph nodes, metastatic breast carcinoma to liver (1 case) and kidney (1 case), non-breast neoplasms (161 cases), and normal human tissues (39 cases). The results showed 31 of the 41 cases of primary breast cancer with axillary lymph node metastases were positive for mammaglobin (76%). In the meantime, we documented expression of mammaglobin in occasional cases of endometrial carcinoma (17%). Our data further validated that mammaglobin is a valuable diagnostic marker for metastatic carcinoma of breast origin, although endometrial carcinoma should be considered as a major differential diagnosis. PMID:19158935

  15. Potential use of humanized antibodies in the treatment of breast cancer.

    PubMed

    Schaefer, Niklaus G; Pestalozzi, Bernhard C; Knuth, Alexander; Renner, Christoph

    2006-07-01

    With the growing knowledge of key cellular pathways in tumor induction and evolution, targeted therapies make up an increasing proportion of new drugs entering clinical testing. In the treatment of breast cancer, humanized antibodies have become a major option. The humanized monoclonal antibody trastuzumab (Herceptin); Genentech, Inc., CA, USA) for HER2-overexpressing, metastatic breast cancer, represents a successful agent associated with impressive survival benefits when combined with chemotherapy. Based on impressive results, trastuzumab will become a standard in the adjuvant treatment of HER2-overexpressing breast cancer. The role of trastuzumab in the neoadjuvant setting is promising, but must be further evaluated in large prospective, randomized trials. However, there is still a large proportion of patients overexpressing HER2 that do not respond to trastuzumab. Regarding this patient cohort, the optimal combination of trastuzumab with other agents needs further evaluation. In breast cancer lacking HER2 amplification, the role of the new antibody pertuzumab remains to be defined. The role of antibodies interfering with angiogenesis, tumor stroma or glycoproteins is of a preliminary nature and warrants further investigation. Here, an overview of humanized antibodies in human breast cancer is provided, with emphasis on the recent advances and future prospects in treating malignant breast cancer.

  16. Overexpression of Galectin-7, A Myoepithelial Cell Marker, Enhances Spontaneous Metastasis of Breast Cancer Cells

    PubMed Central

    Demers, Mélanie; Rose, April A.N.; Grosset, Andrée-Anne; Biron-Pain, Katherine; Gaboury, Louis; Siegel, Peter M.; St-Pierre, Yves

    2010-01-01

    Galectins are members of a family of β-galactosides-binding proteins that have recently emerged as novel modulators in different aspects of cancer. The expression of galectins in tumors and/or the tissue surrounding them has been well documented. Since galectin-7 expression has been associated with epithelial tissues and varies significantly in various types of cancer, we have investigated for the first time its role in breast cancer. Using two preclinical mouse models, high levels of galectin-7 expression in breast cancer cells drastically increased their ability to metastasize to lungs and bones. Significant increases in the number of pulmonary metastases and osteolytic lesions were induced by overexpression of galectin-7 compared with control cells. In human tissues, galectin-7 was specifically found in myoepithelial cells of normal human breast tissue, but not in luminal cells. Its expression was severely altered in breast carcinoma, many samples showing greater than 70% of galectin-7 positive cells. High expression levels of galectin-7 were restricted to high-grade breast carcinomas, including HER2 overexpressing and basal-like groups. In HER2 overexpressing cases, galectin-7 expression was associated with lymph node axillary metastasis. Taken together, our results indicate that galectin-7 may represent a potential target for both specific detection and therapeutic inhibition of metastatic breast cancer. PMID:20382700

  17. Maintenance immunotherapy in metastatic breast cancer.

    PubMed

    Recchia, Francesco; Sica, Gigliola; Candeloro, Giampiero; Necozione, Stefano; Bisegna, Roberta; Bratta, Massimo; Rea, Silvio

    2008-11-01

    Maintenance chemotherapy provides only a modest survival advantage in metastatic breast cancer (MBC). We have previously shown that a maintenance immunotherapy (MI) regimen based on low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) improved the lymphocyte and natural killer cell (NK) counts, and CD4+/CD8+ ratio in patients with a clinical benefit from chemotherapy. With the aim of improving progression-free survival (PFS), 100 consecutive MBC patients with a clinical benefit from chemotherapy were treated with an MI. Patients with MBC were eligible if they had no evidence of progression after 6-8 courses of epirubicin-paclitaxel induction chemotherapy. Treatment consisted of low-dose IL-2 and oral RA given until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were toxicity, overall survival (OS), and changes in immunological parameters. From 04/1997 to 04/2002, 100 patients with MBC were enrolled. After a median follow-up of 49 months, median PFS and OS were 37.1 and 57.5 months, respectively. No WHO grade 3 or 4 toxicity was observed; grade 2 cutaneous toxicity and autoimmune reactions occurred in 19 and 16% of patients, respectively. A sustained improvement in lymphocytes, NKs, and in the CD4+/CD8+ ratio was observed, with respect to baseline values. In conclusion, MI with IL-2 and RA in MBC patients who do not progress after 6-8 courses of chemotherapy is well-tolerated, improves lymphocyte, NK, CD4+/CD8+ ratio, and appears to delay disease recurrence. A randomized trial is warranted.

  18. Defining the illness trajectory of metastatic breast cancer

    PubMed Central

    Reed, Elizabeth; Corner, Jessica

    2015-01-01

    Background With significant developments in the management of metastatic breast cancer, the trajectory of progressive breast cancer is becoming increasingly complex with little understanding of the illness course experienced by women, or their ongoing problems and needs. Aim This study set out to systematically explore the illness trajectory of metastatic breast cancer using models from chronic illness as a framework. Design Longitudinal mixed methods studies detailing each woman's illness trajectory were developed by triangulating of narrative interviews, medical and nursing documentation and an assessment of functional ability using the Karnofsky Scale. The Corbin and Strauss Chronic Illness Trajectory Framework was used as a theoretical framework for the study. Participants Ten women aged between 40 and 78 years, with metastatic breast cancer. Results Women’s illness trajectories from diagnosis of metastatic disease ranged from 13 months to 5 years and 9 months. Eight of the 10 women died during the study. Chronic illness trajectory phases identified by Corbin and Strauss (pretrajectory, trajectory onset, living with progressive disease, downward phase and dying phase) were experienced by women with metastatic breast cancer. Three typical trajectories of different duration and intensity were identified. Women's lives were dominated by the physical burden of disease and treatment with little evidence of symptom control or support. Conclusions This is the first study to systematically explore the experience of women over time to define the metastatic breast cancer illness trajectory and provides evidence that current care provision is inadequate. Alternative models of care which address women's increasingly complex problems are needed. PMID:24644176

  19. Metastatic Breast Cancer in Uterine Cervix: A Rare Presentation.

    PubMed

    Proença, Sara; Reis, Maria Inês; Cominho, Joana; Conde, Pedro Casado; Santos E Pereira, Helena; Ribeiro, Filipa Castro

    2016-01-01

    Uterine cervix involvement by a distant primary tumor is a rare event. We report the following 2 cases of breast tumor metastasis to the uterine cervix with different presentations: case 1 is an isolated cervix metastasis and case 2 is a disseminated metastatic disease with cervix involvement. In both, clinical examination raised the suspicion of cervical tumor, which was confirmed to be a metastatic adenocarcinoma.The poor outcome and lack of symptoms suggest that although its rareness, all patients with breast cancer should undergo a careful routine gynecologic examination.

  20. Long-term survival after high-dose chemotherapy followed by peripheral stem cell rescue for high-risk, locally advanced/inflammatory, and metastatic breast cancer.

    PubMed

    VanderWalde, A; Ye, W; Frankel, P; Asuncion, D; Leong, L; Luu, T; Morgan, R; Twardowski, P; Koczywas, M; Pezner, R; Paz, I B; Margolin, K; Wong, J; Doroshow, J H; Forman, S; Shibata, S; Somlo, G

    2012-08-01

    Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.

  1. Imaging features of carcinoid tumors metastatic to the breast

    PubMed Central

    Jones, Katie N.; Dilaveri, Christina A.; Perry, Kyle; Reynolds, Carol

    2011-01-01

    Abstract The objective of this study was to describe the imaging findings of carcinoid tumors metastatic to the breast, with pathologic and clinical correlations. We searched our surgical database for cases of pathologically proven carcinoid tumors metastatic to the breast from October 1, 2000, to May 31, 2010. Of the approximate 10,000 breast biopsies identified, 7000 had malignant findings. Ten cases of metastatic carcinoid (0.1% of all malignancies), all with imaging studies available for review, were included in the study. All patients were women and had their primary carcinoid in the gastrointestinal tract (n=9) or lung (n = 1). One patient presented with a palpable breast mass and no history of carcinoid tumor; an ileal carcinoid was discovered after the pathologic diagnosis of metastatic carcinoid was established. In the breast, tumors presented as solitary lesions in half the cases. Metastases to the breast typically presented as circumscribed masses mammographically and as hypoechoic circumscribed masses ultrasonographically; some showed increased through-transmission and increased vascularity with color Doppler evaluation. Five patients had octreotide scans; of these, 4 had increased focal activity in the region of metastasis within the breast. Six patients underwent computed tomography. Without contrast, nodular masses were observed; with contrast, the masses showed rapid enhancement during arterial phase imaging. Magnetic resonance imaging (n = 4) also showed rapid enhancement and washout kinetics after contrast administration. Recognition of carcinoid metastases to the breast in patients with known or occult primary carcinoid tumors is important to avoid unnecessary treatment for primary breast cancer. PMID:21771708

  2. Correlation of HER2 overexpression with gene amplification and its relation to chromosome 17 aneuploidy: a 5-year experience with invasive ductal and lobular carcinomas.

    PubMed

    Nassar, Aziza; Khoor, Andras; Radhakrishnan, Reshmitha; Radhakrishnan, Anu; Cohen, Cynthia

    2014-01-01

    The HER2 oncogene shows expression or amplification, or both, in approximately 15% to 20% of breast cancers and has been associated with poor prognosis and a response to trastuzumab therapy. HER2 gene status determines the eligibility of breast cancer patients for trastuzumab therapy and a large fraction (41-56%) of these patients respond to targeted therapy. Several studies have related the increased expression of HER2 to an increased copy number of chromosome 17, rather than amplification of the HER2 gene. We compared the results of immunohistochemistry and fluorescence in situ hybridization in both invasive ductal and invasive lobular carcinomas, to determine the frequency of chromosome 17 aneuploidy associated with discordant results. In total, 390 invasive ductal carcinomas and 180 invasive lobular carcinomas diagnosed from January 2000 to December 2005 were included in the study only if results were available for immunohistochemistry (HercepTest; DAKO, Carpinteria, California) and fluorescence in situ hybridization (PathVysion HER2 DNA Probe Kit; Abbott Laboratories, Des Plaines, Illinois). Tumors classified as invasive ductal carcinomas were graded according to the Bloom-Richardson grading system. Correlation between the results of immunohistochemistry and fluorescence in situ hybridization was performed for all categories. Among invasive ductal carcinomas, 29% (115/390) showed chromosome 17 aneuploidy, mostly associated with grade 3/HER2 2+ (45%) or grade 2/HER2 3+ (55%) that were not amplified. Also, 34% (12/35) of invasive lobular carcinomas showed chromosome 17 aneuploidy; approximately one-third of these cases were HER2 2+ (33%) and HER2 3+ (37%) that were not amplified. Discordance between the results of immunohistochemistry and fluorescence in situ hybridization in both ductal and lobular carcinomas is largely associated with chromosome 17 aneuploidy.

  3. Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression of distant metastatic lesions in patients with metastatic breast cancer.

    PubMed

    Inari, Hitoshi; Suganuma, Nobuyasu; Kawachi, Kae; Yoshida, Tatsuya; Yamanaka, Takashi; Nakamura, Yoshiyasu; Yoshihara, Mitsuyo; Nakayama, Hirotaka; Masudo, Katsuhiko; Oshima, Takashi; Yokose, Tomoyuki; Rino, Yasushi; Shimizu, Satoru; Miyagi, Yohei; Masuda, Munetaka

    2017-04-19

    Surgical biopsy of metastatic lesions followed by pathological confirmation for the investigation of biomarkers is occasionally proposed as an effective strategy in the treatment of metastatic breast cancer. However, few reports have examined Ki-67 immunohistochemical expression in distant metastatic lesions of breast cancer patients. This study aimed to investigate the clinicopathological significance of subtypes and Ki-67 immunohistochemical expression in metastatic breast cancer lesions. We retrospectively studied surgical specimens of primary breast cancer tumors and their corresponding metastatic lesions from patients (n = 68) who underwent surgery for primary breast cancer tumors between December 1977 and March 2013. Tissue microarrays were constructed using primary and metastatic lesions, and were stained with antibodies against estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. We also examined the clinicopathological characteristics and outcome measures of patients with metastatic breast cancer using primary and paired metastatic lesions. Compared with the primary lesions, there was no significant difference in subtypes in the metastatic lesions according to metastatic sites. Metastatic lesions of the brain, viscera, and bone exhibited slightly higher levels of Ki-67 immunohistochemical expression compared with primary lesions. A Cox proportional hazards model using multivariate analysis demonstrated that high Ki-67 immunohistochemical expression in distant metastatic lesions was associated with poorer overall survival outcomes after biopsy of recurrence lesion (hazard ratio 2.307; 95% confidence interval 1.207-4.407, P = 0.011). High Ki-67 immunohistochemical expression levels in distant metastatic lesions were independently associated with poorer overall survival outcomes after biopsy of recurrence lesion in breast cancer patients.

  4. Cold Atmospheric Plasma for Selectively Ablating Metastatic Breast Cancer Cells

    PubMed Central

    Wang, Mian; Holmes, Benjamin; Cheng, Xiaoqian; Zhu, Wei; Keidar, Michael; Zhang, Lijie Grace

    2013-01-01

    Traditional breast cancer treatments such as surgery and radiotherapy contain many inherent limitations with regards to incomplete and nonselective tumor ablation. Cold atomospheric plasma (CAP) is an ionized gas where the ion temperature is close to room temperature. It contains electrons, charged particles, radicals, various excited molecules, UV photons and transient electric fields. These various compositional elements have the potential to either enhance and promote cellular activity, or disrupt and destroy them. In particular, based on this unique composition, CAP could offer a minimally-invasive surgical approach allowing for specific cancer cell or tumor tissue removal without influencing healthy cells. Thus, the objective of this research is to investigate a novel CAP-based therapy for selectively bone metastatic breast cancer treatment. For this purpose, human metastatic breast cancer (BrCa) cells and bone marrow derived human mesenchymal stem cells (MSCs) were separately treated with CAP, and behavioral changes were evaluated after 1, 3, and 5 days of culture. With different treatment times, different BrCa and MSC cell responses were observed. Our results showed that BrCa cells were more sensitive to these CAP treatments than MSCs under plasma dose conditions tested. It demonstrated that CAP can selectively ablate metastatic BrCa cells in vitro without damaging healthy MSCs at the metastatic bone site. In addition, our study showed that CAP treatment can significantly inhibit the migration and invasion of BrCa cells. The results suggest the great potential of CAP for breast cancer therapy. PMID:24040051

  5. 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

    2017-03-10

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

  6. A metastatic breast carcinoma presenting as autoimmune hemolytic anemia.

    PubMed

    Adorno, G; Girelli, G; Perrone, M P; Arista, M C; Coluzzi, S; Masi, M; Giudiceandrea, P; Papa, G

    1991-10-31

    The authors describe the case of a 75-year-old female who was hospitalized for anemia of unknown origin. Physical examination revealed a swelling in the right mammary region, where a mastectomy scar was present from surgery for a breast carcinoma. On admission, laboratory tests disclosed anemia (Hb, 8.5 g/dl), with a reticulocyte count of 65,000/mm3 and slightly increased bilirubin. Immunohematologic study revealed the presence of a red cell autoantibody with anti-D specificity in the serum and in the eluate from the patient's erythrocytes. A biopsy of the swelling was performed and histologic examination showed the presence of metastatic cells of breast carcinoma. The patient was given chemotherapy and radiotherapy. At this writing the anemia was absent, the immunohematologic study was negative, the swelling was greatly reduced, and no other metastatic lesions of breast carcinoma were present.

  7. Metastatic Breast Cancer to the Common Bile Duct Presenting as Obstructive Jaundice.

    PubMed

    Cochrane, Justin; Schlepp, Greg

    2015-01-01

    Metastatic breast cancer is typically identified in the bones, lymph nodes, lungs and liver. Rarely does metastatic breast cancer involve the common bile duct (CBD) without direct extension from liver metastasis into the CBD. We present a woman diagnosed with metastatic breast cancer in the CBD after presenting with obstructive jaundice. Patients with a history of primary breast cancer who present with obstructive jaundice secondary to CBD mass need identification of the mass in order to provide appropriate treatment.

  8. Metastatic Breast Cancer to the Common Bile Duct Presenting as Obstructive Jaundice

    PubMed Central

    Cochrane, Justin; Schlepp, Greg

    2015-01-01

    Metastatic breast cancer is typically identified in the bones, lymph nodes, lungs and liver. Rarely does metastatic breast cancer involve the common bile duct (CBD) without direct extension from liver metastasis into the CBD. We present a woman diagnosed with metastatic breast cancer in the CBD after presenting with obstructive jaundice. Patients with a history of primary breast cancer who present with obstructive jaundice secondary to CBD mass need identification of the mass in order to provide appropriate treatment. PMID:26351417

  9. A Her2-let-7-β2-AR circuit affects prognosis in patients with Her2-positive breast cancer.

    PubMed

    Liu, Dan; Deng, Que; Sun, Limin; Wang, Tao; Yang, Zhengyan; Chen, Hongyu; Guo, Liang; Liu, Yanjun; Ma, Yuanfang; Guo, Ning; Shi, Ming

    2015-11-02

    Our previous studies show that β2-adrenergic receptor (β2-AR) is highly expressed in most Her2-overexpressing breast cancers. However, the mechanisms underlying upregulation of the β2-AR expression in Her2-overexpressing breast cancer cells are not fully understood. The clinical significance of the β2-AR overexpression in breast cancer is unclear. Human breast cancer cells MCF-7 and MCF-7/Her2 were transfected with the let-7 mimics or inhibitors. The expression of β2-AR was analyzed by Western blot. The β2-AR status in primary and metastatic sites of breast cancer and the human breast cancer tissue microarrays containing 49 primary tumors and 50 metastatic lymph node tissues was analyzed by immunohistochemistry. The correlation of lymph node metastasis with the β2-AR level was determined in 59 primary tumor tissues from the patients with Her2-positive breast cancer. The clinical prognostic significance of the β2-AR overexpression in the patients with Her2-positive breast cancers was evaluated by a retrospective study. The let-7f level in Her2-overexpressing breast cancer cells SKBR3 and BT474 was significantly lower than that in MCF-7 cells, which express low level of Her2. Ectopic expression of Her2 in MCF-7 cells (MCF-7/Her2) represses the expression of microRNA let-7f, which is previously identified to regulate baseline β2-AR expression. The treatment with MEK1/2 inhibitors PD98059 or PD184352 effectively restored the let-7f level, suggesting that Her2-overexpression-mediated ERK constitutive activation inhibited let-7f, leading to the upregulation of the β2-AR expression. The transfection with the let-7f mimics markedly downregulated the β2-AR level, whereas the let-7 inhibitor significantly upregulated the β2-AR expression in both parental MCF-7 and MCF-7/Her2 cells. In addition, treatment of MCF-7/Her2 cells with isoproterenol resulted in a concentration-dependent reduction of the let-7f expression, demonstrating that the inhibitory effect of Her2

  10. [Metastatic breast cancer to the stomach: An uncommon evolution of breast carcinoma].

    PubMed

    Hild, C; Talha-Vautravers, A; Hoefler, P; Zirabe, S; Bellocq, J-P; Mathelin, C

    2014-01-01

    Breast carcinoma exceptionally leads to metastatic linitis plastica. Distinguishing a breast cancer metastasis to the stomach from a primary gastric cancer on the basis of clinical and radiological signs is very challenging. Thanks to being cognizant of the previous history of invasive lobular carcinoma and the gastric biopsy followed by immunohistochemical analysis, gastric metastasis can be diagnosed. Despite the use of chemotherapy and hormonal therapy, gastric metastasis remains often associated with poor prognosis. We present a case where gastric biopsy allowed a metastatic breast cancer to the stomach to be diagnosed and we discuss its clinical, diagnostic, pathological and therapeutic particularities. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  11. Fusions of Breast Carcinoma and Dendritic Cells as a Vaccine for the Treatment of Metastatic Breast Cancer

    DTIC Science & Technology

    2005-07-01

    regulate the development of anti-tumor immune responses . Importantly, our results show that, compared to unfused DC and tumor cells, the DC/ breast tumor...AD Award Number: DAMD17-03-1-0487 TITLE: Fusions of Breast Carcinoma and Dendritic Cells as a Vaccine for the Treatment of Metastatic Breast Cancer ...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Fusions of Breast Carcinoma and Dendritic Cells as a Vaccine for the Treatment of Metastatic Breast Cancer

  12. Trafficking of Metastatic Breast Cancer Cells in Bone

    DTIC Science & Technology

    2005-08-01

    at 4wk showing two large metastatic foci, one at each end of the femur . The distal end shows an iatrogenic fracture presumable due to weakness caused...protein (MDA-MB 231 ) were inoculated intracardiacly into athymic mice.; femurs harvested from 1 hr to 6 wk later and analyzed by fluorescence...modifying the bone microenvironment, are needed to improve treatment of osteolytic bone metastases. 15. SUBJECT TERMS Breast cancer, bone, metastasis

  13. Prolonged time to progression with fulvestrant for metastatic breast cancer.

    PubMed

    Mello, Celso A L; Chinen, Ludmilla T D; da Silva, Samantha Cabral Severino; do Nascimento Matias, Carolina; Benevides, Carlos Frederico; Gimenes, Daniel Luiz; Fanelli, Marcello F

    2011-06-01

    Although the incidence of breast cancer has been declining in recent years, the disease is still one of the leading causes of cancer deaths in women. Recently, breast cancer has been treated with innovative approaches that use hormone-sensitive therapies. This is because in at least one-third of breast cancers, estrogens mediated via the estrogen receptor pathway act as endocrine growth factors. Fulvestrant has been studied as both first- and second-line therapy for locally advanced and metastatic breast cancer, but few studies have shown its effect as third-line therapy alone. To observe the disease time to progression (TTP) obtained with fulvestrant when used on metastatic breast cancer as first-, second-, and also third-line therapy. We also aimed to correlate the TTP obtained with fulvestrant with hormone receptor, HER2 expression, and metastatic site. This was a cohort study that retrospectively examined medical records of 73 postmenopausal women with advanced breast cancer who were treated with fulvestrant (250 mg/month i.m. injection) and followed at the Department of Medical Oncology at Hospital do Cancer A. C. Camargo in São Paulo, Brazil from August 2003 to December 2006. The median TTP with fulvestrant was about 11 months. When used as the first-line therapy, TTP was about 13 months; when used as second-line, TTP was about 6 months; and when used as third-line, it was about 12 months. No statistically significant difference was observed regarding the therapy line. In patients with positive ER tumors, TTP was 11 months. No significant difference in TTP was observed in negative ER tumors (TTP = 10 months). In patients with positive PgR tumors, TTP was 13 months and for negative PgR, TTP was 6 months (P = 0.008). According to the HER2 status, the TTP was 5 months for HER2+ and 10 months for HER2-. Our findings indicate that fulvestrant is an effective alternative for treatment of metastatic breast cancer.

  14. Regulation of Metastatic Breast Cancer Dormancy

    DTIC Science & Technology

    2015-09-01

    important knowledge gap we have developed an all-human hepatic bioreactor. In this award period we have established that the hepatic bioreactor is...Ecadherin shRNA and expression. SA1 Task 1b (100% completed) and 1c (80% completed): I validated the soft-walled all human hepatic bioreactor through...Breast cancer cell lines and dormancy in the all-human hepatic bioreactor SA1 Task 1b (100% completed) and 1c (90% completed): I optimized seeding

  15. Metastatic Organotropism: An Intrinsic Property of Breast Cancer Molecular Subtypes.

    PubMed

    Wei, Shi; Siegal, Gene P

    2017-03-01

    It has long been known that some cancers have the propensity to metastasize to certain organs thus creating a nonrandom distribution of sites for distant relapse, a phenomenon known as "metastatic organotropism." Some of these examples include ovary primary to abdominal cavity, prostate primary to bone, and pancreas primary to liver. In contrast, other tumor types, such as mammary and renal cell carcinoma, can relapse in multiple organs although approximately half of advanced breast cancers metastasize to bone. On the other hand gene expression profiling studies have identified various breast cancer classes with prognostic significance. Recent studies have revealed that breast cancer subtypes differ not only in primary tumor characteristics but also in their metastatic behavior. In particular, the luminal tumors are remarkable for their significant bone-seeking phenotype; the HER2 subtype demonstrates a significant liver-homing characteristic; whereas so-called triple-negative breast cancers predispose to lung metastases. These findings suggest that this knowledge could potentially be utilized in the development of effective disease surveillance strategies in the pursuit of precision medicine, thus necessitating further investigation.

  16. Unusual aggressive breast cancer: metastatic malignant phyllodes tumor.

    PubMed

    Singer, Adam; Tresley, Jonathan; Velazquez-Vega, Jose; Yepes, Monica

    2013-02-01

    For the year of 2012, it has been estimated that breast cancer will account for the greatest number of newly diagnosed cancers and the second highest proportion of cancer related deaths among women. Breast cancer, while often lumped together as one disease, represents a diverse group of malignancies with different imaging findings, histological appearances and behavior. While most invasive primary breast cancers are epithelial derived adenocarcinomas, rare neoplasms such as the phyllodes tumor may arise from mesenchymal tissue. Compared to the breast adenocarcinoma, the phyllodes tumor tends to affect a younger population, follows a different clinical course, is associated with different imaging and histological findings and is managed distinctively. There may be difficulty in differentiating the phyllodes tumor from a large fibroadenoma, but the mammographer plays a key role in reviewing the clinical and imaging data in order to arrive at the correct diagnosis. Early diagnosis with proper surgical management can often cure non-metastatic phyllodes tumors. However, in rare cases where metastasis occurs, prognosis tends to be poor. This report describes the presentation, imaging findings and management of a metastatic malignant phyllodes tumor.

  17. Effects of locoregional radiotherapy in patients with metastatic breast cancer.

    PubMed

    Mauro, Geovanne Pedro; de Andrade Carvalho, Heloisa; Stuart, Silva Radwanski; Mano, Max Senna; Marta, Gustavo Nader

    2016-08-01

    This study aims to assess the clinical outcomes of patients with metastatic breast cancer (MBC) who underwent local radiation therapy (RT) for the primary site. Between 2005 and 2013, we retrospectively evaluated patients with MBC who received breast or chest wall RT with or without regional lymph node irradiation. 2761 patients with breast cancer were treated with RT. Of them, 125 women with stage IV breast carcinoma were included. The median follow-up was 15 months (ranging from 3.8 to 168 months), when 54.7% of the patients had died; local progression was observed in 22.8% of the patients. The mean overall survival (OS) and local progression free survival (LoPFS) were 23.4 ± 2.4 months and 45.1 ± 2.9 months, respectively. Three- and five-year overall survival rates were, respectively, 21.2% and 13.3%. Local progression free survival was the same, 67.3%, at three and five years, respectively. Karnofsky Performance Status (KPS) (p = 0.015), number of metastatic sites (p = 0.031), RT dose (p = 0.0001) and hormone therapy (p = 0.0001) were confirmed as independent significant variables correlated with OS. The variables that were independently correlated with LoPFS were the number of previous chemotherapy lines (p = 0.038) and RT dose (p = 0.0001). RT of the primary site in patients with MBC is well tolerated. The factors that presented positive impact on survival were good KPS, low disease burden (1-3 metastatic sites), and the use of hormone therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Metastatic Invasive Lobular Breast Cancer Presenting Clinically with Esophageal Dysphagia

    PubMed Central

    Cuison, Reuben

    2017-01-01

    Background. Intra-abdominal metastases of invasive lobular breast cancer (ILBC) may be insidious. We report a case of metastatic ILBC that presented with dysphagia within weeks of a negative mammogram and before the development of intra-abdominal symptoms. Case. A 70-year-old female developed esophageal dysphagia. She underwent EGD which showed a short segment of stricture of the distal esophagus without significant mucosal changes. Biopsy was unremarkable and patient underwent lower esophageal sphincter (LES) dilation. Severe progressive dysphagia led to esophageal impaction and three LES dilatations. CT scan showed bilateral pleural effusions, more prominent on right side, and ascites. The pleural effusions were transudative. Repeat EGD with biopsy showed lymphocytic esophagitis, and she was started on swallowed fluticasone. Abdominal ultrasound with Doppler showed that the main portal vein had atypical turbulent flow that was felt to possibly be due to retroperitoneal process. The patient underwent diagnostic laparoscopy which revealed diffuse punctate lesions on the peritoneum. Pathology was consistent with metastatic ILBC. Conclusion. Dysphagia in the setting of peritoneal carcinomatosis from metastatic ILBC is a rare finding. The case highlights the importance of metastatic ILBC as a differential diagnosis for female patients with progressive dysphagia and associated ascites or pleural effusions. PMID:28191357

  19. Palbociclib in Treating Patients With Metastatic HER-2 Positive or Triple-Negative Breast Cancer With Brain Metastasis

    ClinicalTrials.gov

    2016-12-13

    Breast Carcinoma Metastatic in the Brain; Estrogen Receptor Negative; HER2/Neu Negative; HER2/Neu Positive; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  20. [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Multiple Metastatic Breast Cancer Patients].

    PubMed

    Sakurai, Kenichi; Fujisaki, Shigeru; Adachi, Keita; Suzuki, Shuhei; Masuo, Yuki; Nagashima, Saki; Hara, Yukiko; Hirano, Tomohiro; Enomoto, Katsuhisa; Tomita, Ryouichi; Gonda, Kenji

    2016-10-01

    We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)during fulvestrant therapyfor multiple metastatic breast cancer patients. IDO activitycan be measured using the tryptophan(Trp)/kynurenine(Kyn)ratio. Trp and Kyn were measured using high-performance liquid chromatography(HPLC). The serum Trp/Kyn level in patients with multiple metastatic breast cancer was lower than in patients without metastases. IDO activityincreased after breast cancer metastases developed. IDO activitywas correlated with the number of metastatic lesions during toremifene and fulvestrant therapy. These results suggested that measurement of the Trp/Kyn ratio is useful to evaluate immunological metastatic status during endocrine therapy.

  1. Sleep disturbances in women with metastatic breast cancer.

    PubMed

    Koopman, Cheryl; Nouriani, Bita; Erickson, Vanessa; Anupindi, Renu; Butler, Lisa D; Bachmann, Michael H; Sephton, Sandra E; Spiegel, David

    2002-01-01

    We examined sleeping problems in women with metastatic breast cancer in relation to depression, social support, and salivary cortisol. Ninety-seven women with metastatic breast cancer were drawn from a larger study on the effects of group therapy on quality of life and survival. This study is based on the baseline assessments conducted prior to randomization into treatment conditions. Sleep, depression symptoms, and social support were assessed by self-reporting. Cortisol was assessed from saliva samples taken over a 3-day period. Medical status and demographic characteristics were also examined in relation to each sleep variable in multiple regression analysis. Most women (63%) reported one or more types of sleep disturbance and 37% reported using sleeping pills in the previous 30 days. Problems with falling to sleep were significantly related to greater pain and depressive symptoms. Problems of waking during the night were significantly associated with greater depression and less education. Problems in waking/getting up were significantly associated with greater depressive symptoms and less social support. Sleepiness during the day was not significantly related to the variables in the regression model. Fewer hours of sleep were significantly associated with metastases to the bone, higher depressive symptoms, and more social support. Women who reported sleeping 9 or more hours per night, compared to those who reported a moderate amount of sleep (6.5-8.5 hours), had significantly lower 9 p.m. cortisol levels. Use of sleeping pills was more frequent among women reporting greater pain and depressive symptoms. These results suggest that women with metastatic breast cancer who are at higher risk for having sleeping problems are those who are less educated, in pain, depressed, have bony metastases, or lack social support.

  2. Evolution of taxanes in the treatment of metastatic breast cancer.

    PubMed

    Binder, Sandra

    2013-02-01

    Taxanes have become effective therapies for patients with metastatic breast cancer (MBC); however, understanding the differences among them is important. Each of the taxanes currently approved for treating MBC has a unique formulation, which translates to differences in toxicity profiles and administration considerations. In this article, the rationale for the development of the taxanes paclitaxel, docetaxel, and nab-paclitaxel is reviewed from a historical perspective. The mechanisms of action, formulations, and indications of taxanes also are discussed. The impact of their formulations on clinical practice and patient care, particularly solvent-based versus novel solvent-free formulations, will be reviewed from the nursing perspective.

  3. [Antiestrogen treatment in postmenopausal patients with metastatic breast cancer].

    PubMed

    Lindberg, Henriette; Nielsen, Dorte Lisbet; Tuxen, Malgorzata; Kamby, Claus

    2007-09-10

    This review discusses the evidence for endocrine treatment in postmenopausal patients with metastatic breast cancer. First line treatment with non-steroid aromatase inhibitors (AI) yields response rates of 30% and improves progression free survival, but not overall survival, compared to tamoxifen. With second line treatment using steroid AI, estrogen antagonists or selective estrogen receptor modulators prolonged disease stabilisation is achieved in 40% of patients. With third line treatment using steroid AI and estrogen antagonists disease stabilisation is achieved in up to 30% of patients.

  4. Psychological interventions for women with metastatic breast cancer.

    PubMed

    Mustafa, Mohammed; Carson-Stevens, Andrew; Gillespie, David; Edwards, Adrian G K

    2013-06-04

    Psychological symptoms are associated with metastatic breast cancer. This is the basis for exploring the impact of psychological interventions on psychosocial and survival outcomes. One early study appeared to show significant survival and psychological benefits from psychological support while subsequent studies have revealed conflicting results. This review is an update of a Cochrane review first published in 2004 and previously updated in 2007. To assess the effects of psychological interventions on psychosocial and survival outcomes for women with metastatic breast cancer. We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCO), online trials and research registers in June/July 2011. Further potentially relevant studies were identified from handsearching references of previous trials, systematic reviews and meta-analyses.  Randomised controlled trials (RCTs) and cluster RCTs of psychological interventions, which recruited women with metastatic breast cancer. Outcomes selected for analyses were overall survival, psychological outcomes, pain, quality of life, condition-specific outcome measures, relationship and social support measures, and sleep quality. Studies were excluded if no discrete data were available on women with metastatic breast cancer.  Two review authors independently extracted the data and assessed the quality of the studies using the Cochrane Collaboration risk of bias tool. Where possible, authors were contacted for missing information. Data on the nature and setting of the intervention, relevant outcome data, and items relating to methodological quality were extracted. Meta-analyses was performed using a random-effects or fixed-effect Mantel-Haenszel model, depending on expected levels of heterogeneity. Ten RCTs with 1378 women were identified. Of the seven RCTs on group psychological interventions, three were on cognitive behavioural therapy and four were

  5. Therapeutic effects of dendrosomal solanine on a metastatic breast tumor.

    PubMed

    Mohsenikia, Maryam; Farhangi, Baharak; Alizadeh, Ali Mohammad; Khodayari, Hamid; Khodayari, Saeed; Khori, Vahid; Arjmand Abbassi, Yasaman; Vesovic, Milica; Soleymani, Ali; Najafi, Farhood

    2016-03-01

    Our previous studies showed that alpha-solanine can inhibit tumor growth in cell culture and animal models of breast cancer. However, solanine is insoluble in common solvents; therefore, we developed a special nanoparticle with high-capacity solubility. The present study is aimed to deliberate the therapeutic effects of dendrosomal solanine (DNS) on a metastatic breast tumor in vitro and in vivo. After DNS preparation and dosing procedures, forty-five mice were equally divided into five groups to investigate the anti-metastatic effects of DNS on mammary tumor-bearing mice. Compared to solanine, DNS significantly suppressed the proliferation of 4 T1 cells in a dose- and time-dependent manner. DNS showed a remarkable safety rate of up to 10mg/kg. A significant decrease in white blood-cell count was seen at 20mg/kg DNS in comparison with control animals. Mice treated with DNS had smaller tumor volume (mm(3)) in comparison with control and solanine groups. Moreover, the incidence of the breast tumor metastases was about 67% in the control animals, where as solanine and DNS 1mg/kg were about 22% and 0%, respectively. Furthermore, the number of metastases per mouse varied from one to three. The tissues of tumor, brain, liver, spleen, and lung showed higher expression levels of Bcl-2 but lower expression levels of Bax, MMP-2, MMP-9, mTOR, and Akt in DNS-treated mice than control and solanine groups. The findings suggest that DNS has a more impactful therapeutic effect than solanine on 4 T1-induced breast tumorigenesis via influencing the tissue microenvironment. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Metastatic Male Breast Cancer: A Retrospective Cohort Analysis

    PubMed Central

    Foerster, Robert; Schroeder, Lars; Foerster, Frank; Wulff, Volker; Schubotz, Birgit; Baaske, Dieter; Rudlowski, Christian

    2014-01-01

    Summary Background Metastasized male breast cancer (MMBC) is a rare disease. Given its low incidence, data regarding tumor biology, current treatment options, and survival rates are scarce. Patients and Methods A chart review was performed of MMBC patients consecutively registered in regional cancer registries in Germany between 1995 and 2011. Tumor characteristics, treatment, and survival rates were documented and statistically evaluated. Results 41 men with MMBC represented 25.6% of a total of 160 patients with MBC. 16 (39%) patients showed primary metastases, and 25 (61%) had recurrent metastases. Median survival from occurrence of metastasis was 32 months. Median overall survival (OS) was 68 months. 68.3% (n = 28) of the cohort received systemic therapy favoring endocrine therapy (n = 25, 61.9%). Prolonged metastatic OS (p = 0.02) was observed in patients having had a systemic treatment. Metastatic patients having received endocrine treatment showed significantly prolonged survival rates. Furthermore, patients receiving palliative chemotherapy had a significant survival benefit compared to those in whom chemotherapy was omitted. Conclusion Our results suggest that systemic treatment in the form of both palliative chemotherapy and endocrine therapy improves outcome of R. Foerster and L. Schroeder contributed equally to this article and are listed in alphabetical order. MMBC. Therefore, it seems reasonable that treatment of MMBC should be based on the guidelines for female breast cancer. PMID:25404886

  7. Oral chemotherapy in elderly women with metastatic breast cancer.

    PubMed

    Molina-Garrido, M J; Mora-Rufete, A; Guillen-Ponce, C

    2014-06-01

    Life expectancy has significantly increased over the past 30 years, with a greater prevalence of diverse disease states, especially cancer. As older persons are a very heterogeneous group with an increased prevalence of comorbidities and a relative inability to tolerate the adverse effects of chemotherapy, the treatment of cancer in the elderly is particularly demanding. The principles of its management are similar to those in younger patients but with special considerations linked to comorbidities and clinical status. The objective of chemotherapeutic treatment in metastatic breast cancer has historically been primarily palliative. The introduction of newer approaches with improved or at least equivalent efficacy and reduced toxicity is highly desirable. Such approaches may include the use of less toxic drugs, more convenient routes of administration (e.g., oral) and home-based (outpatient) rather than hospital-based therapies. The available oral cytostatic drugs include vinorelbine and capecitabine. In this review, we analyze oral cytostatic drugs in the elderly patient diagnosed with metastatic breast cancer.

  8. [New therapeutical strategies in metastatic hormone-dependent breast cancer].

    PubMed

    Vilquin, Paul; Cohen, Pascale; Maudelonde, Thierry; Tredan, Olivier; Treilleux, Isabelle; Bachelot, Thomas; Heudel, Pierre-Etienne

    2015-04-01

    Hormone-dependent breast cancer is the first example of cancer treated by targeted therapy for more than 30 years. Blocking estrogen pathway was the first therapeutical strategy for this subtype of breast cancer, and remains the principle of current standard treatment. Despite the efficacy of drugs used in endocrine therapy, hormone resistance is a major problem for the management of patients with hormone-dependent breast cancer. In this review, we will discuss the development of strategies targeting the PI3K/Akt/mTOR pathway, CDK4/6 (Cyclin Dependent Kinase 4/6) and FGFR (Fibroblast Growth Factor Receptor) in hormone-dependent metastatic breast cancer (ER+). Recent results of clinical trials showed that combination of endocrine therapy with such pharmacological inhibitors is a promising strategy to overcome endocrine resistance. Mutated forms and isoforms of ERα have been recently discovered and its targeting could represent an therapeutic alternative. Future progress will focus on the identification of new compounds and combinations with other targeted therapies to improve the efficacy of such inhibitors in clinical practice.

  9. Individual characterisation of the metastatic capacity of human breast carcinoma.

    PubMed

    Heimann, R; Hellman, S

    2000-08-01

    The clinical implications of understanding the invasive and metastatic proclivities of an individual patient's tumour are substantial because the choice of systemic therapy needs to be guided by the likelihood of occult metastasis as well as by knowing when the metastases will become overt. Malignant potential is dynamic, progressing throughout the natural history of a tumour. Required of tumours is the development of critical phenotypic attributes: growth, angiogenesis, invasion and metastagenicity. Characterisation of the extent of tumour progression with regard to these major tumour phenotypes should allow the fashioning of individual therapy for each patient. To examine the clinical parameters and molecularly characterise the metastatic proclivity we have been studying a series of regionally treated breast cancer patients who received no systemic therapy and have long follow-up. Clinically we describe two parameters: metastagenicity - the metastatic proclivity of a tumour, and virulence--the rate at which these metastases appear. Both attributes increase with tumour size and nodal involvement. However, within each clinical group there is a cured population, even in those with extensive nodal involvement, underscoring the heterogeneity of breast cancers within each group and the need for further molecular characterisation. Using biomarkers that characterise the malignant phenotype we have determined that there is progression in the phenotypic changes. Angiogenesis and loss of nm23 are earlier events than the loss of E-cadherin, or abnormalities in TP53. The strongest biomarkers of poor prognosis are p53 and E-cadherin, but even when both are abnormal 42% of node-negative patients are cured indicating that other determinative steps need to occur before successful metastases are established. Identification of these critical later events will further increase the efficacy of determining the malignant capacities of individual tumours.

  10. Metastatic carcinoid tumor to the breast: report of two cases and review of the literature.

    PubMed

    Lee, Shimwoo; Levine, Pascale; Heller, Samantha L; Hernandez, Osvaldo; Mercado, Cecilia L; Chhor, Chloe M

    The breast is an unusual site for carcinoid metastasis. Due to increasing survival rates for carcinoid tumors, however, awareness of their rare complications is important. Carcinoid metastasis to the breast typically presents as a palpable breast mass or a mass on screening mammogram. Because imaging findings are nonspecific, the diagnosis is established through histological findings of neuroendocrine features corresponding with the known primary carcinoid pathology. Correctly distinguishing metastatic carcinoid from primary breast carcinoma is crucial to avoid more invasive procedures required for the latter. Two cases of metastatic carcinoid to the breast are presented with review of the literature. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis.

    PubMed

    Lefebvre, Celine; Bachelot, Thomas; Filleron, Thomas; Pedrero, Marion; Campone, Mario; Soria, Jean-Charles; Massard, Christophe; Lévy, Christelle; Arnedos, Monica; Lacroix-Triki, Magali; Garrabey, Julie; Boursin, Yannick; Deloger, Marc; Fu, Yu; Commo, Frédéric; Scott, Véronique; Lacroix, Ludovic; Dieci, Maria Vittoria; Kamal, Maud; Diéras, Véronique; Gonçalves, Anthony; Ferrerro, Jean-Marc; Romieu, Gilles; Vanlemmens, Laurence; Mouret Reynier, Marie-Ange; Théry, Jean-Christophe; Le Du, Fanny; Guiu, Séverine; Dalenc, Florence; Clapisson, Gilles; Bonnefoi, Hervé; Jimenez, Marta; Le Tourneau, Christophe; André, Fabrice

    2016-12-01

    Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which

  12. Clinical roundtable monograph. Current treatment options for metastatic breast cancer: what now?

    PubMed

    Rugo, Hope S; O'Shaughnessy, Joyce A; Perez, Edith A

    2011-11-01

    Approximately 30% of patients with breast cancer will develop metastatic breast disease. Metastatic breast cancer is considered an incurable disease, with complete remission rarely achieved after treatment. The goal of treatment for metastatic breast cancer patients is to increase overall survival time and delay disease progression while ameliorating symptoms and improving or maintaining quality of life. Single-agent therapeutic regimens are appropriate for most metastatic breast cancer patients. Patients with the luminal A subtype of breast cancer, which is more indolent in nature and tends to be more sensitive to treatment in general, often respond well to single-agent therapy. Several chemotherapy regimens are recommended for the treatment of metastatic breast cancer. Compared with single-agent regimens, these combination regimens often produce a greater improvement in the rate of objective response as well as a prolongation of progression-free survival. There is little evidence, however, of improvement in overall survival. Combination chemotherapy regimens are often associated with a greater degree of toxicity depending on schedules and doses used. The use of bevacizumab in metastatic breast cancer is currently a topic of controversy. It is hoped that forthcoming trial data will enable the identification of a group of patients, based on tumor biology, who could benefit from bevacizumab-based therapy.

  13. The sensory and coping intervention for women newly diagnosed with metastatic breast cancer.

    PubMed

    Rosenzweig, Margaret; Donovan, Heidi; Slavish, Kathleen

    2010-09-01

    Preparatory information at the time of metastatic breast cancer diagnosis can be used to enhance patients' coping ability. Women with metastatic breast cancer evaluated a multimedia educational intervention designed to provide sensory and coping information regarding illness. Twenty women with metastatic breast cancer evaluated the materials. The intervention was evaluated very favorably and women identified the materials as needed information. However, they expressed dislike of content outlining possible concerns suggesting future iterations include only positive content. Findings confirm the acceptability and usability of these materials for further testing and ultimately for integration into cancer care practice.

  14. HER2-positive metastatic breast cancer: a changing scenario.

    PubMed

    Mustacchi, G; Biganzoli, L; Pronzato, P; Montemurro, F; Dambrosio, M; Minelli, M; Molteni, L; Scaltriti, L

    2015-07-01

    Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic "de novo" HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active.

  15. Eribulin mesylate in the treatment of metastatic breast cancer

    PubMed Central

    Jain, Sarika; Cigler, Tessa

    2012-01-01

    The treatment of metastatic breast cancer (MBC) has become increasingly challenging as the primary goals of therapy include prolonging life without added toxicity. While multiple agents are approved for the therapy of MBC, there is no standard approach for therapy beyond the second-line. Eribulin mesylate, an analog of the marine sponge halichondrin B, is a non-taxane microtubule dynamics inhibitor with a mechanism of action distinct from other tubulin-targeted drugs. Based on a significant extension in overall survival seen in a Phase III clinical trial, eribulin was approved for third-line therapy in MBC patients following anthracycline and taxane failure. Eribulin has a manageable toxicity profile and a low incidence of peripheral neuropathy. In this review, we discuss the natural source of eribulin, pharmacology, mode of action, preclinical and clinical data, and patient-focused perspectives. PMID:22291464

  16. Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential.

    PubMed

    Feeley, Kyle P; Bray, Alexander W; Westbrook, David G; Johnson, Larry W; Kesterson, Robert A; Ballinger, Scott W; Welch, Danny R

    2015-10-15

    Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors influence an individual's predilection for developing metastatic breast cancer. Investigations of tumor latency and metastasis in mice have illustrated differences between inbred strains, but the possibility that mitochondrial genetic inheritance may contribute to such differences in vivo has not been directly tested. In this study, we tested this hypothesis in mitochondrial-nuclear exchange mice we generated, where cohorts shared identical nuclear backgrounds but different mtDNA genomes on the background of the PyMT transgenic mouse model of spontaneous mammary carcinoma. In this setting, we found that primary tumor latency and metastasis segregated with mtDNA, suggesting that mtDNA influences disease progression to a far greater extent than previously appreciated. Our findings prompt further investigation into metabolic differences controlled by mitochondrial process as a basis for understanding tumor development and metastasis in individual subjects. Importantly, differences in mitochondrial DNA are sufficient to fundamentally alter disease course in the PyMT mouse mammary tumor model, suggesting that functional metabolic differences direct early tumor growth and metastatic efficiency.

  17. Breast carcinoma subtypes show different patterns of metastatic behavior.

    PubMed

    Molnár, István Artúr; Molnár, Béla Ákos; Vízkeleti, Laura; Fekete, Krisztina; Tamás, Judit; Deák, Péter; Szundi, Csilla; Székely, Borbála; Moldvay, Judit; Vári-Kakas, Stefan; Szász, Marcell A; Ács, Balázs; Kulka, Janina; Tőkés, Anna-Mária

    2017-03-01

    The aim of our retrospective study was to analyze patterns of subtype specific metastatic spread and to identify the time course of distant metastases. A consecutive series of 490 patients with breast cancer who underwent surgery and postoperative treatment at Semmelweis University, Hungary, and diagnosed between the years 2000 and 2007 was identified from the archives of the 2nd Department of Pathology, Hungary. Molecular subtypes were defined based on the 2011 St. Gallen recommendations. Statistical analysis was performed with SPSS Statistics for Windows, Version 22.0. Distant metastasis free survival (DMFS) was defined as the time elapsed between the first pathological diagnosis of the tumor and the first distant metastasis detection. Distant metastases were detected in 124 patients. Mean time to develop metastasis was 29 months (range 0-127 months). The longest DMFS was observed in the Luminal A (LUMA) subtype (mean 39 months) whereas the shortest was seen in the HER2-positive (HER2+) subtype (mean 21 months; p = 0.012). We confirmed that HER2+ tumors carry a higher risk for distant metastases (42.1%). LUMA-associated metastases were found to be solitary in 59% of cases, whereas HER2+ tumors showed multiple metastases in 79.2% of cases. LUMA tumors showed a preference for bone-only metastasis as compared with HER2+ and triple negative breast cancer (TNBC) cases, which exhibited a higher rate of brain metastasis. The most frequent second metastatic sites of hormone receptor (HR) positive tumors were the lung and liver, whereas the brain was the most affected organ in HR-negative (HR-) cases. Tumor subtypes differ in DMFS and in pattern of distant metastases. HER2+ tumors featured the most aggressive clinical course. Further identification of subtype-specific factors influencing prognosis might have an impact on clinical care and decision-making.

  18. The Uncontrolled Sialylation is Related to Chemoresistant Metastatic Breast Cancer.

    PubMed

    Roncati, Luca; Barbolini, Giuseppe; Gatti, Antonietta Morena; Pusiol, Teresa; Piscioli, Francesco; Maiorana, Antonio

    2016-10-01

    Among the scientific communities, there is a convergence of results supporting a direct relationship between dysregulated sialylation and poor prognosis in many human cancers. For this reason, we have retrospectively investigated 169 cases of invasive ductal carcinoma of the breast, coming from female patients aged between 31 and 76 years old. The whole series was subdivided into two prognostic groups: the first group consisted of 138 patients, who showed a post-treatment survival time more than 5 years, while the second group was made up by 31 patients, died within 5 years despite of chemotherapy. All the surgical specimens were fixed in 10 % neutral buffered formalin, paraffin embedded and, then, submitted to routinely haematoxylin/eosin staining and to a further histochemical (Alcian Blue, DDD-Fast Blue B, Mercury Orange), immunohistochemical (ST3GAL5 sialyltransferase, Ki67, c-erbB2, ER, PR) and chemico-elemental characterization. In the 31 cases of breast cancer belonging to the second group, an overexpression of sialomucins and sialyltransferases has been detected. Our results lead us to support that in aggressive chemoresistant breast cancers, the altered expression of sialic acid, due to an uncontrolled sialylation, creates an excessive negative charge on cell membranes, which stimulates repulsion between neoplastic cells and their subsequent access into the blood stream. This event implies an early metastatization and a rapid disease progression with fatal outcome. The early application of Alcian Blue stain on diagnostic biopsies of breast cancer is able to cheaply reveal the sialomucin accumulations, providing for the disease course.

  19. Primary colorectal adenocarcinoma metastatic to the breast: case report and review of nineteen cases.

    PubMed

    Shackelford, Rodney E; Allam-Nandyala, Pushpa; Bui, Marilyn M; Kiluk, John V; Esposito, Nicole Nicosia

    2011-01-01

    Metastases to the breast from extramammary primaries are uncommon and account for 0.5-6% of all breast malignancies (Georgiannos et al., 2001, and Vizcaíno et al., 2001). Malignant melanoma, lymphoma, and lung and gastric carcinomas are the most frequently encountered nonmammary metastases to the breast in adults (Georgiannos et al., 2001, and Chaignaud et al., 1994). Primary colorectal adenocarcinoma (CRC) metastatic to the breast is extremely rare, with the medical literature having only 19 recorded cases. Typically CRC metastatic to the breast is indicative of widely disseminated disease and a poor prognosis. Here we present a case of poorly differentiated colon cancer metastatic to the breast and review the current literature on this rare event.

  20. Improvement of survival and prospect of cure in patients with metastatic breast cancer.

    PubMed

    Cheng, Yee Chung; Ueno, Naoto T

    2012-07-01

    Patients with metastatic breast cancer have traditionally been considered incurable with conventional treatment. However, 5-10% of those patients survive more than 5 years, and 2-5% survive more than 10 years. Recent studies suggest that the survival of patients with metastatic breast cancer has been slowly improving. In this review, we examine the possible curative approach for a certain group of patients with metastatic breast cancer. We identify that patients most likely to benefit from such an aggressive approach are young and have good performance status, adequate body functional reserve, long disease-free interval before recurrence, oligometastatic disease, and low systemic tumor load. An aggressive multidisciplinary approach including both local treatment of macroscopic disease and systemic treatment of microscopic disease can result in prolonged disease control in certain patients with metastatic breast cancer. Whether patients with prolonged disease control are "cured" remains controversial.

  1. Bone marrow endothelium-targeted therapeutics for metastatic breast cancer.

    PubMed

    Mai, Junhua; Huang, Yi; Mu, Chaofeng; Zhang, Guodong; Xu, Rong; Guo, Xiaojing; Xia, Xiaojun; Volk, David E; Lokesh, Ganesh L; Thiviyanathan, Varatharasa; Gorenstein, David G; Liu, Xuewu; Ferrari, Mauro; Shen, Haifa

    2014-08-10

    Effective treatment of cancer metastasis to the bone relies on bone marrow drug accumulation. The surface proteins in the bone marrow vascular endothelium provide docking sites for targeted drug delivery. We have developed a thioaptamer that specifically binds to E-selectin that is overexpressed in the vasculature of tumor and inflammatory tissues. In this study, we tested targeted delivery of therapeutic siRNA loaded in the E-selectin thioaptamer-conjugated multistage vector (ESTA-MSV) drug carrier to bone marrow for the treatment of breast cancer bone metastasis. We evaluated tumor type- and tumor growth stage-dependent targeting in mice bearing metastatic breast cancer in the bone, and carried out studies to identify factors that determine targeting efficiency. In a subsequent study, we delivered siRNA to knock down expression of the human STAT3 gene in murine xenograft models of human MDA-MB-231 breast tumor, and assessed therapeutic efficacy. Our studies revealed that the CD31(+)E-selectin(+) population accounted for 20.8%, 26.4% and 29.9% of total endothelial cells respectively inside the femur of mice bearing early, middle and late stage metastatic MDA-MB-231 tumors. In comparison, the double positive cells remained at a basal level in mice with early stage MCF-7 tumors, and jumped to 23.9% and 28.2% when tumor growth progressed to middle and late stages. Accumulation of ESTA-MSV inside the bone marrow correlated with the E-selectin expression pattern. There was up to 5-fold enrichment of the targeted MSV in the bone marrow of mice bearing early or late stage MDA-MB-231 tumors and of mice with late stage, but not early stage, MCF-7 tumors. Targeted delivery of STAT3 siRNA in ESTA-MSV resulted in knockdown of STAT3 expression in 48.7% of cancer cells inside the bone marrow. Weekly systemic administration of ESTA-MSV/STAT3 siRNA significantly extended survival of mice with MDA-MB-231 bone metastasis. In conclusion, targeting the overexpressed E

  2. Overcoming Bone Marrow Stroma-Mediated Chemoresistance in Metastatic Breast Cancer Cells

    DTIC Science & Technology

    2004-08-01

    AD Award Number: DAMD17-03- 1 -0524 .TITLE: Overcoming Bone Marrow Stroma- Mediated Chemoresistance in Metastatic Breast Cancer Cells PRINCIPAL...SUBTITLE 5. FUNDING NUMBERS Overcoming Bone Marrow Stroma- Mediated Chemoresistance in DAMD17-03- 1 -0524 Metastatic Breast Cancer Cells 6. AUTHOR(S) Robert...the compound (Figure 1 ). The inhibitor was slightly more effective in T-47D cells than in MCF-7 cells, but did not eradicate dormant clones much past

  3. Recent Insights into the Development of Preclinical Trastuzumab-Resistant HER2+ Breast Cancer Models.

    PubMed

    González-Alonso, Paula; Cristóbal, Ion; Zazo, Sandra; Martín-Aparicio, Ester; Chamizo, Cristina; Madoz-Gúrpide, Juan; Rovira, Ana; Eroles, Pilar; Lluch, Ana; Albanell, Joan; Rojo, Federico

    2016-12-16

    Overexpression and amplification of the human epidermal growth factor receptor 2 (HER2) occurs in 20% of total breast carcinomas. HER2-overexpression is implicated in disease initiation and progression and associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody, is the standard HER2-targeted therapy for early and metastatic HER2-amplified breast cancer patients. Trastuzumab has significantly increased clinical benefit in HER2+ metastatic and adjuvant settings, however, it is not effective for many patients due to primary or acquired resistance to the drug. During the last decade, many studies have revealed a number of novel molecular traits of HER2+ breast cancer, allowing us to uncover the molecular mechanisms involved in trastuzumab resistance and develop strategies to overcome resistance to therapy. In this review, we comprehensively addressed the current achievements in preclinical studies; we discussed molecular mechanisms of acquired trastuzumab resistance in HER2+ breast cancer models and potential therapeutic approaches based on the molecular features for HER2+ breast cancer. Enhanced understanding of the molecular profiles in HER2+ breast cancer may lead to identification of novel biomarkers for development of diagnostic approaches and improvement of therapeutic targets for prevention and treatment of trastuzumab resistant HER2+ breast cancer.

  4. Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells.

    PubMed

    Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-Tae; Iqbal, Samir M

    2017-09-20

    Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

  5. Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells

    NASA Astrophysics Data System (ADS)

    Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-tae; Iqbal, Samir M.

    2017-09-01

    Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

  6. Kinetics of metastatic breast cancer cell trafficking in bone

    PubMed Central

    Phadke, Pushkar A.; Mercer, Robyn R.; Harms, John F.; Jia, Yujiang; Frost, Andra R.; Jewell, Jennifer L.; Bussard, Karen M.; Nelson, Shakira; Moore, Cynthia; Kappes, John C.; Gay, Carol V.; Mastro, Andrea M.; Welch, Danny R.

    2006-01-01

    Purpose In vivo studies have focused on the latter stages of the bone metastatic process (osteolysis), while little is known about earlier events, e.g., arrival, localization, initial colonization. Defining these initial steps may potentially identify critical points susceptible to therapeutic intervention. Experimental Design MDA-MB-435 human breast cancer cells engineered with green fluorescent protein (GFP) were injected into the cardiac left ventricle of athymic mice. Femurs were analyzed by fluorescence microscopy, immunohistochemistry, real-time PCR, flow cytometry and histomorphometry at times ranging from 1 hr to 6 wk. Results Single cells were found in distal metaphyses at 1 hr post-injection and remained as single cells up to 72 hr. Diaphyseal arrest occurred rarely and few cells remained there after 24 hr. At 1 wk, numerous foci (2–10 cells) were observed, mostly adjacent to osteoblast-like cells. By 2 wk, fewer but larger foci (≥50 cells) were seen. Most bones had a single large mass at 4 wk (originating from a colony or coalescing foci) which extended into the diaphysis by 4–6 wk. Little change (<20%) in osteoblast or osteoclast numbers was observed at 2 wk; but, at 4–6 wk osteoblasts were dramatically reduced (8% of control), while osteoclasts were reduced modestly (to ~60% of control). Conclusions Early arrest in metaphysis and minimal retention in diaphysis highlight the importance of local milieu in determining metastatic potential. These results extend the Seed and Soil hypothesis by demonstrating both inter- and intra-tissue differences governing metastasis location. Ours is the first in vivo evidence that tumor cells influence not only osteoclasts, as widely believed, but also eliminate functional osteoblasts, thereby restructuring the bone microenvironment to favor osteolysis. The data also explain why bisphosphonates do heal bone despite inhibiting resorption, implying that concurrent strategies that restore osteoblast function are

  7. Concurrence of primary hyperparathyroidism and metastatic breast carcinoma affected a parathyroid gland.

    PubMed

    Lee, Sang Hee; Kim, Bo Hyun; Bae, Min Jung; Yi, Yang Seon; Kim, Won Jin; Jeon, Yun Kyung; Kim, Sang Soo; Kim, Yong Ki; Kim, In Joo

    2013-08-01

    Involvement of the parathyroid glands by metastatic tumor is rare. Breast is 1 of the primary sites in metastatic cancers. We introduce a rare case of metastatic breast carcinoma affecting a parathyroid gland, which was clinically combined with parathyroid gland hyperplasia. A 65-year-old woman was referred due to hypercalcemia and constipation. The patient had a history of left breast carcinoma. She was admitted to the hospital because of the recent discovery of hypercalcemia and elevation of PTH. A Tc99m-sestamibi scan showed retained uptake in the right thyroid and in the lower pole of the left thyroid gland. Aspiration biopsy results revealed that the nodule in the posterior portion of the right thyroid was metastatic breast cancer and the nodule in the left thyroid gland was the hyperplastic parathyroid gland. This case illustrates that hyperparathyroidism caused by parathyroid hyperplasia was concurrent with metastatic breast cancer to a parathyroid gland without disseminated systemic metastasis. Although this case is very uncommon and it is not clear whether there is a relationship between breast cancer and primary hyperparathyroidism, that possibility should always be considered as the cause of hypercalcemia in patients with breast cancer.

  8. Phase II trial of piroxantrone in metastatic breast cancer. A Southwest Oncology Group study.

    PubMed

    Ravdin, P M; Green, S; Doroshow, J H; Martino, S

    1994-01-01

    Thirty-two eligible patients with advanced metastatic breast cancer who had received no more than 1 prior chemotherapy regimen for metastatic disease (16 had received prior doxorubicin) were treated with piroxantrone at a dose of 120 mg/m2 intravenously every 21 days. In the twenty-seven patients evaluable for response, two partial responses were seen. Toxicities observed were primarily hematologic with grade 3 or greater granulocytopenia occurring in 34% of the patients. One patient developed symptomatic congestive heart failure at a total cumulative dose of 960 mg/m2. We conclude that piroxantrone given at this dose and schedule has minimal activity in patients with metastatic breast cancer.

  9. Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis

    PubMed Central

    Pedrero, Marion; Campone, Mario; Soria, Jean-Charles; Massard, Christophe; Lévy, Christelle; Arnedos, Monica; Lacroix-Triki, Magali; Garrabey, Julie; Boursin, Yannick; Deloger, Marc; Commo, Frédéric; Scott, Véronique; Kamal, Maud; Diéras, Véronique; Gonçalves, Anthony; Romieu, Gilles; Vanlemmens, Laurence; Mouret Reynier, Marie-Ange; Théry, Jean-Christophe; Le Du, Fanny; Guiu, Séverine; Dalenc, Florence; Bonnefoi, Hervé; Jimenez, Marta; Le Tourneau, Christophe; André, Fabrice

    2016-01-01

    Background Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. Methods and Findings Whole-exome sequencing was performed on 216 tumor–blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9–155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2−) mBCs (19%). HR+/HER2− mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2− eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2− metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone

  10. Expression of Yes-associated protein (YAP) in metastatic breast cancer.

    PubMed

    Kim, Hye Min; Jung, Woo Hee; Koo, Ja Seung

    2015-01-01

    The purpose of this study was to investigate the expression of Yes-associated protein (YAP) in different metastatic sites in metastatic breast cancer and to determine the clinical implications of these patterns. Immunohistochemical staining was used to investigate the expression of YAP and phospho-YAP in tissue microarrays from 122 cases of metastatic breast cancer (bone metastasis = 29, brain metastasis = 38, liver metastasis = 12, and lung metastasis = 43). The expression levels of YAP and phospho-YAP differed according to the metastatic site in metastatic breast cancer. Specifically, nuclear expression of phospho-YAP was high in brain metastasis but low in lung metastasis (P = 0.010). The effects of YAP and phospho-YAP expression on clinical outcomes were investigated by univariate analysis. This analysis showed that nuclear YAP positivity (P = 0.008) and nuclear phospho-YAP positivity (P = 0.003) were both associated with shorter overall survival. In conclusion, the level of YAP expression varies according to the metastatic site in metastatic breast cancer. Moreover, high YAP expression was correlated with poor prognosis.

  11. Optical redox ratio identifies metastatic potential-dependent changes in breast cancer cell metabolism

    PubMed Central

    Alhallak, Kinan; Rebello, Lisa G.; Muldoon, Timothy J.; Quinn, Kyle P.; Rajaram, Narasimhan

    2016-01-01

    The development of prognostic indicators of breast cancer metastatic risk could reduce the number of patients receiving chemotherapy for tumors with low metastatic potential. Recent evidence points to a critical role for cell metabolism in driving breast cancer metastasis. Endogenous fluorescence intensity of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) can provide a label-free method for assessing cell metabolism. We report the optical redox ratio of FAD/(FAD + NADH) of four isogenic triple-negative breast cancer cell lines with varying metastatic potential. Under normoxic conditions, the redox ratio increases with increasing metastatic potential (168FARN>4T07>4T1), indicating a shift to more oxidative metabolism in cells capable of metastasis. Reoxygenation following acute hypoxia increased the redox ratio by 43 ± 9% and 33 ± 4% in the 4T1 and 4T07 cells, respectively; in contrast, the redox ratio decreased 14 ± 7% in the non-metastatic 67NR cell line. These results demonstrate that the optical redox ratio is sensitive to the metabolic adaptability of breast cancer cells with high metastatic potential and could potentially be used to measure dynamic functional changes that are indicative of invasive or metastatic potential. PMID:27895979

  12. Chronic Stress, Depression and Immunity in Spouses of Metastatic Breast Cancer Patients

    ERIC Educational Resources Information Center

    Mortimer, Jane S. Blake; Sephton, Sandra E.; Kimerling, Rachel; Butler, Lisa; Bernstein, Aaron S.; Spiegel, David

    2005-01-01

    Objective: The objective of this study was to examine how the chronicity of stress affects psychological stress-responses, depressive symptoms, and "in vivo" immunocompetence in spouses of women with metastatic breast cancer. Methods: Participants were 34 spouses of breast cancer patients. Their wives had been living with a diagnosis of…

  13. Chronic Stress, Depression and Immunity in Spouses of Metastatic Breast Cancer Patients

    ERIC Educational Resources Information Center

    Mortimer, Jane S. Blake; Sephton, Sandra E.; Kimerling, Rachel; Butler, Lisa; Bernstein, Aaron S.; Spiegel, David

    2005-01-01

    Objective: The objective of this study was to examine how the chronicity of stress affects psychological stress-responses, depressive symptoms, and "in vivo" immunocompetence in spouses of women with metastatic breast cancer. Methods: Participants were 34 spouses of breast cancer patients. Their wives had been living with a diagnosis of…

  14. The clinical value of hybrid sentinel lymphoscintigraphy to predict metastatic sentinel lymph nodes in breast cancer.

    PubMed

    Na, Chang Ju; Kim, Jeonghun; Choi, Sehun; Han, Yeon-Hee; Jeong, Hwan-Jeong; Sohn, Myung-Hee; Youn, Hyun Jo; Lim, Seok Tae

    2015-03-01

    Hybrid imaging techniques can provide functional and anatomical information about sentinel lymph nodes in breast cancer. Our aim in this study was to evaluate which imaging parameters on hybrid sentinel lymphoscintigraphy predicted metastatic involvement of sentinel lymph nodes (SLNs) in patients with breast cancer. Among 56 patients who underwent conventional sentinel lymphoscintigraphy, 45 patients (age, 53.1 ± 9.5 years) underwent hybrid sentinel lymphoscintigraphy using a single-photon emission computed tomography (SPECT)/computed tomography (CT) gamma camera. On hybrid SPECT/CT images, we compared the shape and size (long-to-short axis [L/S] ratio) of the SLN, and SLN/periareolar injection site (S/P) count ratio between metastatic and non-metastatic SLNs. Metastatic involvement of sentinel lymph nodes was confirmed by pathological biopsy. Pathological biopsy revealed that 21 patients (46.7 %) had metastatic SLNs, while 24 (53.3 %) had non-metastatic SLNs. In the 21 patients with metastatic SLNs, the SLN was mostly round (57.1 %) or had an eccentric cortical rim (38.1 %). Of 24 patients with non-metastatic SLNs, 13 patients (54.1 %) had an SLN with a C-shape rim or eccentric cortex. L/S ratio was 2.04 for metastatic SLNs and 2.38 for non-metastatic SLNs. Seven (33 %) patients had T1 primary tumors and 14 (66 %) had T2 primary tumors in the metastatic SLN group. In contrast, 18 (75 %) patients had T1 primary tumors and six (25 %) had T2 tumors in the non-metastatic SLN group. S/P count ratio was significantly lower in the metastatic SLN group than the non-metastatic SLN group for those patients with a T1 primary tumor (p = 0.007). Hybrid SPECT/CT offers the physiologic data of SPECT together with the anatomic data of CT in a single image. This hybrid imaging improved the anatomic localization of SLNs in breast cancer patients and predicted the metastatic involvement of SLNs in the subgroup of breast cancer patients with T1 primary tumors.

  15. Somatic mutations of the HER2 in metastatic breast cancer.

    PubMed

    Fang, Yi; Jiang, Yanxia; Wang, Xin; Yang, Xue; Gao, Yinqi; Wang, Jing

    2014-12-01

    Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the full length of HER2 in 198 metastatic breast cancers (MBC) as well as 34 other epithelial cancers (bladder, prostate, and colorectal cancers) and compared the mutational status with clinic pathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 11.6 % (23 of 198) of MBC and were absent in other types of cancers. HER2 mutations were located in exon 15 and the in-frame insertions in exon 20 with corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in patient after the administration of trastuzumab (34.8 %, 8 of 23; P = 0.02). Mutations in exon 15 and 20 were more potent than wild-type HER2 in associating with activating signal transducers and inducing survival, invasiveness, and tumorigenicity.

  16. Docetaxel combined with targeted therapies in metastatic breast cancer.

    PubMed

    Cortes, Javier; Roché, Henri

    2012-08-01

    The treatment of metastatic breast cancer (MBC) is essentially palliative and should be based on hormone therapy or optimized chemotherapy designed to delay disease progression and maximize survival with good quality of life. Novel chemotherapeutic agents introduced in the 1990 s include the taxanes (notably docetaxel), which are among the most potent of current anticancer drugs. Current research is also focusing on molecular targeted agents including those against the HER family of transmembrane receptors and vascular endothelial growth factor. Optimal effects are obtained when these compounds are used in combination with chemotherapy, as shown in preclinical models and more recently in clinical trials. Results of a large randomized trial have demonstrated a significant survival advantage for trastuzumab plus docetaxel compared with docetaxel monotherapy. Docetaxel plus bevacizumab combinations have recently been shown to significantly improve progression-free survival and objective response rate compared with docetaxel monotherapy. Overall, docetaxel in combination with novel targeted agents in MBC appears to be highly active in patients with MBC, and such combinations represent promising treatment regimens for clinical investigation. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Metabolic reprogramming underlies metastatic potential in an obesity-responsive murine model of metastatic triple negative breast cancer.

    PubMed

    O'Flanagan, Ciara H; Rossi, Emily L; McDonell, Shannon B; Chen, Xuewen; Tsai, Yi-Hsuan; Parker, Joel S; Usary, Jerry; Perou, Charles M; Hursting, Stephen D

    2017-01-01

    The vast majority of cancer-related deaths are due to metastatic disease, whereby primary tumor cells disseminate and colonize distal sites within the body. Triple negative breast cancer typically displays aberrant Wnt signaling, lacks effective targeted therapies, and compared with other breast cancer subtypes, is more likely to recur and metastasize. We developed a Wnt-driven lung metastasis model of triple negative breast cancer (metM-Wnt(lung)) through serial passaging of our previously described, nonmetastatic, claudin-low M-Wnt cell line. metM-Wnt(lung) cells displayed characteristics of epithelial-to-mesenchymal transition (e.g., increased invasiveness) with some re-epithealization (e.g., increased adhesion, tight colony formation, increased E-cadherin expression, and decreased Vimentin and Fibronectin expression). When orthotopically transplanted into syngeneic mice, metM-Wnt(lung) cells readily formed tumors and metastasized in vivo, and tumor growth and metastasis were enhanced in obese mice compared with non-obese mice. Gene expression analysis revealed several genes and pathways altered in metM-Wnt(lung) cells compared with M-Wnt cells, including multiple genes associated with epithelial-to-mesenchymal transition, energy metabolism and inflammation. Moreover, obesity caused significant transcriptomic changes, especially in metabolic pathways. Metabolic flux analyses showed greater metabolic plasticity, with heightened mitochondrial and glycolytic energetics in metM-Wnt(lung) cells relative to M-Wnt cells. Similar metabolic profiles were found in a second triple negative breast cancer progression series, M6 and M6C cells. These findings suggest that metabolic reprogramming is a feature of metastatic potential in triple negative breast cancer. Thus, targeting metastases-associated metabolic perturbations may represent a novel strategy for reducing the burden of metastatic triple negative breast cancer, particularly in obese women.

  18. Fine-needle aspiration of metastatic melanoma presenting as bilateral breast cysts.

    PubMed

    Inouye, Casey M; Cimino-Mathews, Ashley; Eisner, David; Rosenthal, Dorothy L; VandenBussche, Christopher J

    2017-05-01

    Melanoma is the second most common non-hematopoietic malignancy after carcinomas to metastasize to the breast and often appears as a well-circumscribed, dense nodule on imaging. Although metastatic lesions presenting as bilateral cysts have been reported, this presentation is not common and may mimic benign breast cysts. We present a challenging case of metastatic melanoma presenting as bilateral breast cysts with spindled cytomorphology in a patient with a history of mammary carcinoma. Discordance between the spindled cytomorphology and the morphology of the core biopsy, which was similar to the patient's primary breast cancer, allowed for entertainment of other tumors and disease processes. Confirmatory immunostaining of the cytology material with HMB-45 was important to establish the diagnosis of metastatic melanoma. Diagn. Cytopathol. 2017;45:446-451. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. Emerging therapeutic targets in metastatic progression: a focus on breast cancer

    PubMed Central

    Li, Zhuo; Kang, Yibin

    2016-01-01

    Metastasis is the underlying cause of death for the majority of breast cancer patients. Despite significant advances in recent years in basic research and clinical development, therapies that specifically target metastatic breast cancer remain inadequate, and represents the single greatest obstacle to reducing mortality of late-stage breast cancer. Recent efforts have leveraged genomic analysis of breast cancer and molecular dissection of tumor-stromal cross-talk to uncover a number of promising candidates for targeted treatment of metastatic breast cancer. Rational combinations of therapeutic agents targeting tumor-intrinsic properties and microenvironmental components provide a promising strategy to develop precision treatments with higher specificity and less toxicity. In this review, we discuss the emerging therapeutic targets in breast cancer metastasis, from tumor-intrinsic pathways to those that involve the host tissue components, including the immune system. PMID:27000769

  20. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells.

    PubMed

    Lawson, Devon A; Bhakta, Nirav R; Kessenbrock, Kai; Prummel, Karin D; Yu, Ying; Takai, Ken; Zhou, Alicia; Eyob, Henok; Balakrishnan, Sanjeev; Wang, Chih-Yang; Yaswen, Paul; Goga, Andrei; Werb, Zena

    2015-10-01

    Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated

  1. Correlation between conductivity and prognostic factors in invasive breast cancer using magnetic resonance electric properties tomography (MREPT).

    PubMed

    Kim, Soo-Yeon; Shin, Jaewook; Kim, Dong-Hyun; Kim, Min Jung; Kim, Eun-Kyung; Moon, Hee Jung; Yoon, Jung Hyun

    2016-07-01

    To investigate the correlation between conductivity and prognostic factors of invasive breast cancer using magnetic resonance electric properties tomography (MREPT). This retrospective study was approved by the Institutional Review Board, and verbal informed consent was obtained prior to breast MRI. This study included 65 women with surgically confirmed invasive breast cancers measuring 1 cm or larger on T2-weighted fast spin echo (FSE). Phase-based MREPT and the coil combination technique were used to reconstruct conductivity. Simple and multiple linear regression analysis were used to find an independent factor associated with conductivity. In total tumours, tumours with HER-2 overexpression showed lower conductivity than those without, and HER-2 overexpression was independently associated with conductivity. In 37 tumours 2 cm or larger, tumours with high mitosis or PR positivity showed higher conductivity than those without, and high mitosis and PR positivity were independently associated with conductivity. In 28 tumours 1-2 cm in size, there were no differences in conductivity according to the prognostic factors. Conductivity values measured using MREPT are associated with the HER-2 overexpression status, and may provide information about mitosis and the PR status of invasive breast cancers 2 cm or larger. • In all tumours, HER-2 overexpression was independently associated with conductivity. • In tumours ≥ 2 cm, high mitosis and PR positivity were associated with conductivity. • Conductivity is associated with the HER-2 overexpression status of invasive breast cancers.

  2. Comparative metabolic and lipidomic profiling of human breast cancer cells with different metastatic potentials

    PubMed Central

    Kim, So-Hyun; Kwon, Yeo-Jung; Chun, Young-Jin; Choi, Hyung-Kyoon

    2016-01-01

    This study conducted comprehensive and comparative metabolic and lipidomic profiling of a human epithelial breast cell line (MCF-10A), a slightly metastatic (MCF-7), and a highly metastatic (MDA-MB-231) breast cancer cell line using gas chromatography mass spectrometry (GC-MS) and direct infusion mass spectrometry (DI-MS). Among 39 metabolites identified by GC-MS analysis, xanthine, glucose-6-phosphate, mannose-6-phosphate, guanine, and adenine were selected as prognostic markers of breast cancer metastasis. Major metabolic pathways involved in differentiation of the cell lines were alanine, aspartate, and glutamate metabolism, purine metabolism and glycine, serine, and threonine metabolism. Among 44 intact lipid species identified by DI-MS analysis, the levels of most phospholipids were higher in both metastatic groups than in normal cells. Specifically, the levels of phosphatidylserine (PS) 18:0/20:4, phosphatidylinositol (PI) 18:0/20:4, and phosphatidylcholine (PC) 18:0/20:4 were markedly higher while those of phosphatidylethanolamine (PE) 18:1/18:1 and PI 18:0/18:1 were lower in MDA-MB-231 cells than in MCF-7 cells. A partial-least-squares regression model was developed and validated for predicting the metastatic potential of breast cancer cells. The information obtained in this study will be useful when developing diagnostic tools and for identifying potential therapeutic targets for metastatic breast cancer. PMID:27564096

  3. Predicting Survival of De Novo Metastatic Breast Cancer in Asian Women: Systematic Review and Validation Study

    PubMed Central

    Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G. M.; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M.

    2014-01-01

    Background In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. Materials and Methods We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). Results We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48–0.53) to 0.63 (95% CI, 0.60–0.66). Conclusion The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making. PMID:24695692

  4. Living Well? Strategies Used by Women Living With Metastatic Breast Cancer.

    PubMed

    Lewis, Sophie; Willis, Karen; Yee, Jasmine; Kilbreath, Sharon

    2016-07-01

    Metastatic breast cancer is a disease of changing status-once an imminent death sentence, now a chronic (albeit incurable) disease. Medical intervention advances mean women with metastatic breast cancer now have symptoms alleviated and, potentially, life extended. Living with this disease, however, requires more than a medical approach to symptoms. We were interested to know whether women manage, and if so, how, to "live well" with metastatic cancer. We conducted interviews with 18 women. Women differed in the approaches they used. Most common was the attempt to reestablish a sense of normality in their lives. However, a second group reevaluated and reprioritized their lives; and a third group was restricted in their capacity to live well because of symptoms. The findings provide the foundation for future research exploring normalization of experiences of metastatic cancer, and other chronic illnesses, where people are living with knowledge that they have contracted time. © The Author(s) 2015.

  5. Lobular Carcinoma of the Breast Metastatic to the Spleen and Accessory Spleen: Report of a Case

    PubMed Central

    2016-01-01

    Despite the fact that accessory spleen (also known as supernumerary spleen, splenunculus, or splenule) can be found in 10–30% of patients undergoing autopsies, metastatic disease occurring in this organ has been barely reported. A case of lobular breast carcinoma metastatic to the spleen and accessory spleen found incidentally at therapeutic splenectomy for severe anemia and thrombocytopenia is described. On microscopic examination both organs revealed severe fibrocongestive changes and extramedullary hematopoiesis with no obvious carcinomatous involvement. Cytokeratin 7, estrogen receptors, and GATA3 immunohistochemistry disclosed the presence of numerous metastatic breast carcinoma cells infiltrating the splenic parenchyma. This case demonstrates that metastatic carcinoma can be encountered, although rarely, in accessory spleens and that cytokeratin stain should be performed in sections of spleens and/or accessory spleens excised from cancer patients in which the presence of malignant epithelial cells is not recognized on routine sections. PMID:27672468

  6. 'Tablet burden' in patients with metastatic breast cancer.

    PubMed

    Milic, Marina; Foster, Anna; Rihawi, Karim; Anthoney, Alan; Twelves, Chris

    2016-03-01

    The implications for patients with cancer, of the 'tablet burden' resulting from increasing use of oral anticancer drugs and medication for co-morbidities have not previously been well explored. We sought to (i) quantify tablet burden in women with metastatic breast cancer (MBC), (ii) establish which groups of drug contribute most to this burden and (iii) gain insight into patients' attitudes towards oral anti-cancer treatment. One hundred patients with MBC anonymously completed a questionnaire describing their medication histories and attitudes towards their tablets. The patients (mean age 60, range 31-95) were all female and taking a median of six tablets (range 0-31) daily; 37 patients were taking >10 tablets. Oral anticancer treatment constituted the category of treatment taken by the highest proportion of patients, followed by symptomatic cancer treatments, proton pump inhibitors and cardiovascular medication. Numerically, however, symptomatic drugs accounted for 44% of all tablets and specific anti-cancer treatment for 15%; medication not directly related to the cancer accounted for the remaining 40% of tablets. A quarter of patients reported inconvenience in taking their tablets, the main reason being tablet size and one third reported forgetting their tablets at least once a week. Nearly two thirds of patients expressing a preference favoured oral anticancer treatment, the commonest reason being greater convenience. Tablet burden is considerable for many patients with MBC and can be problematic. A significant proportion of tablets represent treatment for co-morbidities, the significance of which may be questionable in women with MBC. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Endocrinological study of the dopaminergic regulation of prolactin release in metastatic breast cancer.

    PubMed

    Mandalà, M; Lissoni, P; Ardizzoia, A; Barni, S; Rovelli, F; Confalonieri, G; Malugani, F; Moro, C; Fumagalli, G; Giani, L; Tancini, G

    1999-01-01

    Prolactin (PRL) may be a growth factor for breast cancer. Abnormally high levels of PRL have been proven to be associated with a poor prognosis in metastatic breast cancer. However, most studies have been limited to the evaluation of basal levels of PRL rather than its response to the classical endocrine dynamic tests. This study was performed to analyse the dynamic secretion of PRL under stimulatory and inhibitory tests in metastatic breast cancer. The study included 10 untreated metastatic breast cancer women, who were evaluated after the classical stimulatory and inhibitory tests for PRL secretion with the antidopaminergic agent Metoclopramide (10 mg iv as a bolus) and with L-dopa, respectively. Serum levels of PRL were measured by RIA before and at subsequent intervals after drug administration. PRL levels were considered to be elevated when they were higher than 25 ng/ml. Abnormally high basal levels of PRL were seen in 6/10 patients. L-dopa was unable to inhibit PRL secretion, whose mean concentrations paradoxically significantly increased in response to L-dopa, with values comparable to those observed after the classical stimulatory test with metoclopramide. This study confirm the existence of hyperprolactinemia associated with metastatic breast cancer. In addition, by showing a paradoxical rise of PRL in response to L-dopa, which inhibits PRL secretion in physiological conditions, this study would suggest that breast cancer-related hyperprolactinemia may depend at least in part on endogenous disease-related neuroendocrine alterations.

  8. Metastatic Colonic Adenocarcinoma in Breast: Report of Two Cases and Review of the Literature

    PubMed Central

    Kothadia, Jiten P.; Arju, Rezina; Kaminski, Monica; Ankireddypalli, Arvind; Duddempudi, Sushil; Chow, Jonathan; Giashuddin, Shah

    2015-01-01

    Metastatic adenocarcinoma to the breast from an extramammary site is extremely rare. In the literature, the most current estimate is that extramammary metastases account for only 0.43% of all breast malignancies and that, of these extramammary sites, colon cancer metastases form a very small subset. Most commonly seen metastasis in breast is from a contralateral breast carcinoma, followed by metastasis from hematopoietic neoplasms, malignant melanoma, sarcoma, lung, prostate, and ovary and gastric neoplasms. Here we present two rare cases, in which colonic adenocarcinomas were found to metastasize to the breast. In both cases, core biopsies were obtained from the suspicious areas identified on mammogram. Histopathology revealed neoplastic proliferation of atypical glandular components within benign breast parenchyma which were morphologically consistent with metastatic adenocarcinoma. By immunohistochemical staining, it was confirmed that the neoplastic components were immunoreactive to colonic markers and nonreactive to breast markers, thus further supporting the morphologic findings. It is extremely important to make this distinction between primary breast cancer and a metastatic process, in order to provide the most effective and appropriate treatment for the patient and to avoid any harmful or unnecessary surgical procedures. PMID:25883818

  9. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation.

    PubMed

    Mohanty, Sambit K; Kim, Stacey A; DeLair, Deborah F; Bose, Shikha; Laury, Anna R; Chopra, Shefali; Mertens, Richard B; Dhall, Deepti

    2016-08-01

    Metastatic neuroendocrine neoplasms to the breast may show considerable morphologic overlap with primary mammary carcinomas, particularly those showing evidence of neuroendocrine differentiation, and may be misdiagnosed as such. Accurate distinction between these two entities is crucial for determination of appropriate clinical management. The histologic and immunohistochemical features of metastatic neuroendocrine neoplasms to the breast were studied and compared with the features of primary invasive mammary carcinomas with neuroendocrine differentiation, which served as controls. Of the metastatic neuroendocrine neoplasms, 15 were well-differentiated neuroendocrine tumors with carcinoid tumor-type morphology and 7 were poorly differentiated/high-grade neuroendocrine carcinomas with small-cell or large-cell neuroendocrine carcinoma morphology. The majority of the metastatic neoplasms originated in the lung and gastrointestinal tract. There were histologic similarities between metastatic neuroendocrine neoplasms and invasive mammary carcinomas with neuroendocrine differentiation, both of which exhibited neuroendocrine histologic features (nested and trabecular architecture, minimal tubular differentiation, and characteristic nuclear features). Only one case of the invasive mammary carcinomas with neuroendocrine differentiation was modified Bloom-Richardson grade 1 (largely due to minimal tubular differentiation on most such tumors), and the invasive mammary carcinomas with neuroendocrine differentiation were often associated with in situ carcinoma. Immunohistochemistry was helpful in distinguishing metastatic neuroendocrine neoplasms from invasive mammary carcinomas with neuroendocrine differentiation. Whereas the majority of invasive mammary carcinomas with neuroendocrine differentiation were positive for estrogen receptor and GATA3, metastatic neuroendocrine neoplasms were typically negative for estrogen receptor and GATA3, and metastatic well

  10. Eribulin (Halaven): a new, effective treatment for women with heavily pretreated metastatic breast cancer

    PubMed Central

    Menis, J; Twelves, C

    2011-01-01

    Although metastatic breast cancer remains essentially incurable, many patients previously treated with an anthracycline, taxane, and capecitabine are relatively fit and keen to receive further therapy. Several drugs are used in this setting, but with little evidence of clinically relevant benefit, and none have previously shown improved survival. Eribulin (Halaven®) is a nontaxane tubulin-binding agent with a novel mode of action, and was recently approved by the European Medicines Agency and US Food and Drug Agency as a single agent for patients with heavily pretreated metastatic breast cancer. This review provides an overview of the discovery, and preclinical and clinical development of eribulin, culminating in the recently published EMBRACE metastatic breast cancer study. PMID:24367180

  11. Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer

    PubMed Central

    Yoo, Byunghee; Kavishwar, Amol; Wang, Ping; Ross, Alana; Pantazopoulos, Pamela; Dudley, Michael; Moore, Anna; Medarova, Zdravka

    2017-01-01

    Treatment of stage IV metastatic breast cancer patients is limited to palliative options and represents an unmet clinical need. Here, we demonstrate that pharmacological inhibition of miRNA-10b - a master regulator of metastatic cell viability – leads to elimination of distant metastases in a mouse model of metastatic breast cancer. This was achieved using the miRNA-10b inhibitory nanodrug, MN-anti-miR10b, which consists of magnetic nanoparticles, conjugated to LNA-based miR-10b antagomirs. Intravenous injection of MN-anti-miR10b into mice bearing lung, bone, and brain metastases from breast cancer resulted in selective accumulation of the nanodrug in metastatic tumor cells. Weekly treatments of mice with MN-anti-miR-10b and low-dose doxorubicin resulted in complete regression of pre-existing distant metastases in 65% of the animals and a significant reduction in cancer mortality. These observations were supported by dramatic reduction in proliferation and increase in apoptosis in metastatic sites. On a molecular level, we observed a significant increase in the expression of HOXD10, which is a known target of miRNA-10b. These results represent first steps into the uncharted territory of therapy targeted to the metastatic niche. PMID:28322342

  12. Increased Secretory Leukocyte Protease Inhibitor (SLPI) Production by Highly Metastatic Mouse Breast Cancer Cells

    PubMed Central

    Sayers, Kevin T.; Brooks, Alan D.; Sayers, Thomas J.; Chertov, Oleg

    2014-01-01

    The precise molecular mechanisms enabling cancer cells to metastasize from the primary tumor to different tissue locations are still largely unknown. Secretion of some proteins by metastatic cells could facilitate metastasis formation. The comparison of secreted proteins from cancer cells with different metastatic capabilities in vivo might provide insight into proteins involved in the metastatic process. Comparison of the secreted proteins from the mouse breast cancer cell line 4T1 and its highly metastatic 4T1.2 clone revealed a prominent differentially secreted protein which was identified as SLPI (secretory leukocyte protease inhibitor). Western blotting indicated higher levels of the protein in both conditioned media and whole cell lysates of 4T1.2 cells. Additionally higher levels of SLPI were also observed in 4T1.2 breast tumors in vivo following immunohistochemical staining. A comparison of SLPI mRNA levels by gene profiling using microarrays and RT-PCR did not detect major differences in SLPI gene expression between the 4T1 and 4T1.2 cells indicating that SLPI secretion is regulated at the protein level. Our results demonstrate that secretion of SLPI is drastically increased in highly metastatic cells, suggesting a possible role for SLPI in enhancing the metastatic behavior of breast cancer cell line 4T1. PMID:25110884

  13. Roles and types of radiation in breast cancer treatment: early breast cancer, locoregionally advanced, and metastatic disease.

    PubMed

    McCloskey, Susan A; Lee, Steve P; Steinberg, Michael L

    2011-02-01

    To describe the current role of radiation therapy and specific types of radiation therapy used in the management of early stage, locoregionally advanced, and metastatic breast cancer. The role of radiation therapy in the management of breast cancer has not changed in recent decades, however methods of treatment delivery have advanced considerably. Hypofractionation and accelerated partial breast irradiation, which substantially reduce radiation treatment duration, have emerged as appropriate alternatives to conventional whole breast radiation in select patient subsets, and intensity modulated radiation therapy, breathing-adapted radiation therapy, and prone-positioning technique address challenging anatomic issues and reduce treatment-associated toxicity. Stereotactic radiosurgery and stereotactic body radiation therapy continue to advance the management of distant metastatic disease. Radiation therapy plays a significant role in the management of early stage, locoregionally advanced, and metastatic breast cancer. Technological advances are allowing for greater patient convenience and comfort in locoregional radiation therapy delivery and for expanded radiation therapy indications in the setting of metastatic disease.

  14. Trials with TALL-1O4 Cells for Treatment of Metastatic Breast Cancer

    DTIC Science & Technology

    1999-10-01

    AD Award Number: DAMD17-97-C- 7056 TITLE: Phase I Trial~with TALL-104 Cells for Treatment of Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Daniela...Metastatic Breast Cancer DAMD17-97-C- 7056 It AU1ITDI(SI Da~iela Sa~mol, Ph.D. 7. PERFORMING ORGANIZATION NAMEM(S N0 A•ESS . PERFORMING ORGANIZATIONREPORT...a commercial PCR kit (ATCC, Rockville, MD). Three times a week, cells were harvested by centrifugation in 250 ml conical tubes ( Corning , New York, NY

  15. Effective role of hormonal therapy in metastatic primary neuroendocrine breast carcinoma.

    PubMed

    Buttar, Amanpreet; Mittal, Kriti; Khan, Ashraf; Bathini, Venu

    2011-10-01

    Primary neuroendocrine carcinoma (PNEC) of the breast is extremely rare.(1) Because of the rarity of this cancer, long-term prognosis, biologic behavior, and treatment are not well known. PNEC can have high expression of estrogen receptor (ER) and progesterone receptor (PR). It is important to differentiate PNEC of the breast from other metastatic diseases to the breast because of the differences in treatment. We herein report the successful treatment of a patient with PNEC of the breast and high expression of ER and PR by means of hormonal therapy.

  16. Eribulin mesylate: a promising new antineoplastic agent for locally advanced or metastatic breast cancer.

    PubMed

    Cortes, Javier; Lorca, Rebeca

    2011-03-01

    More than one million women worldwide are diagnosed with breast cancer every year. For those diagnosed with metastatic breast cancer, the 5-year survival rates are low as, ultimately, patients develop tumors that become refractory to treatment. In clinical trials, eribulin mesylate (E7389) - a novel nontaxane microtubule dynamics inhibitor - demonstrated efficacy in patients with various solid tumors, in particular, those with heavily pretreated metastatic breast cancer. The Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389 (EMBRACE) study observed a significant increase in overall survival with eribulin compared with treatment of physician's choice (median: 13.1 vs 10.6 months, respectively). Based on these results, eribulin recently received approval by the US FDA for the treatment of patients with metastatic breast cancer who have received at least two prior chemotherapeutic regimens including an anthracyline and a taxane. In addition, eribulin has a manageable tolerability profile, requires no premedication and has shorter infusion times than most other microtubule-targeted agents.

  17. Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives

    PubMed Central

    2014-01-01

    Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome, and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations, the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future, advances in targeted therapy will depend on the availability of metastatic tissue. PMID:25032257

  18. Survival impact of integrative cancer care in advanced metastatic breast cancer.

    PubMed

    Block, Keith I; Gyllenhaal, Charlotte; Tripathy, Debu; Freels, Sally; Mead, Mark N; Block, Penny B; Steinmann, William C; Newman, Robert A; Shoham, Jacob

    2009-01-01

    Integrative cancer treatment is of substantial interest to many cancer patients. Research is needed to evaluate the effects of integrative treatment on patient outcomes. We report survival data for a consecutive case series of advanced metastatic breast cancer patients who received a comprehensive clinical program combining conventional treatments with nutrition and supplementation, fitness and mind-spirit instruction at the Block Center for Integrative Cancer Treatment. Treatment outcomes using integrative care for this disease have not previously been documented; survival data will thus contribute to decisions concerning future research directions and design. Ninety consecutive patients with metastatic breast cancer diagnosed during 1984-1997 who received chemotherapy at the integrative cancer center were included. Prognostic factors, treatments and survival from onset of metastases were determined from analysis of scans, labs, pathology and medical records. The log-rank test and Cox proportional hazards analyses were used, and a Kaplan-Meier curve was calculated. All patients had metastatic disease at baseline, 96% were relapsed and 52% had received prior chemotherapy for metastatic disease. Median age at onset of metastasis was 46 years. Median survival was 38 months (95% CI 27,48). Published literature on populations with somewhat more favorable prognostic factors treated in conventional clinics showed median survivals of 20 to 23 months. Through the 1990s, median survival reported in metastatic breast cancer trials or observations generally ranged from 12 to 24 months. Five-year survival was 27% for Center versus 17% for comparison patients. Despite a higher proportion of younger and relapsed patients, survival of metastatic breast cancer patients at the Center was approximately double that of comparison populations and possibly even higher compared to trials published during this period. Explanations for the advantage relative to conventional treatment alone

  19. Recombinant viral protein VP1 suppresses HER-2 expression and migration/metastasis of breast cancer.

    PubMed

    Hung, Shao-Wen; Chiu, Ching-Feng; Chen, Tai-An; Chu, Chiao-Li; Huang, Chi-Chang; Shyur, Lie-Fen; Liang, Chi-Ming; Liang, Shu-Mei

    2012-11-01

    /metastasis of breast cancer and HER-2 expression suggests that it may be suitable for serving as potential therapeutics for metastatic breast cancer particularly HER-2-overexpressing cancer.

  20. In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone

    PubMed Central

    Arrigoni, Chiara; Bersini, Simone; Gilardi, Mara; Moretti, Matteo

    2016-01-01

    Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps. PMID:27571063

  1. Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer.

    PubMed

    Tolaney, Sara M; Tan, Sally; Guo, Hao; Barry, William; Van Allen, Eliezer; Wagle, Nikhil; Brock, Jane; Larrabee, Katherine; Paweletz, Cloud; Ivanova, Elena; Janne, Pasi; Overmoyer, Beth; Wright, John J; Shapiro, Geoffrey I; Winer, Eric P; Krop, Ian E

    2015-10-01

    MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0-25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0-25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.

  2. Metastatic progression and gene expression between breast cancer cell lines from African American and Caucasian women

    PubMed Central

    Yancy, Haile F; Mason, Jacquline A; Peters, Sharla; Thompson, Charles E; Littleton, George K; Jett, Marti; Day, Agnes A

    2007-01-01

    African American (AA) women have a lower overall incidence of breast cancer than do Caucasian (CAU) women, but a higher overall mortality. Little is known as to why the incidence of breast cancer is lower yet mortality is higher in AA women. Many studies speculate that this is only a socio-economical problem. This investigation suggests the possibility that molecular mechanisms contribute to the increased mortality of AA women with breast cancer. This study investigates the expression of 14 genes which have been shown to play a role in cancer metastasis. Cell lines derived from AA and CAU patients were analyzed to demonstrate alterations in the transcription of genes known to be involved in cancer and the metastatic process. Total RNA was isolated from cell lines and analyzed by RT-PCR analysis. Differential expression of the 14 targeted genes between a spectrum model (6 breast cancer cell lines and 2 non-cancer breast cell lines) and a metastasis model (12 metastatic breast cancer cell lines) were demonstrated. Additionally, an in vitro comparison of the expression established differences in 5 of the 14 biomarker genes between African American and Caucasian breast cell lines. Results from this study indicates that altered expression of the genes Atp1b1, CARD 10, KLF4, Spint2, and Acly may play a role in the aggressive phenotype seen in breast cancer in African American women. PMID:17472751

  3. Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer.

    PubMed

    Simone, Brittany A; Dan, Tu; Palagani, Ajay; Jin, Lianjin; Han, Sunny Y; Wright, Christopher; Savage, Jason E; Gitman, Robert; Lim, Meng Kieng; Palazzo, Juan; Mehta, Minesh P; Simone, Nicole L

    2016-09-01

    Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease. An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model. CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR. CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer.

  4. Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer

    PubMed Central

    Simone, Brittany A.; Dan, Tu; Palagani, Ajay; Jin, Lianjin; Han, Sunny Y.; Wright, Christopher; Savage, Jason E.; Gitman, Robert; Lim, Meng Kieng; Palazzo, Juan; Mehta, Minesh P.; Simone, Nicole L.

    2016-01-01

    ABSTRACT Purpose: Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease. Methods: An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model. Results: CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR. Conclusions: CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer. PMID:27027731

  5. Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes.

    PubMed

    Winnard, Paul T; Zhang, Chi; Vesuna, Farhad; Kang, Jeon Woong; Garry, Jonah; Dasari, Ramachandra Rao; Barman, Ishan; Raman, Venu

    2017-03-21

    Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities - a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy.

  6. Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes

    PubMed Central

    Winnard, Paul T.; Zhang, Chi; Vesuna, Farhad; Kang, Jeon Woong; Garry, Jonah; Dasari, Ramachandra Rao; Barman, Ishan; Raman, Venu

    2017-01-01

    Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities – a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy. PMID:28145887

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

    PubMed

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

    2015-06-01

    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. © The Author (2015). Published by Oxford University Press on

  8. First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study

    PubMed Central

    Aitelhaj, Meryem; Lkhoyaali, Siham; Rais, Ghizlane; Boutayeb, Saber; Errihani, Hassan

    2016-01-01

    Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide. Metastatic breast cancer (MBC) is conventionally considered to be incurable. In first-line treatment of HER-2 positive MBC, randomized trials have demonstrated that trastuzumab when combined with chemotherapy significantly improves progression free survival and overall survival. To evaluate survival and toxicity of chemotherapy with Trastuzumab as first line therapy of human epithermal growth factor receptor 2 positive metastatic breast cancer, in Moroccan population. It is a phase IV observational institutional monocentric study. Including patients with metastatic breast cancer HER2 positive, as first-line chemotherapy combined with Trastuzumab from March 2009 until March 2010. Primary end point: progression free survival, secondary end point response rate and overall survival. A total of 20 patients were enrolled between March 2009 and March 2010. The lung was the first metastatic site in 60% of the cases, followed by bone, liver, nodes, skin and brain. All patients received chemotherapy with Trastuzumab: 9 of them with Docetaxel, 8 with vinorelbine, and 3 with capecitabine. The progression free survival was estimated by the Kaplan-Meier method, from the date of first cycle to the date of progression or at the last consultation, and the median was 12.8 months. Trastuzumab based chemotherapy was generally well tolerated; 5 patients (25%) presented cardiotoxicity. The results of this study join the literature and show the benefit of Trastuzumab to chemotherapy in first line metastatic breast cancer HER-2 positive. PMID:28154679

  9. Metastatic breast cancer presenting as air-space consolidation on chest computed tomography.

    PubMed

    Ohnishi, Hiroshi; Haruta, Yoshinori; Yokoyama, Akihito; Nakashima, Taku; Hattori, Noboru; Kohno, Nobuoki

    2009-01-01

    A 56-year-old woman suffered from hepatic and bone metastases of breast cancer. Two months after starting combination chemotherapy with trastuzumab and docetaxel, air-space consolidation was observed in the right lower lung lobe on a chest computed tomography (CT) and a high serum KL-6 level was detected. Drug-induced pneumonitis with organizing pneumonia type was suspected, however, a transbronchial lung biopsy and cytological examination of the bronchoalveolar lavage fluid provided evidence of metastatic breast cancer. While the lung is a frequently affected site from metastasis of breast cancer, we report a rare case presenting as air-space consolidation on a chest CT.

  10. Everolimus-associated Acute Kidney Injury in Patients with Metastatic Breast Cancer.

    PubMed

    Chandra, A; Rao, N S; Malhotra, K P; Rastogi, M; Khurana, R

    2017-01-01

    Recently, everolimus (Evl) has been introduced in the management of hormone receptor-positive metastatic breast cancer, in combination with aromatase inhibitors. Evl-induced acute kidney injury has hitherto been described in other malignancies, especially renal cell cancer, but only once before in a patient with breast cancer. We describe two cases of Evl-associated nephrotoxicity in patients with breast cancer, one of whom underwent a renal biopsy showing acute tubular necrosis. Both our patients improved after withdrawal of the offending agent and have normal renal functions on follow-up.

  11. 'Inflammatory breast cancer' due to metastatic adenocarcinoma of lung.

    PubMed

    Ninan, Jacob; Naik, Vinay; George, Gemy Maria

    2016-09-01

    A 67-year-old woman with a history of lung adenocarcinoma presented with 3 weeks of redness, pain, swelling and skin changes in her right breast. Her vital signs and physical examination were within physiological limits except for the right breast. She had extensive red streaks radiating from the right nipple with peau d'orange appearance of her overlying skin. Her breast was tender on examination and did not have any associated cervical or axillary lymphadenopathy. Her mammography revealed thickening of the skin, increased parenchymal markings and shrinkage the breast. Multiple skin biopsies demonstrated moderately differentiated lung adenocarcinoma with lymphovascular invasion. The patient made an informed decision to undergo radiotherapy following discussion with her oncologist and breast surgeon. She succumbed to her illness 2 months after the diagnosis of metastasis to her breast. 2016 BMJ Publishing Group Ltd.

  12. Organtropic Metastatic Secretomes and Exosomes in Breast Cancer

    DTIC Science & Technology

    2016-10-01

    ABSTRACT Metastasis to distant vital organs (bone, lung , brain) is the most devastating feature of breast cancer . We proposed to extend our current...integrative genomic, proteomic and transcriptomic analysis on the crosstalk between breast cancer cells and bone and lung microenvironments during...organ-tropic metastasis of breast cancer to bone and lung has tremendous potential impact on improving the diagnosis, prognosis and treatment of

  13. Mammaglobin-A Immunohistochemistry in Primary Central Nervous System Neoplasms and Intracranial Metastatic Breast Carcinoma

    PubMed Central

    Cimino, Patrick J.; Perrin, Richard J.

    2014-01-01

    Metastases represent the most common type of intracranial neoplasm. In women, 30% of such tumors derive from breast carcinoma. In neurosurgical cases with ambiguous cellular morphology and/or limited biopsy material, immunohistochemistry (IHC) is often performed to distinguish metastases from primary central nervous system (CNS) neoplasms. IHC for mammaglobin-A (MGA), a protein expressed in a majority of breast carcinomas, is commonly applied in this setting, but its utility for distinguishing primary CNS neoplasms from metastatic breast carcinoma is unknown; the reactivity of MGA in primary and metastatic CNS neoplasms has never been described. Here, we describe the frequency and patterns of IHC reactivity for MGA in metastatic and primary CNS neoplasms from patients with well-documented histories of breast carcinoma. Following a published protocol previously applied to non-CNS neoplasms, MGA staining of moderate to strong intensity within 5% or more of a neoplasm was considered positive. Based on these criteria, 3 of 12 (25.0%) glioblastomas, 1 of 10 (10.0%) meningiomas, and 47 of 95 (49.5%) metastases were positive. Importantly, the cytoarchitectural staining characteristics among all four MGA positive primary CNS neoplasms (cytoplasmic and nuclear) differed from those of the metastases (cytoplasmic and membranous). These findings suggest that MGA IHC staining intensity and distribution can distinguish metastases from primary CNS neoplasms (**P=0.0086) in women with a history of breast carcinoma but also indicate that cytological staining patterns must be interpreted for more accurate tumor classification. PMID:23958549

  14. Mammaglobin-A immunohistochemistry in primary central nervous system neoplasms and intracranial metastatic breast carcinoma.

    PubMed

    Cimino, Patrick J; Perrin, Richard J

    2014-07-01

    Metastases represent the most common type of intracranial neoplasm. In women, 30% of such tumors derive from breast carcinoma. In neurosurgical cases with ambiguous cellular morphology and/or limited biopsy material, immunohistochemistry (IHC) is often performed to distinguish metastases from primary central nervous system (CNS) neoplasms. IHC for mammaglobin-A (MGA), a protein expressed in a majority of breast carcinomas, is commonly applied in this setting, but its utility for distinguishing primary CNS neoplasms from metastatic breast carcinoma is unknown; the reactivity of MGA in primary and metastatic CNS neoplasms has never been described. Here, we describe the frequency and patterns of IHC reactivity for MGA in metastatic and primary CNS neoplasms from patients with well-documented histories of breast carcinoma. Following a published protocol previously applied to non-CNS neoplasms, MGA staining of moderate to strong intensity within 5% or more of a neoplasm was considered positive. On the basis of these criteria, 3 of 12 (25.0%) glioblastomas, 1 of 10 (10.0%) meningiomas, and 47 of 95 (49.5%) metastases were positive. Importantly, the cytoarchitectural staining characteristics among all 4 MGA-positive primary CNS neoplasms (cytoplasmic and nuclear) differed from those of the metastases (cytoplasmic and membranous). These findings suggest that MGA IHC staining intensity and distribution can distinguish metastases from primary CNS neoplasms (P=0.0086) in women with a history of breast carcinoma but also indicate that cytologic staining patterns must be interpreted for more accurate tumor classification.

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

    PubMed

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

    2015-01-01

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

  16. A medieval description of metastatic breast cancer; from Avicenna's view point.

    PubMed

    Zarshenas, Mohammad M; Mohammadi-Bardbori, Afshin

    2017-02-01

    Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscript so called "the Edwin Smith Papyrus" dating back to the Pyramid Age. However, apart from all respective documents remained from the antiquity, concepts and standpoints of Avicenna (Ibn Sina; a famous Persian physician) in regard of the cancer are interesting. A case of breast cancer and metastatic condition has been reported by Avicenna in the Canon of Medicine. This report can be considered as a very early report of metastatic or stage IV breast cancer. He underlined that cancer should be diagnosed and cured in the early stages. With views of Avicenna, cancer is an atrabilious (black bile) swelling (tumor) which sometimes may be accompanied by pain or swelling. He also mentioned that some vessels may be appeared around the cancerous part. Avicenna extrapolated the cancer with legs of cancer crab which can to grow around the other organs and tissues. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Comparative effectiveness of imaging modalities to determine metastatic breast cancer treatment response.

    PubMed

    Lee, Christoph I; Gold, Laura S; Nelson, Heidi D; Chou, Roger; Ramsey, Scott D; Sullivan, Sean D

    2015-02-01

    We performed a systematic review to address the comparative effectiveness of different imaging modalities in evaluating treatment response among metastatic breast cancer patients. We searched seven multidisciplinary electronic databases for relevant publications (January 2003-December 2013) and performed dual abstraction of details and results for all clinical studies that involved stage IV breast cancer patients and evaluated imaging for detecting treatment response. Among 159 citations reviewed, 17 single-institution, non-randomized, observational studies met our inclusion criteria. Several studies demonstrate that changes in PET/CT standard uptake values are associated with changes in tumor volume as determined by bone scan, MRI, and/or CT. However, no studies evaluated comparative test performance between modalities or determined relationships between imaging findings and subsequent clinical decisions. Evidence for imaging's effectiveness in determining treatment response among metastatic breast cancer patients is limited. More rigorous research is needed to address imaging's value in this patient population.

  18. Evolutionary strategy for systemic therapy of metastatic breast cancer: balancing response with suppression of resistance.

    PubMed

    Kam, Yoonseok; Das, Tuhin; Minton, Susan; Gatenby, Robert A

    2014-07-01

    Conventional systemic therapy for disseminated breast cancer is based on the general assumption that the greatest patient benefit is achieved by killing the maximum number of tumor cells. While this strategy often achieves a significant reduction in tumor burden, most patients with metastatic breast cancer ultimately die from their disease as therapy fails because tumor cells evolve resistance. We propose that the conventional maximum dose/maximum cell kill cancer therapy, when viewed from an evolutionary vantage, is suboptimal and likely even harmful as it accelerates evolution and growth of the resistant phenotypes that ultimately cause patient death. As an alternative, we are investigating evolutionary therapeutic strategies that shift the treatment goal from killing the maximum number of cancer cells to maximizing patient survival. Here we introduce two novel approaches for systemic therapy for metastatic breast cancer, considering the evolutionary nature of tumor progression; adaptive therapy and double-bind therapy.

  19. Metronomic Chemotherapy for Primary Non-Metastatic Breast Cancer – a Systematic Review of the Literature

    PubMed Central

    Banys-Paluchowski, Malgorzata; Ruckhäberle, Eugen; Schütz, Florian; Krawczyk, Natalia; Fehm, Tanja

    2017-01-01

    Conventional chemotherapy is based on the “maximum tolerated dose” principle and aims at administering high doses of cytotoxic drugs followed by a rest period necessary for the body to recover. In the last decades alternative strategies have been developed to avoid serious side effects of conventional treatment, among them the metronomic chemotherapy. Much like a metronome keeps steady rhythm, metronomic therapy is administered continuously in low doses for a long time. In metastatic breast cancer, metronomic therapy is a valid option in pretreated or vulnerable patients and its use has recently been incorporated into various guidelines. In early breast cancer, the role of metronomic treatment remains to be clarified. A systematic review of PubMed/MEDLINE, ClinicalTrials.gov, the European Clinical Trials Database (EudraCT) and the Cochrane Database was conducted. In the present review, we discuss the current evidence on metronomic chemotherapy in non-metastatic breast cancer. PMID:28331236

  20. Therapeutic effect of taxanes on metastatic breast cancer of various immunohistochemical subtypes

    PubMed Central

    FUKADA, IPPEI; ARAKI, KAZUHIRO; KOBAYASHI, KOKORO; KOBAYASHI, TAKAYUKI; HORII, RIE; AKIYAMA, FUTOSHI; TAKAHASHI, SHUNJI; IWASE, TAKUJI; ITO, YOSHINORI

    2016-01-01

    Taxane drugs play a central role in chemotherapy for breast cancer. However, previous studies have reported that taxanes are relatively ineffective in patients with operable luminal breast cancer compared with other subtypes. Between January 2000 and August 2008, 293 patients with metastatic breast cancer were treated with taxanes in The Cancer Institute Hospital of The Japanese Foundation for Cancer Research and were included in the present study. The patients were divided into 4 subtypes based on the immunohistochemically evaluated estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status. The clinicopathological features, response rate (RR) and time to progression (TTP) were analyzed retrospectively. In total, 159 patient tissues were classified as luminal type (ER+ and/or PgR+ and HER2−), 28 patient tissues were classified as luminal-HER2 type (ER+ and/or PgR+ and HER2+), 57 patient tissues were classified as HER2 type (ER−, PgR− and HER2+), and 49 patient tissues were classified as triple-negative type (ER−, PgR− and HER2−). Among the 4 subtypes, the clinical benefit rate was 51.6, 78.6, 71.9 and 40.8%, respectively. There were significant differences in TTP between subtypes (median TTP, 8.3 months in luminal, 14.1 months in luminal-HER2, 10.6 months in HER2, and 4.2 months in triple-negative; P<0.001). Patients with luminal type tumors had a significantly longer TTP than patients with triple-negative type tumors. The present data suggested that the immunohistochemical subtypes were associated with the therapeutic effect of taxanes for metastatic breast cancer and that taxanes yielded an acceptable RR and TTP in luminal metastatic breast cancer. Additional investigations are required to elucidate the predictive markers of taxane therapy for patients with metastatic breast cancer in each immunohistochemical subtype. PMID:27347197

  1. Randomized trial of a physical activity intervention in women with metastatic breast cancer.

    PubMed

    Ligibel, Jennifer A; Giobbie-Hurder, Anita; Shockro, Laura; Campbell, Nancy; Partridge, Ann H; Tolaney, Sara M; Lin, Nancy U; Winer, Eric P

    2016-04-15

    Exercise interventions improve fitness, functional capacity, and quality of life in patients with early-stage breast cancer, but to the authors' knowledge there are few data regarding the feasibility or potential benefits of exercise in women with metastatic breast cancer. Individuals with metastatic breast cancer were randomized 1:1 to a 16-week moderate-intensity exercise intervention or wait-list control group. Intervention goals included 150 minutes of moderate-intensity aerobic exercise per week. The baseline and 16-week evaluations included a modified Bruce Ramp treadmill test, 7-day Physical Activity Recall interview, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C-30) questionnaire. A total of 101 participants were randomized (48 to the intervention group and 53 to the control group). The median age of the participants was 49 years, the median time since the diagnosis of metastatic breast cancer was 1.1 years, and approximately 42% of participants were undergoing chemotherapy at the time of enrollment. Study attrition was higher in the intervention arm (14 participants vs 8 participants; P = .15). Women randomized to the exercise intervention experienced a nonsignificant increase with regard to minutes of weekly exercise (62.4 minutes vs 46.0 minutes; P = .17) and physical functioning (EORTC QLQ C30: 4.79 vs 0.93 [P = .23] and Bruce Ramp Treadmill test: 0.61 minutes vs 0.37 minutes [P = .35]) compared with control participants. Participation in an exercise intervention did not appear to result in significant improvements in physical functioning in a heterogeneous group of women living with advanced breast cancer. Given the significant benefits of exercise in women with early-stage breast cancer, more work is needed to explore alternative interventions to determine whether exercise could help women with metastatic disease live more fully with fewer symptoms from disease and treatment. © 2016

  2. Metastatic metaplastic carcinoma of the breast (MCB): an uncharacteristic pattern of presentation with clinicopathologic correlation.

    PubMed

    Catroppo, J F; Lara, J F

    2001-11-01

    Metaplastic carcinoma of the breast (MCB) is a well recognized but uncommon aberrant manifestation of poorly differentiated invasive carcinoma containing both epithelial (ductal) and mesenchymal elements as well as a transitional form between them. This heterogeneous tumor characteristically contains ductal carcinoma cells mixed with areas of diverse morphologic phenotype displaying spindle, squamous, chondroid, or osseous differentiation. Some studies have suggested that certain types of metaplastic carcinoma have a more favorable prognosis as compared with others. We describe a case involving a 67-yr-old woman who presented with metastatic nodules in the lungs and a vague but recent history of breast cancer. The case highlights a subtype of MCB with a predominant spindle cell component metastatic to the lung. Fine-needle aspiration biopsy (FNAB) smears of the nodules revealed a bland, spindle cell, mesenchymal proliferation with minimal evidence of an epithelial component. A second primary was clinically excluded and a request for review of the original slides identified a metaplastic component to the original tumor with a histologic and immunohistochemical profile identical to the metastatic tumor, confirming origin from the breast. Metaplastic carcinomas of the breast commonly bypass axillary lymph nodes and present as distant metastases. FNAB diagnosis of metaplastic carcinoma of the breast is quite difficult at the primary site and poses a formidable diagnostic challenge at a metastatic site, especially when the dominant pattern is not of the usual type. The literature is reviewed, confirming the rarity of such a presentation and the novelty of this case. Confirmation by FNAB is also quite difficult but may become more commonplace as a trend toward minimal intervention continues to gain popularity. This case emphasizes the importance of recognizing and reporting metaplastic elements in primary breast tumors, as well as the value of direct morphologic

  3. ‘Being there' for women with metastatic breast cancer: a pan-European patient survey

    PubMed Central

    Harding, V; Afshar, M; Krell, J; Ramaswami, R; Twelves, C J; Stebbing, J

    2013-01-01

    Background: Understanding their experiences of diagnosis is integral to improving the quality of care for women living with advanced/metastatic breast cancer. Methods: A survey, initiated in March 2011, was conducted in two stages. First, the views of 47 breast cancer-related patient groups in eight European countries were sought on standards of breast cancer care and unmet needs of patients. Findings were used to develop a patient-centric survey to capture personal experiences of advanced breast cancer to determine insights into the ‘trade-off' between extending overall survival and side effects associated with its treatment. The second online survey was open to women with locally advanced or metastatic breast cancer, or their carers, and responders were recruited through local patient groups. Data were collected via anonymous local language questionnaires. Results: The online stage II survey received a total of 230 responses from 17 European countries: 94% of respondents had locally advanced or metastatic breast cancer and 6% were adult carers. Although the overall experience of care was generally good/excellent (77%), gaps were still perceived in terms of treatment choice and information provision. Treatment choice for patients was felt to be lacking by 32% of responders. In addition, 68% of those who responded would have liked more information about future medical treatments and research, with 57% wishing to receive this information from their oncologist. Two-thirds (66%) of women with advanced breast cancer, or their carers, believed life-extending treatment to be important so that they can spend more time with family and friends, and 67% said that the treatment was worthwhile, despite potential associated side effects. Conclusion: These findings show a continuing need to provide women with advanced breast cancer with better information and emphasise the importance that these patients often place on prolonging survival. PMID:24002595

  4. Human epidermal growth factor receptor 2 overexpression in breast cancer of patients with anti-Yo--associated paraneoplastic cerebellar degeneration.

    PubMed

    Rojas-Marcos, Iñigo; Picard, Geraldine; Chinchón, David; Gelpi, Ellen; Psimaras, Dimitri; Giometto, Bruno; Delattre, J Y; Honnorat, J; Graus, F

    2012-04-01

    Isolated case reports suggest that breast tumors from patients with paraneoplastic cerebellar degeneration (PCD) and Yo antibodies overexpress human epidermal growth factor receptor 2 (HER2). HER2 overexpression is present in 15%-25% of breast cancers and is associated with poor prognosis. We retrospectively analyzed the status of HER2 in breast tumors of 27 patients with anti-Yo-associated PCD to evaluate whether HER2 overexpression in this group of patients is higher than expected. In addition, we analyzed HER2 status of 19 breast tumors from patients with paraneoplastic neurological syndromes and Ri antibodies to see whether HER2 was specifically related to anti-Yo-associated PCD. We also assessed cdr2 expression (the onconeural antigen recognized by Yo antibodies) in 21 HER2-positive breast tumors from patients without paraneoplastic neurological syndromes. HER2 was overexpressed in 26 patients (96.3%) with anti-Yo-associated PCD but only in 2 patients (10.5%) with paraneoplastic neurological syndromes associated with Ri antibodies (P< .0001). Only 5 (23.8%) of the 21 HER2-positive breast tumors showed cdr2 immunoreactivity. This study shows a very high frequency of HER2 overexpression in breast cancers in patients with anti-Yo-associated PCD but not in those from patients with Ri antibodies. Although the expression of cdr2 onconeural antigen is not high in HER2-positive breast cancers, HER2 overexpression seems to be an important requirement to develop an anti-Yo-associated PCD.

  5. Periostin is identified as a putative metastatic marker in breast cancer-derived exosomes

    PubMed Central

    Vardaki, Ioulia; Ceder, Sophia; Rutishauser, Dorothea; Baltatzis, George; Foukakis, Theodoros; Panaretakis, Theocharis

    2016-01-01

    Breast cancer (BrCa) is the most frequent cancer type in women and a leading cause of cancer related deaths in the world. Despite the decrease in mortality due to better diagnostics and palliative care, there is a lack of prognostic markers of metastasis. Recently, the exploitation of liquid biopsies and in particular of the extracellular vesicles has shown promise in the identification of such prognostic markers. In this study we compared the proteomic content of exosomes derived from metastatic and non-metastatic human (MCF7 and MDA-MB-231) and mouse (67NR and 4T1) cell lines. We found significant differences not only in the amount of secreted exosomes but most importantly in the protein content of exosomes secreted from metastatic versus non-metastatic ones. We identified periostin as a protein that is enriched in exosomes secreted by metastatic cells and validated its presence in a pilot cohort of breast cancer patient samples with localized disease or lymph node (LN) metastasis. PMID:27589561

  6. HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer.

    PubMed

    Zimel, Melissa N; Horowitz, Chloe B; Rajasekhar, Vinagolu K; Christ, Alexander B; Wei, Xin; Wu, Jianbo; Wojnarowicz, Paulina M; Wang, Dong; Goldring, Steven R; Purdue, P Edward; Healey, John H

    2017-08-22

    Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAMs) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro, and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+TAMs co-stained with pan macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Copyright ©2017, American Association for Cancer Research.

  7. Concomitant endometrial and gallbladder metastasis in advanced multiple metastatic invasive lobular carcinoma of the breast: A rare case report

    PubMed Central

    Bezpalko, Kseniya; Mohamed, Mohamed A.; Mercer, Leo; McCann, Michael; Elghawy, Karim; Wilson, Kenneth

    2015-01-01

    Introduction At time of presentation, fewer than 10% of patients have metastatic breast cancer. The most common sites of metastasis in order of frequency are bone, lung, pleura, soft tissue, and liver. Breast cancer metastasis to the uterus or gallbladder is rare and has infrequently been reported in the English literature. Presentation of case A 47 year old female with a recent history of thrombocytopenia presented with abnormal vaginal bleeding. Pelvic ultrasound revealed multiple uterine fibroids and endometrial curettings revealed cells consistent with lobular carcinoma of the breast. Breast examination revealed edema and induration of the lower half of the right breast. Biopsy of the right breast revealed invasive lobular carcinoma. Bone marrow aspiration obtained at a previous outpatient visit revealed extensive involvement by metastatic breast carcinoma. Shortly after discharge, the patient presented with acute cholecystitis and underwent cholecystectomy. Microscopic examination of the gallbladder revealed metastatic infiltrating lobular carcinoma. The final diagnosis was invasive lobular carcinoma of the right breast with metastasis to the bone marrow, endometrium, gallbladder, regional lymph nodes, and peritoneum. Discussion The growth pattern of invasive lobular carcinoma of the breast is unique and poses a challenge in diagnosing the cancer at an early stage. Unlike other types of breast cancer, it tends to metastasize more to the peritoneum, ovary, and gastrointestinal tract. Metastasis to the endometrium or gallbladder is rare. Conclusion Metastatic spread should be considered in the differential diagnosis of patients with invasive lobular breast carcinoma presenting with abnormal vaginal bleeding or acute cholecystitis. PMID:26275738

  8. [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer].

    PubMed

    Sakurai, Kenichi; Fujisaki, Shigeru; Suzuki, Shuhei; Adachi, Keita; Nagashima, Saki; Masuo, Yuki; Tomita, Ryouichi; Gonda, Kenji; Enomoto, Katsuhisa; Amano, Sadao; Matsuo, Sadanori; Umeda, Nao

    2015-10-01

    We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy.

  9. ERCC1 Expression in Metastatic Triple Negative Breast Cancer Patients Treated with Platinum-Based Chemotherapy

    PubMed

    EL Baiomy, Mohamed Ali; El Kashef, Wagdi F

    2017-02-01

    Background: Possible targeted therapies for metastatic triple negative breast cancer (TNBC) include cytotoxic chemotherapy that causes interstrand breaks (platinum-based drugs). The excision repair cross-complementation 1 (ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway, removing platinum-induced DNA adducts and contributing to cisplatin resistance. Detecting ERCC1 overexpression is important in considering treatment options for metastatic TNBC, including individualized approaches to therapy, and may facilitate improved responses or reduction of unnecessary toxicity. We hypothesized that assigning cisplatin based on pretreatment ERCC1 expression would improve response and survival. This study was conducted to assess the impact of ERCC1 expression on PFS, OS and response rates in metastatic triple negative breast cancer patients treated with platinum-based chemotherapy. Methods: From June 2012 to November 2013, 52 metastatic triple negative breast cancer patients were enrolled. ERCC1 protein expression was detected from pretreatment biopsies by Immunohistochemistry. All patients received cisplatin plus paclitaxel. The primary end point was the impact of ERCC1 expression on PFS and OS. Results: 34 patients (65.4%) showed positive ERCC1 expression while 18 (34.6%) proved negative. Positive ERCC1 expression was associated with short PFS (median, 5 months vs. 7 months; P = 0.043), short OS (median, 9 months vs. 11 months; P = 0.033) and poor response to cisplatin based chemotherapy (P = 0.046). Conclusions: This prospective study further validated ERCC1 as a reliable biomarker for customized chemotherapy in metastatic triple negative breast cancer patients. High expression of ERCC1 was thereby fond to be significantly associated with poor outcome in patients treated with platinum based chemotherapy. Creative Commons Attribution License

  10. A Distinct Macrophage Population Mediates Metastatic Breast Cancer Cell Extravasation, Establishment and Growth

    PubMed Central

    Qian, Binzhi; Deng, Yan; Im, Jae Hong; Muschel, Ruth J.; Zou, Yiyu; Li, Jiufeng; Lang, Richard A.; Pollard, Jeffrey W.

    2009-01-01

    Background The stromal microenvironment and particularly the macrophage component of primary tumors influence their malignant potential. However, at the metastatic site the role of these cells and their mechanism of actions for establishment and growth of metastases remain largely unknown. Methodology/Principal Findings Using animal models of breast cancer metastasis, we show that a population of host macrophages displaying a distinct phenotype is recruited to extravasating pulmonary metastatic cells regardless of species of origin. Ablation of this macrophage population through three independent means (genetic and chemical) showed that these macrophages are required for efficient metastatic seeding and growth. Importantly, even after metastatic growth is established, ablation of this macrophage population inhibited subsequent growth. Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation. Conclusion/Significance These data indicate a direct enhancement of metastatic growth by macrophages through their effects on tumor cell extravasation, survival and subsequent growth and identifies these cells as a new therapeutic target for treatment of metastatic disease. PMID:19668347

  11. Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models.

    PubMed

    Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M

    2017-03-01

    We previously developed and characterized a highly invasive and metastatic triple-negative breast cancer (TNBC) variant by serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Eventually, a highly invasive and metastatic variant of human TNBC was isolated after lymph node metastases was harvested and orthotopically re-implanted into the mammary gland of nude mice for two cycles. The variant thereby isolated is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present report, we observed that high-metastatic MDA-MB-231H-RFP cells produced significantly larger subcutaneous tumors compared with parental MDA-MB-231 cells in nude mice. Extensive lymphatic trafficking by high-metastatic MDA-MB-231 cells was also observed. High-metastatic MDA-MB-231 developed larger recurrent tumors 2 weeks after tumor resection compared with tumors that were not resected in orthotopic models. Surgical resection of the MDA-MB-231 high-metastatic variant primary tumor in orthotopic models also resulted in rapid and enhanced lymphatic trafficking of residual cancer cells and extensive lymph node and lung metastasis that did not occur in the non-surgical mice. These results suggest that surgical resection of high metastatic TNBC can greatly increase the malignancy of residual cancer. J. Cell. Biochem. 118: 559-569, 2017. © 2016 Wiley Periodicals, Inc.

  12. Patient-Reported Outcomes in Metastatic Breast Cancer: A Review of Industry-Sponsored Clinical Trials

    PubMed Central

    Krohe, Meaghan; Hao, Yanni; Lamoureux, Roger E.; Galipeau, Nina; Globe, Denise; Foley, Catherine; Mazar, Iyar; Solomon, Jeffrey; Shields, Alan L.

    2016-01-01

    INTRODUCTION Patient-reported outcome (PRO) measures serve to capture vital patient information not otherwise obtained by primary study endpoints. This paper examines how PROs are utilized as endpoints in industry-sponsored metastatic breast cancer clinical trials. METHODS A search was conducted in the clinicaltrials.gov web site for trials involving common treatments for metastatic breast cancer. Thirty-eight clinical trials were identified which included a PRO endpoint in the study, and data were extracted and summarized. RESULTS Overall, 17 unique PRO questionnaires and 14 concepts of measurement were identified as secondary or exploratory endpoints. The Functional Assessment of Cancer Therapy—Breast was the most frequently utilized questionnaire, commonly implemented to assess quality of life. The EORTC QLQ-C30 was also frequently used to measure quality of life or pain. CONCLUSION This review shares insights into the role of PROs in trials for metastatic breast cancer from which treatment developers and other stakeholders can enhance successful implementation of the patient voice into future trials. PMID:27441001

  13. nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer.

    PubMed

    Megerdichian, Christine; Olimpiadi, Yuliya; Hurvitz, Sara A

    2014-06-01

    Taxanes are highly active chemotherapeutic agents used in the treatment of early-stage and metastatic breast cancer. Novel formulations have been developed to improve efficacy and decrease toxicity associated with these cytotoxic agents. nab-Paclitaxel is a biologically interactive, solvent-free, 130-nm-sized albumin-bound paclitaxel, developed to avoid the Cremophor vehicle used in solvent-based paclitaxel. Based on a pivotal phase 3 study, nab-paclitaxel was shown to be safely infused at a significantly higher dose of paclitaxel than the doses used with standard paclitaxel therapy, and had a shorter infusion time, no premedication, and higher response rates. It is now approved in the United States for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant therapy, and has demonstrated promising efficacy and favorable tolerability. Recently, several phase 2 and 3 studies have suggested a role for nab-paclitaxel in combination with biologically targeted agents for the treatment of early- and late-stage breast cancer. This review will discuss the findings of clinical trials evaluating nab-paclitaxel in combination with biologically targeted therapeutic agents for breast cancer in the neoadjuvant, adjuvant, and metastatic settings. Published by Elsevier Ltd.

  14. Breast adenocarcinoma metastatic to epidural cervical spine meningioma: case report and review of the literature.

    PubMed

    Aghi, Manish; Kiehl, Tim-Rasmus; Brisman, Jonathan L

    2005-11-01

    While several cases of cancer metastatic to cranial meningiomas have been reported, metastasis to spinal meningioma has been reported only once, and a mechanism for such metastases has not been investigated. We report a case of breast carcinoma metastatic to an epidural cervical meningioma, summarize the literature on metastases to central nervous system meningiomas, and suggest a possible mechanism. Our patient, a 55-year-old woman, presented with difficulty walking, back pain, and quadriparesis. Magnetic resonance imaging revealed an enhancing C3-4 epidural lesion and an L4 compression fracture. Because of concern that the fracture and epidural lesion might represent metastases, we performed a metastatic work-up, which revealed a right breast mass. The patient underwent C3-C4 laminectomies and an epidural lesion was encountered. Intraoperative frozen section revealed mixed meningioma and breast adenocarcinoma. A gross total resection was achieved and the patient subsequently received spinal irradiation and hormonal therapy. Whereas a literature review revealed numerous reports of metastases to cranial meningiomas, this represents only the second reported case of such pathology in the spine. Mechanisms of this unusual process likely include meningiomas' vascularity, meningiomas' slow growth providing nutrient availability, and perhaps, as suggested by our analysis, E-cadherin expression by both meningiomas and breast cancer. Metastasis to meningioma must be considered in an epidural spinal lesion in all patients with a known malignancy, with surgical aggressiveness tailored to the intraoperative pathologic diagnosis.

  15. Increased autophagic response in a population of metastatic breast cancer cells.

    PubMed

    Li, Y I; Libby, Emily Falk; Lewis, Monica J; Liu, Jianzhong; Shacka, John J; Hurst, Douglas R

    2016-07-01

    Breast cancer cells are heterogeneous in their ability to invade and fully metastasize, and thus also in their capacity to survive the numerous stresses encountered throughout the multiple steps of the metastatic cascade. Considering the role of autophagy as a survival response to stress, the present study hypothesized that distinct populations of breast cancer cells may possess an altered autophagic capacity that influences their metastatic potential. It was observed that a metastatic breast cancer cell line, MDA-MB-231, that was sensitive to autophagic induction additionally possessed the ability to proliferate following nutrient deprivation. Furthermore, a selected subpopulation of these cells that survived multiple exposures to starvation conditions demonstrated a heightened response to autophagic induction compared to their parent cells. Although this subpopulation maintained a more grape-like pattern in three-dimensional culture compared to the extended spikes of the parent population, autophagic induction in this subpopulation elicited an invasive phenotype with extended spikes. Taken together, these results suggest that autophagic induction may contribute to the ability of distinct breast cancer cell populations to survive and invade.

  16. Osteopontin knockdown suppresses tumorigenicity of human metastatic breast carcinoma, MDA-MB-435

    PubMed Central

    Shevde, Lalita A.; Samant, Rajeev S.; Paik, Jason C.; Metge, Brandon J.; Chambers, Ann F.; Casey, Graham; Frost, Andra R.; Welch, Danny R.

    2006-01-01

    Elevated expression of osteopontin (OPN), a secreted phosphoglycoprotein, is frequently associated with many transformed cell lines. Various studies suggest that OPN may contribute to tumor progression as well as metastasis in multiple tumor types. High levels of OPN have been reported in patients with metastatic cancers, including breast. We found that the expression of OPN corroborates with the aggressive phenotype of the breast cancer cells i.e. the expression of OPN is acquired as the breast cancer cells become more aggressive. To assess the role(s) of OPN in breast carcinoma, expression of endogenous OPN was knocked down in metastatic MDA-MB-435 human breast carcinoma cells using RNA interference. We targeted multiple regions of the OPN transcript for RNA interference, along with ‘scrambled’ and ‘non-targeting siRNA pool’ controls to distinguish between target-specific and potential off-target effects including interferon-response gene (PeIF2-α) induction. The OPN knockdown by shRNA suppressed tumor take in immunocompromised mice. The ‘silenced’ cells also showed significantly lower invasion and migration in modified Boyden chamber assays and reduced ability to grow in soft agar. Thus, in addition to the widely reported roles of OPN in late stages of tumor progression, these results provide functional evidence that OPN contributes to breast tumor growth as well. PMID:16830223

  17. Monitoring the progression of metastatic breast cancer on nanoporous silica chips

    PubMed Central

    Fan, Jia; Deng, Xiaoyong; Gallagher, James W.; Huang, Haiyu; Huang, Yi; Wen, Jianguo; Ferrari, Mauro; Shen, Haifa; Hu, Ye

    2012-01-01

    Breast cancer accounted for 15 per cent of total cancer deaths in female patients in 2010. Although significant progress has been made in treating early-stage breast cancer patients, there is still no effective therapy targeting late-stage metastatic breast cancers except for the conventional chemotherapy interventions. Until effective therapy for later-stage cancers emerges, the identification of biomarkers for the early detection of tumour metastasis continues to hold the key to successful management of breast cancer therapy. Our study concentrated on the low molecular weight (LMW) region of the serum protein and the information it contains for identifying biomarkers that could reflect the ongoing physiological state of all tissues. Owing to technical difficulties in harvesting LMW species, studying these proteins/peptides has been challenging until now. In our study, we have recently developed nanoporous chip-based technologies to separate small proteins/peptides from the large proteins in serum. We used nanoporous silica chips, with a highly periodic nanostructure and uniform pore size distribution, to isolate LMW proteins and peptides from the serum of nude mice with MDA-MB-231 human breast cancer lung metastasis. By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and biostatistical analysis, we were able to identify protein signatures unique to different stages of cancer development. The approach and results reported in this study possess a significant potential for the discovery of proteomic biomarkers that may significantly enhance personalized medicine targeted at metastatic breast cancer. PMID:22509065

  18. Anemia and jejunal intussusception: An unusual presentation for a metastatic phyllodes breast tumor.

    PubMed

    Schechet, Sidney A; Askenasy, Erik P; Dhamne, Sagar; Scott, Bradford G

    2012-01-01

    Phyllodes tumor of the breast is a rare cause of breast cancer, accounting for less than 0.5% of breast cancers. These tumors are classified as benign, borderline, or malignant, with malignant tumors compromising nearly 25% of cases. Metastases occur in 20% of malignant tumors, lungs, bones, liver and brain being the frequent sites of metastases. We present a case of a metastatic phyllodes tumor to the small bowel causing jejunal intussusception, symptomatic anemia, and small bowel obstruction. Patients with phyllodes tumor of the breast can develop disease recurrence even years after initial treatment. Phyllodes tumor metastasizing to the small bowel is extremely rare, with only three known previously described case reports in the literature. High risk patients, with a past medical history of phyllodes breast cancer, should be monitored closely. Even years after breast cancer treatment, these patients may present with gastrointestinal complaints such as obstruction or bleeding, and therefore metastatic disease to the small bowel should be considered on the differential with subsequent abdominal imaging obtained.

  19. Anemia and jejunal intussusception: An unusual presentation for a metastatic phyllodes breast tumor

    PubMed Central

    Schechet, Sidney A.; Askenasy, Erik P.; Dhamne, Sagar; Scott, Bradford G.

    2011-01-01

    INTRODUCTION Phyllodes tumor of the breast is a rare cause of breast cancer, accounting for less than 0.5% of breast cancers. These tumors are classified as benign, borderline, or malignant, with malignant tumors compromising nearly 25% of cases. Metastases occur in 20% of malignant tumors, lungs, bones, liver and brain being the frequent sites of metastases. PRESENTATION OF CASE We present a case of a metastatic phyllodes tumor to the small bowel causing jejunal intussusception, symptomatic anemia, and small bowel obstruction. DISCUSSION Patients with phyllodes tumor of the breast can develop disease recurrence even years after initial treatment. Phyllodes tumor metastasizing to the small bowel is extremely rare, with only three known previously described case reports in the literature. CONCLUSION High risk patients, with a past medical history of phyllodes breast cancer, should be monitored closely. Even years after breast cancer treatment, these patients may present with gastrointestinal complaints such as obstruction or bleeding, and therefore metastatic disease to the small bowel should be considered on the differential with subsequent abdominal imaging obtained. PMID:22288047

  20. Molecular Mechanisms of Metastatic Progression in Breast Cancer

    DTIC Science & Technology

    2005-07-31

    15243 Redondo M, Villar E, Torres-Muñoz J, Tellez T, Morell M & Petito CK: Overexpression of clusterin in human breast carcinoma. Am J Pathol 2000...sites. Biochem 2002, 41:282-291. 21. de Silva HV, Stuart WD, Park YB, Mao SJ, Gil CM, Wetterau JR, Busch SJ, Harmony JA: Purification and characterization...reactant proteins in sera and breast lesions of patients with malignant and benign tumors. Electrophoresis 2004, 25:2392-2401. 33. Redondo M, Villar E

  1. Increased Expression of P-Glycoprotein Is Associated with Doxorubicin Chemoresistance in the Metastatic 4T1 Breast Cancer Model

    PubMed Central

    Bao, Lili; Haque, Aliyya; Jackson, Kamilah; Hazari, Sidhartha; Moroz, Krzysztof; Jetly, Rachna; Dash, Srikanta

    2011-01-01

    Development of drug resistance is one of the major causes of breast cancer treatment failure. The goal of this study was to understand the chemoresistance mechanism using the highly metastatic 4T1 breast cancer model, which emulates stage IV breast cancer in humans. The metastatic 4T1 breast cancer cell line treated with either doxorubicin or 5-FU showed a concentration-dependent reduced cell proliferation, with induced G2-phase growth arrest (doxorubicin) or G1-phase growth arrest (5-FU). Doxorubicin treatment partially suppressed the multiorgan metastasis of 4T1 breast cancer cells in the lung, heart, liver, and bone, compared with either 5-FU or cyclophosphamide. We isolated and characterized 4T1 breast cancer cells from doxorubicin-resistant metastatic tumors (cell line 4T1-R). Multiorgan metastasis of drug-resistant 4T1 breast tumors was totally resistant to doxorubicin treatment. Our results indicate that doxorubicin is localized exclusively in the cytoplasm of resistant 4T1 breast cancer cells and that it cannot reach the nucleus because of increased nuclear expression of P-glycoprotein. Pretreatment of doxorubicin-resistant 4T1-R breast cancer cells with verapamil, a general inhibitor of P-glycoprotein, increased nuclear translocation of doxorubicin and cellular cytotoxicity. Thus, impaired nuclear translocation of doxorubicin due to increased expression of P-glycoprotein is associated with doxorubicin resistance of highly metastatic 4T1 breast cancer. PMID:21281816

  2. Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2016-03-01

    intravital imaging and whole tissue clearing based imaging to dissect the interaction between tumor cell and its brain metastatic microenvironment. We...have successfully expanded GFAP-GFP mouse line (brain astrocyte specific) and performed preliminary testing on the intravital imaging capability. In...breast cancer driver genes. 2. Keywords……………………………………………………………. Breast cancer, brain metastasis, metastatic outgrowth, brain intravital imaging

  3. A case of Meigs syndrome mimicking metastatic breast carcinoma

    PubMed Central

    Lanitis, Sophocles; Sivakumar, Sivahamy; Behranwala, Kasim; Zacharakis, Emmanouil; Al Mufti, Ragheed; Hadjiminas, Dimitri J

    2009-01-01

    Background Adnexal masses are not uncommon in patients with breast cancer. Breast cancer and ovarian malignancies are known to be associated. In patients with breast cancer and co-existing pleural effusions, ascites and adnexal masses, the probability of disseminated disease is high. Nevertheless, benign ovarian masses can mimic this clinical picture when they are associated with Meigs' syndrome making the work-up and management of these patients challenging. To our knowledge, there are no similar reports in the literature and therefore we present this case to highlight this entity. Case presentation A 56-year old woman presented with a 4 cm, grade 2, invasive ductal carcinoma of her left breast. Pre-treatment staging investigations showed a 13.5 cm mass in her left ovary, a small amount of ascites and a large right pleural effusion. Serum tumour markers showed a raised CA125 supporting the malignant nature of the ovarian mass. The cytology from the pleural effusion was indeterminate but thoracoscopic biopsy failed to show malignancy. The patient was strongly against mastectomy and she was commenced on neo-adjuvant Letrozole 2.5 mg daily with a view to perform breast conserving surgery. After a good response to the hormone manipulation, the patient had breast conserving surgery, axillary sampling and laparoscopic excision of the ovarian mass which was eventually found to be a benign ovarian fibroma. Conclusion Despite the high probability of disseminated malignancy when an ovarian mass associated with ascites if found in a patient with a breast cancer and pleural effusion, clinicians should be aware about rare benign syndromes, like Meigs', which may mimic a similar picture and mislead the diagnosis and management plan. PMID:19161612

  4. Pathological fracture of the femur ten years after successful radiation therapy for metastatic breast cancer.

    PubMed

    Hatano, Hiroshi; Morita, Tetsuro; Kobayashi, Hiroto; Ito, Takui; Segawa, Hiroyuki; Saito, Mari

    2004-01-01

    We describe a case involving a 75-year-old woman presenting with a femur fracture 10 years after radiation therapy for metastatic breast cancer, which developed in the right femur. The lesion showed complete response with bone healing following radiation therapy; however, the patient sustained a femur fracture ten years later. Histological examination of the specimens obtained from the lesion revealed features of radiation osteonecrosis, but there was no histological evidence of tumor. To our knowledge, there has been no reported case of pathological fracture ten years after radiation therapy from radiation osteonecrosis rather than progression of the metastatic lesion. Late complications of radiation therapy should be considered with care, even when metastatic lesions demonstrate complete response to treatment.

  5. The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic sites

    PubMed Central

    Gao, Hua; Chakraborty, Goutam; Lee-Lim, Ai Ping; Mo, Qianxing; Decker, Markus; Vonica, Alin; Shen, Ronglai; Brogi, Edi; Brivanlou, Ali H.; Giancotti, Filippo G.

    2012-01-01

    SUMMARY The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific anti-metastatic signals in order to undergo reactivation. PMID:22901808

  6. T Cells Induce Pre-Metastatic Osteolytic Disease and Help Bone Metastases Establishment in a Mouse Model of Metastatic Breast Cancer

    PubMed Central

    Monteiro, Ana Carolina; Leal, Ana Carolina; Gonçalves-Silva, Triciana; Mercadante, Ana Carolina T.; Kestelman, Fabiola; Chaves, Sacha Braun; Azevedo, Ricardo Bentes; Monteiro, João P.; Bonomo, Adriana

    2013-01-01

    Bone metastases, present in 70% of patients with metastatic breast cancer, lead to skeletal disease, fractures and intense pain, which are all believed to be mediated by tumor cells. Engraftment of tumor cells is supposed to be preceded by changes in the target tissue to create a permissive microenvironment, the pre-metastatic niche, for the establishment of the metastatic foci. In bone metastatic niche, metastatic cells stimulate bone consumption resulting in the release of growth factors that feed the tumor, establishing a vicious cycle between the bone remodeling system and the tumor itself. Yet, how the pre-metastatic niches arise in the bone tissue remains unclear. Here we show that tumor-specific T cells induce osteolytic bone disease before bone colonization. T cells pro-metastatic activity correlate with a pro-osteoclastogenic cytokine profile, including RANKL, a master regulator of osteoclastogenesis. In vivo inhibition of RANKL from tumor-specific T cells completely blocks bone loss and metastasis. Our results unveil an unexpected role for RANKL-derived from T cells in setting the pre-metastatic niche and promoting tumor spread. We believe this information can bring new possibilities for the development of prognostic and therapeutic tools based on modulation of T cell activity for prevention and treatment of bone metastasis. PMID:23935856

  7. A Systematic Approach to Preclinical Trials in Metastatic Breast Cancer

    PubMed Central

    Rashid, OM; Maurente, D; Takabe, K

    2016-01-01

    The process of developing new agents for therapy against breast cancer is inefficient and relies on animal models to screen for efficacy for preclinical studies. However, there has been limited validation of these models, despite the increasing costs in the rapidly growing era of personalized medicine and targeted therapy. Recently, there have been multiple studies which have critically evaluated animal models for breast cancer drug discovery. We recently reviewed the transgenic, xenograft, and syngeneic murine breast cancer models, the ectopic, orthotopic and intravenous methods of cell implantation, tumor gene expression profiles, as well as the ethics of animal experimentation, and we provide important information for investigators in this challenging field. Because of the complexities of treating breast cancer and the increasing costs of developing new agents, the choice of the appropriate murine model must carefully consider each model available, including the tumor gene expression profile. Such a critical approach to the in vivo portion of drug development will further increase the efficiency of breast cancer drug research and development. PMID:27695662

  8. A Systematic Approach to Preclinical Trials in Metastatic Breast Cancer.

    PubMed

    Rashid, O M; Maurente, D; Takabe, K

    2016-09-01

    The process of developing new agents for therapy against breast cancer is inefficient and relies on animal models to screen for efficacy for preclinical studies. However, there has been limited validation of these models, despite the increasing costs in the rapidly growing era of personalized medicine and targeted therapy. Recently, there have been multiple studies which have critically evaluated animal models for breast cancer drug discovery. We recently reviewed the transgenic, xenograft, and syngeneic murine breast cancer models, the ectopic, orthotopic and intravenous methods of cell implantation, tumor gene expression profiles, as well as the ethics of animal experimentation, and we provide important information for investigators in this challenging field. Because of the complexities of treating breast cancer and the increasing costs of developing new agents, the choice of the appropriate murine model must carefully consider each model available, including the tumor gene expression profile. Such a critical approach to the in vivo portion of drug development will further increase the efficiency of breast cancer drug research and development.

  9. A Randomized Controlled Trial of Emotionally Expressive Writing for Women With Metastatic Breast Cancer

    PubMed Central

    Low, Carissa A.; Stanton, Annette L.; Bower, Julienne E.; Gyllenhammer, Lauren

    2011-01-01

    Objective To test the effects of emotionally expressive writing in a randomized controlled trial of metastatic breast cancer patients and to determine whether effects of the intervention varied as a function of perceived social support or time since metastatic diagnosis. Design Women (N = 62) living with Stage IV breast cancer were randomly assigned to write about cancer-related emotions (EMO; n = 31) or the facts of their diagnosis and treatment (CTL; n = 31). Participants wrote at home for four 20-min sessions within a 3-week interval. Main Outcome Measures Depressive symptoms, cancer-related intrusive thoughts, somatic symptoms, and sleep quality at 3 months postintervention. Results No significant main effects of experimental condition were observed. A significant condition × social support interaction emerged on intrusive thoughts; EMO writing was associated with reduced intrusive thoughts for women reporting low emotional support (η2 = .15). Significant condition × time since metastatic diagnosis interactions were also observed for somatic symptoms and sleep disturbances. Relative to CTL, EMO participants who were more recently diagnosed had fewer somatic symptoms (η2 = .10), whereas EMO participants with longer diagnosis duration exhibited increases in sleep disturbances (η2 = .09). Conclusion Although there was no main effect of expressive writing on health among the current metastatic breast cancer sample, expressive writing may be beneficial for a subset of metastatic patients (including women with low levels of emotional support or who have been recently diagnosed) and contraindicated for others (i.e., those who have been living with the diagnosis for years). PMID:20658835

  10. A randomized controlled trial of emotionally expressive writing for women with metastatic breast cancer.

    PubMed

    Low, Carissa A; Stanton, Annette L; Bower, Julienne E; Gyllenhammer, Lauren

    2010-07-01

    To test the effects of emotionally expressive writing in a randomized controlled trial of metastatic breast cancer patients and to determine whether effects of the intervention varied as a function of perceived social support or time since metastatic diagnosis. Women (N = 62) living with Stage IV breast cancer were randomly assigned to write about cancer-related emotions (EMO; n = 31) or the facts of their diagnosis and treatment (CTL; n = 31). Participants wrote at home for four 20-min sessions within a 3-week interval. Depressive symptoms, cancer-related intrusive thoughts, somatic symptoms, and sleep quality at 3 months postintervention. No significant main effects of experimental condition were observed. A significant condition x social support interaction emerged on intrusive thoughts; EMO writing was associated with reduced intrusive thoughts for women reporting low emotional support (eta2 = .15). Significant condition x time since metastatic diagnosis interactions were also observed for somatic symptoms and sleep disturbances. Relative to CTL, EMO participants who were more recently diagnosed had fewer somatic symptoms (eta2 = .10), whereas EMO participants with longer diagnosis duration exhibited increases in sleep disturbances (eta2 = .09). Although there was no main effect of expressive writing on health among the current metastatic breast cancer sample, expressive writing may be beneficial for a subset of metastatic patients (including women with low levels of emotional support or who have been recently diagnosed) and contraindicated for others (i.e., those who have been living with the diagnosis for years). PsycINFO Database Record (c) 2010 APA, all rights reserved.

  11. ESR1 mutations in circulating plasma tumor DNA from metastatic breast cancer patients

    PubMed Central

    Chu, David; Paoletti, Costanza; Gersch, Christina; VanDenBerg, Dustin A.; Zabransky, Daniel J.; Cochran, Rory L.; Wong, Hong Yuen; Toro, Patricia Valda; Cidado, Justin; Croessmann, Sarah; Erlanger, Bracha; Cravero, Karen; Kyker-Snowman, Kelly; Button, Berry; Parsons, Heather; Dalton, W. Brian; Gillani, Riaz; Medford, Arielle; Aung, Kimberly; Tokudome, Nahomi; Chinnaiyan, Arul M.; Schott, Anne; Robinson, Dan; Jacks, Karen S.; Lauring, Josh; Hurley, Paula; Hayes, Daniel F.; Rae, James; Park, Ben Ho

    2016-01-01

    Purpose Mutations in the estrogen receptor-alpha (ER) gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Due to limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from metastatic breast cancer patients. Experimental Design We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild type ESR1 identified by next generation sequencing (NGS) of biopsied metastatic tissues. Three common ESR1 mutations were queried for using droplet digital polymerase chain reaction (ddPCR). In a prospective cohort, metastatic tissue and plasma were collected contemporaneously from eight ER-positive and four ER-negative patients. Tissue biopsies were sequenced by NGS and ptDNA ESR1 mutations were analyzed by ddPCR. Results In the retrospective cohort, all corresponding mutations were detected in ptDNA, with two patients harboring additional ESR1 mutations not present in their metastatic tissues. In the prospective cohort, three ER-positive patients did not have adequate tissue for NGS, and no ESR1 mutations were identified in tissue biopsies from the other nine patients. In contrast, ddPCR detected seven ptDNA ESR1 mutations in six of twelve patients (50%). Conclusions We show that ESR1 mutations can occur at a high frequency and suggest that blood can be used to identify additional mutations not found by sequencing of a single metastatic lesion. PMID:26261103

  12. Maintenance hormonal and chemotherapy treatment in metastatic breast cancer: a systematic review.

    PubMed

    Rossi, Sabrina; Schinzari, Giovanni; Basso, Michele; Strippoli, Antonia; Dadduzio, Vincenzo; D'Argento, Ettore; Cassano, Alessandra; Barone, Carlo

    2016-05-01

    Endocrine treatment is the first-line therapy in hormone-sensitive metastatic breast cancer while chemotherapy is the first option in tumors refractory to endocrine therapy and in hormone-negative disease. Optimal duration, efficacy and safety of a maintenance endocrine therapy or chemotherapy after an induction treatment are still a matter of debate. We performed a literature review to identify studies regarding maintenance hormonal and chemotherapy treatments in metastatic breast cancer. We analyzed data relating to efficacy (improvement of progression-free survival and overall survival) and safety (symptoms relief and quality of life [QoL]). Maintenance endocrine therapy could prolong progression-free survival with a better control of symptoms and improving QoL. Maintenance chemotherapy prolong the response to a previous treatment, worsening the QoL, except for metronomic capecitabine.

  13. Oophorectomy versus radiation ablation of ovarian function in patients with metastatic carcinoma of the breast

    SciTech Connect

    Lees, A.W.; Giuffre, C.; Burns, P.E.; Hurlburt, M.E.; Jenkins, H.J.

    1980-12-01

    A retrospective study of two methods of ovarian ablation as primary therapy for metastatic carcinoma of the breast was carried out using records from this cancer institute. Sixty-one radiation and 97 surgical ovarian ablations, performed from 1972 to 1977, were assessed. Over-all response was similar for the surgical and irradiation groups. Survival from the time of ovarian ablation was greater in both groups in those who responded positively than in those who did not. Factors other than estrogen receptor status can determine the response of patients with metastatic carcinoma of the breast to ovarian ablation. The results indicate that clinical determinates and not the efficiency of one method over the other should be the main criteria for choosing between ovarian ablation by irradiation or by oophorectomy.

  14. Breast cancer metastatic to the pituitary gland: a case report.

    PubMed

    Spinelli, Gian Paolo; Lo Russo, Giuseppe; Miele, Evelina; Prinzi, Natalie; Tomao, Federica; Antonelli, Manila; Giangaspero, Felice; Stati, Valeria; Strudel, Martina; Tomao, Silverio

    2012-07-09

    Metastases to the pituitary gland are rare events, and usually indicate widespread malignant disease. The lung and the breast are the most common sites of primary tumors that metastasize to the pituitary gland.Metastases are more frequent in older patients and the most common symptoms at presentation are diabetes insipidus and visual alterations. 72-year-old white woman was treated for a breast carcinoma with right superoexternal quadrantectomy, radiotherapy, and hormone therapy. Twelve years later, the patient presented with bone pain, bilateral progressive visual decline, and onset of hypopituitarism. A diagnosis of secondary bone involvement and pituitary metastasis was made. This was an unusual disease course, and stresses the importance of intensive follow-up in patients with breast cancer even many years after the initial diagnosis This case emphasizes that diagnosis can be difficult and controversial when relapse occurs at uncommon sites.

  15. Identification of molecular determinants of primary and metastatic tumour re-initiation in breast cancer.

    PubMed

    Ross, Jason B; Huh, Doowon; Noble, Lisa B; Tavazoie, Sohail F

    2015-05-01

    Through in vivo selection of multiple ER-negative human breast cancer populations for enhanced tumour-forming capacity, we have derived subpopulations that generate tumours more efficiently than their parental populations at low cell numbers. Tumorigenic-enriched subpopulations exhibited increased expression of LAMA4, FOXQ1 and NAP1L3—genes that are also expressed at greater levels by independently derived metastatic subpopulations. These genes promote metastatic efficiency. FOXQ1 promotes LAMA4 expression, and LAMA4 enhances clonal expansion following substratum detachment in vitro, tumour re-initiation in multiple organs, and disseminated metastatic cell proliferation and colonization. The promotion of cancer cell proliferation and tumour re-initiation by LAMA4 requires β1-integrin. Increased LAMA4 expression marks the transition of human pre-malignant breast lesions to malignant carcinomas, and tumoral LAMA4 overexpression predicts reduced relapse-free survival in ER-negative patients. Our findings reveal common features that govern primary and metastatic tumour re-initiation and identify a key molecular determinant of these processes.

  16. Not all secondary bone tumours are secondaries. Concurrent metastatic breast carcinoma and chondrosarcoma of the femur.

    PubMed

    Nath, Preethy; Sankey, Elizabeth; Murray, Elisabeth; Kurup, Harish

    2015-04-09

    We present a case of metastatic adenocarcinoma of the breast in a patient who sustained a pathological fracture of the distal femur. Histology of the distal femur lesion excised at the time of endoprosthetic replacement confirmed this to be a primary chondrosarcoma. We have reviewed the literature and identified previously documented cases of concurrent breast carcinoma and chondrosarcoma of bone. A high index of suspicion is warranted and the diagnosis must be first confirmed before rushing to internal fixation (therapeutic or prophylactic) assuming them to be secondary bone lesions from the known primary cancer even in patients with multiple metastases.

  17. External Jugular Vein Thrombosis as a Sign of Metastatic Breast Cancer

    PubMed Central

    Yalaza, Metin; Kafadar, Mehmet Tolga; Çıvgın, Esra Yurduseven; Düzgün, Arife Polat

    2017-01-01

    External jugular vein thrombosis is a rare vascular event which may lead fatal complication such as sepsis and pulmonary embolism. Its relation to the visceral solid tumor as an etiologic factor has been established well. Although external jugular vein thrombosis may be seen in malignancy, it is unusual to see as a sign of breast cancer. Most of the external jugular vein thrombosis occurs secondary to compression of the vein. Vascular thrombosis due to hypercoagulability is known as Trousseau syndrome. Herein, we present a case of metastatic breast cancer which presented with external jugular vein thrombosis; Trousseau syndrome. PMID:28331768

  18. Newer Therapies for the Treatment of Metastatic Breast Cancer: a Clinical Update

    PubMed Central

    Mohan, Anjana; Ponnusankar, S.

    2013-01-01

    Breast cancer is the foremost common malignancy among the female population around the world. Female breast cancer incidence rates have increased since 1980, slowed in 1990, the rate of increase have leveled off since 2001. In spite of the advances in the early detection, treatment, surgery and radiation support, almost 70% of the patients develop metastasis and die of the disease. Around 10% of the patients when diagnosed with breast cancer have metastases. Survival among the breast cancer patients have increased due to the introduction of novel single agent, combination of chemotherapeutic agents and targeted biologic agents, which is breast cancer specific. The staging of tumor-node-metastasis is significant for the prognosis and treatment. Predominantly the combination of chemotherapeutic regimen is given to improve the rate of clinical benefit and the overall survival rate. Novel mono-therapeutic options are being used often in metastatic setting as they will not be able to endure the toxicity of the combination regimen. Usually, endocrine therapy is recommended for hormone-responsive breast cancer due to efficacy and favorable side effect profile but chemotherapy becomes an option when endocrine therapy fails. This review summarizes the newer therapeutic options for early breast cancer and advanced breast cancer that are pretreated heavily on other chemotherapeutic agents. Further it provides monotherapies and other emerging novel combination regime which can be opted for first line or second line setting. PMID:24082340

  19. Metastatic chordoma of the breast: an extremely rare lesion mimicking mucinous cancer.

    PubMed

    Tot, Tibor

    2006-10-01

    Metastases in the breast are rare, with metastatic chordoma being one of the rarest. To our knowledge, only one such case has previously been published in the literature. We report a case of a 74-year-old woman who presented with a palpable lump in her right breast. The lump was mammographically suggestive of mucinous breast cancer because it was a solitary, small, circular, and moderately dense lesion yielding abundant mucoid aspirate. The tumor resembled mucinous carcinoma upon histologic and immunohistochemical examination: it had a mucinous stroma, and the tumor cells strongly expressed epithelial markers. However, the patient had previously undergone surgery for a recurrent sacral chordoma. In addition to the clinical history, the presence of typical physaliferous cells expressing neither estrogen receptors nor cytokeratin 7, but staining positively for S-100 protein, allowed the proper diagnosis. Although extremely rare, metastatic chordoma may represent a challenge in the differential diagnosis of breast lesions. Discriminating metastases of mucin-producing tumors in the breast from primary mucinous carcinomas is important with regard to the striking difference in prognosis of these lesions.

  20. Radiotherapy for Metastatic Breast Cancer in Mexico: Results from the 2015 National Survey.

    PubMed

    Álvarez-Águila, Nora; Cook, Hilary; Prada, Diddier; Mota-García, Aida; Herrera, Luis A; Mohar-Betancourt, Alejandro; Meneses-García, Abelardo; Knaul, Felicia M

    2017-01-01

    Radiation therapy is a keystone to improve survival and quality of life in breast cancer patients. In Mexico, however, scarce information is available on the obstacles faced by radio-oncologists to provide appropriate treatment. To determine the most frequent issues faced by physicians to provide radiation therapy for metastatic breast cancer in Mexico. A survey of 16 multiple-choice questions to be answered electronically by 167 radio-oncologists currently working in Mexico was designed and thereafter analyzed for differences between private and public practices, based on the responses from the surveyed participants. 98.5% of surveyed responders attended patients with breast cancer. We observed a significant difference between private vs. public practice for the main difficulties in providing radiation therapy, with an increased frequency (85.8%) of "treatment cost by itself" in private practice vs. 50.7% in public practice (p < 0.05). Significant differences were observed in the "Time to initiate treatment" question, with "Less than one week" as the response in 86% of those physicians in private practice vs. 50% for those in public practice (p < 0.001). Using a survey targeted at radio-oncologists, we analyzed the most important obstacles for accessing radiation therapy for metastatic breast cancer in Mexico. This information may be useful for healthcare decisions related to radiation therapy in women with breast cancer in Mexico.

  1. Novel Molecular Imaging Agents to Detect Biomarkers of Metastatic Breast Cancer

    DTIC Science & Technology

    2006-01-01

    chemistry with HBTU and HOBt as coupling agents. The coupling efficiency of each amino acid residues were checked by Kaiser’s ninhydrin test . The...of each amino acid residues were checked by Kaiser’s ninhydrin test . The starting resin had 1.0mmol/g of OH groups and the scale of peptide synthesis...assess biomarkers of metastatic breast cancer (Months 4-6). This task has been successfully accomplished by testing our peptide-DOTA imaging

  2. Spontaneous nasal perforation in a bevacizumab-treated patient with metastatic breast cancer.

    PubMed

    Rodriguez, Cesar A; Martin, Teresa; Lozano, Rebeca; Gomez, Amalia; Cruz, Juan J

    2017-08-27

    Nasal septum perforation in patients with cancer receiving systemic therapy is rare, and its association with bevacizumab use has described recently in the literature. Here, we report the case of a 34-year-old woman with hormone-sensitive, HER-2/neu negative, metastatic breast cancer who develope a nasal septum perforation during the treatment with paclitaxel and bevacizumab. © 2017 Wiley Periodicals, Inc.

  3. Metastatic lobular carcinoma of the breast diagnosed in cervicovaginal samples. A case report.

    PubMed

    Mallow, D W; Humphrey, P A; Soper, J T; Johnston, W W

    1997-01-01

    Malignant tumors with extragenital origins are rare in cervicovaginal samples. A case of metastatic lobular carcinoma of the breast was diagnosed in a cervicovaginal smear. Histologic correlation was performed. Marker studies for carcinoembryonic antigen, human milk fat globule membrane, epidermal growth factor receptor, epithelial membrane antigen and cytokeratin were positive. Recognition of extrauterine cancer in the cervicovaginal smear has important diagnostic, prognostic, and therapeutic implications.

  4. Recent developments and translational aspects in targeted therapy for metastatic breast cancer

    PubMed Central

    Marhold, Maximilian; Bartsch, Rupert; Zielinski, Christoph

    2016-01-01

    Biologically distinct subtypes of metastatic breast cancer (MBC) have been defined by multiple efforts in recent years, showing broad heterogeneity at the molecular level of disease. Throughout this endeavour, oncogenic drivers within MBC were identified as potential therapeutic targets. With recent results from clinical trials targeting these well-known cancer-promoting pathways, this review is trying to elucidate as well as summarise current new therapeutic aspects in MBC and shed light on translational aspects within this entity. PMID:27843605

  5. Role of connexins in metastatic breast cancer and melanoma brain colonization

    PubMed Central

    Stoletov, Konstantin; Strnadel, Jan; Zardouzian, Erin; Momiyama, Masashi; Park, Frederick D.; Kelber, Jonathan A.; Pizzo, Donald P.; Hoffman, Robert; VandenBerg, Scott R.; Klemke, Richard L.

    2013-01-01

    Summary Breast cancer and melanoma cells commonly metastasize to the brain using homing mechanisms that are poorly understood. Cancer patients with brain metastases display poor prognosis and survival due to the lack of effective therapeutics and treatment strategies. Recent work using intravital microscopy and preclinical animal models indicates that metastatic cells colonize the brain, specifically in close contact with the existing brain vasculature. However, it is not known how contact with the vascular niche promotes microtumor formation. Here, we investigate the role of connexins in mediating early events in brain colonization using transparent zebrafish and chicken embryo models of brain metastasis. We provide evidence that breast cancer and melanoma cells utilize connexin gap junction proteins (Cx43, Cx26) to initiate brain metastatic lesion formation in association with the vasculature. RNAi depletion of connexins or pharmacological blocking of connexin-mediated cell–cell communication with carbenoxolone inhibited brain colonization by blocking tumor cell extravasation and blood vessel co-option. Activation of the metastatic gene twist in breast cancer cells increased Cx43 protein expression and gap junction communication, leading to increased extravasation, blood vessel co-option and brain colonization. Conversely, inhibiting twist activity reduced Cx43-mediated gap junction coupling and brain colonization. Database analyses of patient histories revealed increased expression of Cx26 and Cx43 in primary melanoma and breast cancer tumors, respectively, which correlated with increased cancer recurrence and metastasis. Together, our data indicate that Cx43 and Cx26 mediate cancer cell metastasis to the brain and suggest that connexins might be exploited therapeutically to benefit cancer patients with metastatic disease. PMID:23321642

  6. Apoptotic circulating tumor cells in early and metastatic breast cancer patients.

    PubMed

    Kallergi, Galatea; Konstantinidis, Georgios; Markomanolaki, Harris; Papadaki, Maria A; Mavroudis, Dimitris; Stournaras, Christos; Georgoulias, Vassilis; Agelaki, Sofia

    2013-09-01

    The detection of circulating tumor cells (CTC) in breast cancer is strongly associated with disease relapse. Since it is unclear whether all CTCs are capable of generating metastasis, we investigated their apoptotic and proliferative status in 56 CTC-positive (29 early and 27 metastatic) patients with breast cancer. Double-staining immunofluorescence experiments were carried out in peripheral blood mononuclear cells (PBMC) cytospins, using the pancytokeratin A45-B/B3 antibody and either M30 (apoptotic marker) or Ki67 (proliferation marker) antibodies. Apoptosis was also evaluated using a polycaspase detection kit. Patients with metastatic disease had significantly lower numbers of apoptotic CTCs compared with patients with early breast cancer (polycaspase kit: 8.1% vs. 47.4% of the total CTC number; P = 0.0001; M30-antibody: 32.1% vs. 76.63%; P = 0.002). The median percentage of apoptotic CTCs per patient was also lower in patients with advanced compared with those with early disease (polycaspase kit: 0% vs. 53.6%; M30-antibody: 15% vs. 80%). Ki67-positive CTCs were identified in 51.7% and 44% of patients with early and metastatic disease, respectively. Adjuvant chemotherapy reduced both the number of CTCs per patient and the number of proliferating CTCs (63.9% vs. 30%). In conclusion, apoptotic CTCs could be detected in patients with breast cancer irrespective of their clinical status, though the incidence of detection is higher in early compared with metastatic patients. The detection of CTCs that survive despite adjuvant therapy implies that CTC elimination should be attempted using agents targeting their distinctive molecular characteristics.

  7. Functional Analysis and Therapeutic Potential of miR-708 in Metastatic Breast Cancer

    DTIC Science & Technology

    2014-10-01

    Our objective is to dissect the epigenetic regulation of miR-708, so that epigenetic therapies can be considered for metastatic breast cancer, and...evaluate the therapeutic efficacy of synthetic miR-708. Dissecting the epigenetic regulation of miR-708 will generate translational opportunities for...patients with TNBC. For example, insights into the role of PRC2 to directly mediate miR-708 silencing will allow the evaluation of epigenetic

  8. Role of connexins in metastatic breast cancer and melanoma brain colonization.

    PubMed

    Stoletov, Konstantin; Strnadel, Jan; Zardouzian, Erin; Momiyama, Masashi; Park, Frederick D; Kelber, Jonathan A; Pizzo, Donald P; Hoffman, Robert; VandenBerg, Scott R; Klemke, Richard L

    2013-02-15

    Breast cancer and melanoma cells commonly metastasize to the brain using homing mechanisms that are poorly understood. Cancer patients with brain metastases display poor prognosis and survival due to the lack of effective therapeutics and treatment strategies. Recent work using intravital microscopy and preclinical animal models indicates that metastatic cells colonize the brain, specifically in close contact with the existing brain vasculature. However, it is not known how contact with the vascular niche promotes microtumor formation. Here, we investigate the role of connexins in mediating early events in brain colonization using transparent zebrafish and chicken embryo models of brain metastasis. We provide evidence that breast cancer and melanoma cells utilize connexin gap junction proteins (Cx43, Cx26) to initiate brain metastatic lesion formation in association with the vasculature. RNAi depletion of connexins or pharmacological blocking of connexin-mediated cell-cell communication with carbenoxolone inhibited brain colonization by blocking tumor cell extravasation and blood vessel co-option. Activation of the metastatic gene twist in breast cancer cells increased Cx43 protein expression and gap junction communication, leading to increased extravasation, blood vessel co-option and brain colonization. Conversely, inhibiting twist activity reduced Cx43-mediated gap junction coupling and brain colonization. Database analyses of patient histories revealed increased expression of Cx26 and Cx43 in primary melanoma and breast cancer tumors, respectively, which correlated with increased cancer recurrence and metastasis. Together, our data indicate that Cx43 and Cx26 mediate cancer cell metastasis to the brain and suggest that connexins might be exploited therapeutically to benefit cancer patients with metastatic disease.

  9. Surgical treatment and outcomes of metastatic breast cancer to the spine.

    PubMed

    Walcott, Brian P; Cvetanovich, Gregory L; Barnard, Zachary R; Nahed, Brian V; Kahle, Kristopher T; Curry, William T

    2011-10-01

    Metastatic vertebral body and spinal epidural lesions cause significant pain and neurological morbidity and negatively impact quality of life and survival. In instances of metastatic epidural spinal cord compression, treatment typically involves surgery and radiotherapy. The incidence of spinal metastases in breast cancer patients is high. In the light of recent improvements in survival among some patients with breast cancer, we reviewed the treatments and outcomes for patients with breast cancer who presented to our institution with metastatic epidural spinal cord compression. We identified all patients undergoing open surgery for the treatment of breast cancer metastases to the spine at our center from 1 January 2001 to 31 December 2009. We retrospectively reviewed records for the details of medical history, treatment, surgery, radiographic imaging, and follow-up. The Death Master File from the United States Social Security Administration was queried to identify the date of death where the medical record was incomplete. Outcomes were assessed by overall survival as well as preoperative and postoperative ambulatory status, bladder function, and the American Spinal Injury Association impairment classification system (ASIA). A total of 15 female patients were identified as having surgical intervention directly related to breast cancer metastasis to the spine. Most lesions (12/15) were located in the anterior vertebral column (vertebral body and/or pedicle). Two patients required re-operation, one for epidural fluid collection and one for infection. Roughly half of the patients (8/15) had well-controlled systemic disease at the time of surgery. Five patients had non-contiguous metastatic lesions elsewhere in the spine. Median survival following surgery was 1,025 days; control of systemic disease did not predict duration of postoperative survival. Seven patients had documented improvement in their ability to ambulate in the first 30 days following surgery. Bladder

  10. [The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer].

    PubMed

    Jerusalem, G; Rorive, A; Collignon, J

    2014-09-01

    Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.

  11. Exosomes enriched in stemness/metastatic-related mRNAS promote oncogenic potential in breast cancer.

    PubMed

    Rodríguez, Marta; Silva, Javier; Herrera, Alberto; Herrera, Mercedes; Peña, Cristina; Martín, Paloma; Gil-Calderón, Beatriz; Larriba, María Jesús; Coronado, M Josés; Soldevilla, Beatriz; Turrión, Víctor S; Provencio, Mariano; Sánchez, Antonio; Bonilla, Félix; García-Barberán, Vanesa

    2015-12-01

    Cancer cells efficiently transfer exosome contents (essentially mRNAs and microRNAs) to other cell types, modifying immune responses, cell growth, angiogenesis and metastasis. Here we analyzed the exosomes release by breast tumor cells with different capacities of stemness/metastasis based on CXCR4 expression, and evaluated their capacity to generate oncogenic features in recipient cells. Breast cancer cells overexpressing CXCR4 showed an increase in stemness-related markers, and in proliferation, migration and invasion capacities. Furthermore, recipient cells treated with exosomes from CXCR4-cells showed increased in the same abilities. Moreover, inoculation of CXCR4-cell-derived exosomes in immunocompromised mice stimulated primary tumor growth and metastatic potential. Comparison of nucleic acids contained into exosomes isolated from patients revealed a "stemness and metastatic" signature in exosomes of patients with worse prognosis. Finally, our data supported the view that cancer cells with stem-like properties show concomitant metastatic behavior, and their exosomes stimulate tumor progression and metastasis. Exosomes-derived nucleic acids from plasma of breast cancer patients are suitable markers in the prognosis of such patients.

  12. Study on adherence to capecitabine among patients with colorectal cancer and metastatic breast cancer.

    PubMed

    Figueiredo Junior, Adiel Goes de; Forones, Nora Manoukian

    2014-01-01

    Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. To investigate the adhesion to treatment with oral capecitabine in breast and colorectal cancer, and to determine any correlation with changes in patient's quality of life. Patients with colorectal cancer or breast cancer using capecitabine were included. The patients were asked to bring any medication left at the time of scheduled visits. The QLQ-C30 questionnaire was applied at the first visit and 8-12 weeks after treatment. Thirty patients were evaluated. Adherence was 88.3% for metastatic colon cancer, 90.4% for non-metastatic colon cancer, 94.3% for rectal cancer and 96.2% for metastatic breast cancer. No strong correlation between adherence and European Organisation for Research and Treatment of Cancer QLQ-C30 functional or symptom scale rates had been found. There was no statistically significant correlation between compliance and the functional and symptom scales of the questionnaire before and after chemotherapy, with the exception of dyspnea. Although no absolute adherence to oral capecitabine treatment had been observed, the level of adherence was good. Health professionals therefore need a greater focus in the monitoring the involvement of patients with oral treatment regimens. Patients with lesser degrees of dyspnea had greater compliance.

  13. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer.

    PubMed

    Gunasinghe, N P A Devika; Wells, Alan; Thompson, Erik W; Hugo, Honor J

    2012-12-01

    As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed. Breast cancer metastases often look (and may even function) as 'normal' breast tissue, a bizarre observation against the backdrop of the organ structure of the lung, liver, bone or brain. Mesenchymal to epithelial transition (MET), the opposite of EMT, has been proposed as a mechanism for establishment of the metastatic neoplasm, leading to questions such as: Can MET be clearly demonstrated in vivo? What factors cause this phenotypic switch within the cancer cell? Are these signals/factors derived from the metastatic site (soil) or expressed by the cancer cells themselves (seed)? How do the cancer cells then grow into a detectable secondary tumour and further disseminate? And finally--Can we design and develop therapies that may combat this dissemination switch? This review aims to address these important questions by evaluating long-standing paradigms and novel emerging concepts in the field of epithelial mesencyhmal plasticity.

  14. Phase II trial of metronomic chemotherapy as salvage therapy for patients with metastatic breast cancer.

    PubMed

    Salem, Dina A; Gado, Nevine M; Abdelaziz, Nashwa N; Essa, Ahmed E; Abdelhafeez, Zeinab M; Kamel, Tarek H

    2008-06-01

    To evaluate the efficacy and tolerability of metronomic chemotherapy (which is the continuous administration of chemotherapy at relatively low minimally toxic doses on a frequent schedule of administration at close regular intervals with no prolonged drug-free breaks) in metastatic breast cancer patients as salvage therapy. In this phase II study we evaluated the clinical efficacy and tolerability of low dose, oral Methotrexate (MTX) and Cyclophosphamide (CTX) in patients with metastatic breast cancer. Between January 2004 and December 2005, 42 patients received MTX 2.5mg bid on day 1 and 2 each week and CTX 50mg/day administered continuously. Forty two patients were evaluable. The overall clinical benefit was 31% complete response, partial response and stable disease (CR+PR+SD >or=24 weeks), while the overall response rate was 16.7% (none of the patients attained CR). Toxicity was generally mild. The most common non hematological toxicity was elevation in transaminases level, it was reported in 40.4% of patients and was reversible, while mild grade 1 or 2 neutropenia was the most common hematological toxicity, (28.5% of patients). Median time to response was 3+/-0.18 while progression free survival (PFS) among patients with clinical benefit was 10 months (95% CI 6.65-13.44). This phase II study shows that, the combination of continuously low dose MTX and CTX is an active minimally toxic and significantly cost effective regimen for the treatment of metastatic breast cancer patients.

  15. FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma.

    PubMed

    Brunello, Eleonora; Brunelli, Matteo; Bogina, Giuseppe; Caliò, Anna; Manfrin, Erminia; Nottegar, Alessia; Vergine, Marco; Molino, Annamaria; Bria, Emilio; Massari, Francesco; Tortora, Giampaolo; Cingarlini, Sara; Pedron, Serena; Chilosi, Marco; Zamboni, Giuseppe; Miller, Keith; Martignoni, Guido; Bonetti, Franco

    2012-12-27

    Lobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed. Fifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases.FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3-6 signals) of the locus specific FGFR-1 gene. Three (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3-6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals.The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases. 1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the

  16. Bone Factors Regulating the Osteotropism of Metastatic Breast Cancer

    DTIC Science & Technology

    1998-10-01

    is a recent predictor of metastasis . Little is known about the regulation of such events. We are using in vitro and in vivo models to characterize...painful bone metastasis in invasive breast cancer, offering hope for innovative therapy. Given the unchanging survival outlook for patients with... osteosarcoma cell line, DNAsed, reverse transcribed and amplified using these primers. The amplimer was then gel purified using a Quiaex II kit. The gel

  17. Combination of miR-21 with Circulating Tumor Cells Markers Improve Diagnostic Specificity of Metastatic Breast Cancer.

    PubMed

    Yang, Xingwang; Wang, Xiaoming; Shen, Hongyan; Deng, Rong; Xue, Kecheng

    2015-09-01

    Circulating miR-21 is upregulated in breast cancer. However, correlation of miR-21 expression with clinic pathologic characteristics remains questionable. In this study, we investigate whether combination of circulation miR-21 with circulating tumor cells (CTCs) marker (EpCAM, MUS1, HER2) could improve diagnostic specificity of metastatic breast cancer. Total 223 breast cancer patients were included. 89 % patients were associated with upregulation of miR-21 compared with health control. 20 % patients were detected for CTCs marker positive. For higher specificity purpose, triple marker positive samples were selected as true CTCs positive, which only occupied 59.5 % of total metastatic breast cancer patients. Specificity of detection of CTCs was 96.7 %. Furthermore, 59.5 % metastatic breast cancer patients were shown both abnormal miR-21 and true CTCs positive according to distribution of true CTCs positive and abnormal miR-21; Combination of miR-21 and CTCs was increased specificity of metastatic detection to 100 %. Our findings suggested that combination of miR-21 with CTCs marker could be used for better diagnosis of metastatic breast cancer in the future.

  18. Lactoferrin selectively triggers apoptosis in highly metastatic breast cancer cells through inhibition of plasmalemmal V-H+-ATPase

    PubMed Central

    Pereira, Cátia S.; Guedes, Joana P.; Gonçalves, Marília; Loureiro, Luís; Castro, Lisandra; Gerós, Hernâni; Rodrigues, Lígia R.; Côrte-Real, Manuela

    2016-01-01

    Breast cancer is the most common type of cancer affecting women. Despite the good prognosis when detected early, significant challenges remain in the treatment of metastatic breast cancer. The recruitment of the vacuolar H+-ATPase (V-H+-ATPase) to the plasma membrane, where it mediates the acidification of the tumor microenvironment (TME), is a recognized feature involved in the acquisition of a metastatic phenotype in breast cancer. Therefore, inhibitors of this pump have emerged as promising anticancer drugs. Lactoferrin (Lf) is a natural pro-apoptotic iron-binding glycoprotein with strong anticancer activity whose mechanism of action is not fully understood. Here, we show that bovine Lf (bLf) preferentially induces apoptosis in the highly metastatic breast cancer cell lines Hs 578T and MDA-MB-231, which display a prominent localisation of V-H+-ATPase at the plasma membrane, but not in the lowly metastatic T-47D or in the non-tumorigenic MCF-10-2A cell lines. We also demonstrate that bLf decreases the extracellular acidification rate and causes intracellular acidification in metastatic breast cancer cells and, much like the well-known proton pump inhibitors concanamycin A and bafilomycin A1, inhibits V-H+-ATPase in sub-cellular fractions. These data further support that bLf targets V-H+-ATPase and explain the selectivity of bLf for cancer cells, especially for highly metastatic breast cancer cells. Altogether, our results pave the way for more rational in vivo studies aiming to explore this natural non-toxic compound for metastatic breast cancer therapy. PMID:27556694

  19. Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

    PubMed

    Toss, Angela; Venturelli, Marta; Peterle, Chiara; Piacentini, Federico; Cascinu, Stefano; Cortesi, Laura

    2017-01-04

    In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.

  20. Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system.

    PubMed

    Wheeler, S E; Clark, A M; Taylor, D P; Young, C L; Pillai, V C; Stolz, D B; Venkataramanan, R; Lauffenburger, D; Griffith, L; Wells, A

    2014-12-09

    Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases. Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added. The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU(-) or Ki67(-)). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent. These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy.

  1. Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system

    PubMed Central

    Wheeler, S E; Clark, A M; Taylor, D P; Young, C L; Pillai, V C; Stolz, D B; Venkataramanan, R; Lauffenburger, D; Griffith, L; Wells, A

    2014-01-01

    Background: Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases. Methods: Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added. Results: The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU− or Ki67−). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent. Conclusions: These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy. PMID:25314052

  2. Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

    PubMed Central

    Toss, Angela; Venturelli, Marta; Peterle, Chiara; Piacentini, Federico; Cascinu, Stefano; Cortesi, Laura

    2017-01-01

    In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer. PMID:28054957

  3. Impact of molecular subtypes on metastatic breast cancer patients: a SEER population-based study

    PubMed Central

    Gong, Yue; Liu, Yi-Rong; Ji, Peng; Hu, Xin; Shao, Zhi-Ming

    2017-01-01

    To investigate the significance and impact of molecular subtyping stratification on metastatic breast cancer patients, we identified 159,344 female breast cancer patients in the Surveillance, Epidemiology and End Results (SEER) database with known hormone receptor (HoR) and human epidermal growth factor receptor 2 (HER2) status. 4.8% of patients were identified as having stage IV disease, and were more likely to be HER2+/HoR−, HER2+/HoR+, or HER2−/HoR−. Stage IV breast cancer patients with a HER2+/HoR+ status exhibited the highest median overall survival (OS) (44.0 months) and those with a HER2−/HoR− status exhibited the lowest median OS (13.0 months). Patients with a HER2−/HoR+ status had more bone metastasis, whereas patients with a HER2+/HoR− status had an increased incidence of liver metastasis. Brain and lung metastasis were more likely to occur in women with a HER2−/HoR− status. The multivariable analysis revealed a significant interaction between single metastasis and molecular subtype. No matter which molecular subtype, women who did not undergo primary tumour surgery had worse survival than those who experienced primary tumour surgery. Collectively, our findings advanced the understanding that molecular subtype might lead to more tailored and effective therapies in metastatic breast cancer patients. PMID:28345619

  4. Disease-related surgery in patients with distant metastatic breast cancer.

    PubMed

    Amann, E; Huang, D J; Weber, W P; Eppenberger-Castori, S; Schmid, S M; Hess, T H; Güth, U

    2013-11-01

    This study evaluates the frequency of and indications for disease-related surgical procedures in the palliative breast cancer (BC) situation. Based on a cohort of women who were treated for newly diagnosed BC during a 20-year period (1990-2009), we analyzed 340 patients who developed distant metastatic disease (DMD) until 2011 and died (i.e. still ongoing palliative disease courses were not included). One hundred and twenty-seven surgical procedures were performed in 100 patients (29.4% of all patients with metastatic disease). The most common site for surgery was breast (n = 60, 47.2%). The primary tumor was removed at first diagnosis of DMD in 43 patients (33.9%); sixteen operations (12.6%) were performed for local recurrence. In 37 patients, 50 surgical procedures (39.4%) were necessary to stabilize osseous structures due to metastases. Procedures were rarely performed on other common metastatic sites: lung: n = 1 (0.8%); liver: n = 1 (0.8%), brain: n = 4 (3.1%). When excluding surgery for primary breast tumors at initial diagnosis of DMD from analysis, 34 of 84 surgeries (40.4%) were performed in the first third of survival follow-up (i.e. period of metastatic disease survival); operations in the last two-thirds each totaled 29.8% (n = 25). The median survival after surgery was 16 months (range: 0.5-89 months). In a cohort of BC patients who had primary or developed secondary DMD, nearly one third of the patients received disease-related surgical procedures during their palliative disease course. This high rate of operations shows that surgery has a clearly established role in the palliative therapy concept. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor.

    PubMed

    Farhangi, Baharak; Alizadeh, Ali Mohammad; Khodayari, Hamid; Khodayari, Saeed; Dehghan, Mohammad Javad; Khori, Vahid; Heidarzadeh, Alemeh; Khaniki, Mahmood; Sadeghiezadeh, Majid; Najafi, Farhood

    2015-07-05

    Curcumin has been shown to inhibit migration and invasion of cancer angiogenesis via interacting with key regulatory molecules like NF-κB. Rapidly metabolized and conjugated in the liver, curcumin has the limited systemic bioavailability. Previous results have shown a new light of potential biocompatibility, biodegradability, as well as anti-cancer effects of dendrosomal curcumin (DNC) in biological systems. The present study aims to deliberate the protective effects of DNC on metastatic breast tumor in vitro and in vivo. After the dosing procedure, twenty-seven female mice were divided into 40 and 80mg/kg groups of DNC, along with a control group to investigate the anti-metastatic effects of DNC on mammary tumor-bearing mice. In vitro results showed that the different concentrations of DNC reduced the migration and the adhesion of 4T1 cells after 24h (P<0.05). Under the dosing procedure, DNC was safe at 80mg/kg and lower doses. The treated DNC animals had a higher survival rate and lower metastatic signs (14%) compared to control (100%) (P<0.05). The metastatic tumors were more common in control mice than the treated groups in the lung, the liver and the sternum tissues. Animals treated with DNC had smaller tumor volume in comparison with control group (P<0.05). Final mean tumor volume reached to approximately 1.11, 0.31 and 0.27cm(3) in the control, and 40 and 80mg/kg DNC groups, respectively (P<0.05). Furthermore, suppression of NF-κB expression by DNC led to down-regulation of VEGF, COX-2, and MMP-9 expressions in the breast tumor, the lung, the brain, the spleen and the liver tissues (P<0.05). These outcomes indicate that dendrosomal curcumin has a chemoprotective effect on the breast cancer metastasis through suppression of NF-κB and its regulated gene products.

  6. Lack of correlation between histologic findings and response to chemotherapy in metastatic breast cancer.

    PubMed

    Ziegler, L D; Connelly, J H; Frye, D; Smith, T L; Hortobagyi, G N

    1991-08-01

    A retrospective analysis was undertaken to assess the prognostic role of histologic findings in response to chemotherapy and survival in patients with metastatic breast cancer. Histologic material was available for 395 of 1587 patients treated for metastatic breast cancer at the M.D. Anderson Cancer Center between 1973 and 1984. Chemotherapy consisted of 5-fluorouracil, doxorubicin, and cyclophosphamide or similar drugs, with or without tamoxifen. Maintenance cyclophosphamide, methotrexate, and 5-fluorouracil was continued for 2 years after a cumulative doxorubicin dose of 450 mg/m2 was administered. The histologic distribution was as follows: infiltrating ductal carcinoma, 353; invasive lobular, 14; mixed histology, ten; mucinous, seven; signet ring, four; tubular, three; papillary, two; sarcomatoid, one; and apocrine, one. Because individual histologic types occurred infrequently, the patients were divided into infiltrating ductal and nonductal groups. Baseline patient characteristics included age, performance status, estrogen-receptor status, prior hormone response, disease extent, and levels of alkaline phosphatase, bilirubin, and lactate dehydrogenase. These were similar in the two groups. Significantly more patients with nonductal histology had greater than three metastatic sites. There were also more patients with hemoglobin less than 10 mg/dl and albumin less than 3.5 mg/dl in the nonductal group of patients. However, statistically these factors did not have an impact on the results. There was a 63% response rate (17% complete and 46% partial) for the ductal group and a 60% response rate (12% complete and 48% partial) for the nonductal group. The time from initiation of chemotherapy to disease progression was identical (12 months) for the two groups. Survival from initiation of chemotherapy was not significantly different (22 months for ductal and 27 months for nonductal). Based on this study, the authors conclude that histologic findings have no bearing on

  7. The role of a community palliative care specialist nurse team in caring for people with metastatic breast cancer.

    PubMed

    Leadbeater, Maria

    2013-02-01

    An audit was undertaken of people with a diagnosis of breast cancer who were referred to a community palliative care specialist nursing team over a 12-month period, to explore the reasons for referral to the service and the duration of involvement with the service. Breast cancer patients accounted for 10% of the total referrals to the specialist service, with symptom management (including pain control) and emotional support being the main reasons for referral. The majority of people referred with breast cancer had metastatic breast cancer (87%); interestingly, 13% had primary breast cancer. The mean duration of intervention was 3 months and 1 week. Referrals seemed to occur late in patients' disease trajectories, and total numbers were lower than might be expected. It may be concluded that there is scope for the specialist palliative care team to be a more integral part of care for patients with metastatic breast cancer.

  8. Capecitabine: indications and future perspectives in the treatment of metastatic colorectal and breast cancer.

    PubMed

    Cassata, A; Procoplo, G; Alù, M; Ferrari, L; Ferrario, E; Beretta, E; Longarini, R; Busto, G; De Candis, D; Bajetta, E

    2001-01-01

    Fluoropyrimidines remain the most important drugs in the treatment of breast and colorectal carcinoma, but response rates and survival time have been disappointing. Optimal administration is by continuous intravenous infusion, which makes it cumbersome to use and compromises patient independence. Recently, a number of new agents, including fluorouracil prodrugs and selective dihydropyrimidine dehydrogenase inhibitors, have been studied, with promising results. Capecitabine is the first in a new class of fluoropyrimidines. It is an oral, tumor-activated anticancer drug whose activity mimics that of continuously infused 5-fluorouracil. Capecitabine circumvents dihydropyrimidine dehydrogenase catabolism and appears to be at least as active against metastatic colorectal and breast cancer as conventionally administered intravenous 5-fluorouracil, with significantly less toxicity, an improved quality of life, and lesser cost. Capecitabine may ultimately provide enhanced antitumor activity to fluorouracil-containing regimes for advanced colorectal and breast cancer.

  9. Ductal Breast Carcinoma Metastatic to the Stomach Resembling Primary Linitis Plastica in a Male Patient

    PubMed Central

    Leonardi, Giulia Costanza; Ravaioli, Noemi; De Giglio, Andrea; Brambilla, Marta; Prosperi, Enrico; Ribacchi, Franca; Meacci, Marialuisa; Crinò, Lucio; Maiettini, Daniele; Chiari, Rita; Metro, Giulio

    2016-01-01

    Breast cancer metastases to the gastrointestinal tract are very rare occurrences. Among the histological subtypes of breast cancer, invasive lobular carcinomas have a high capacity of metastasis to uncommon sites including the stomach. Conversely, there has not been sufficient evidence supporting the gastric metastasis of invasive ductal carcinoma. Herein, we report a unique case of metastatic ductal breast carcinoma mimicking primary linitis plastica in a male patient, particularly focusing on the clinical and pathological features of presentation. Moreover, we propose a immunohistochemical panel of selected antibodies including those for cytokeratin 20, cytokeratin 7, estrogen receptor, progesterone receptor, E-cadherin, gross cystic disease fluid protein 15, and GATA binding protein 3 for an accurate differential diagnosis. PMID:27721883

  10. Anorectal melanoma metastatic to the breast: a case report and review of the literature

    PubMed Central

    Feng, Liang; Qi, Dian-Jun; Zhang, Qing-Fu

    2016-01-01

    Melanoma develops from melanocytes and typically occurs on the skin and mucosa with a high degree of malignancy. Intensive local invasion and distant metastasis of melanoma result in poor patient prognosis, owing to frequent metastases to the lungs, bones, brains, and other parts of the body. In the present study, we report a case of anorectal melanoma in a 56-year-old woman who was admitted to our hospital because of local recurrence 9 months after local resection. She subsequently underwent radical surgery. Metastasis to the left breast occurred within 4 months after radical surgery. Metastasis of anorectal melanoma to the breast is very rare. In the present case report and literature review, we analyzed the clinical manifestation, diagnosis, and treatment of anorectal melanoma metastatic to the breast. PMID:27563250

  11. Bone Factors Regulating the Osteotropism of Metastatic Breast Cancer

    DTIC Science & Technology

    1999-10-01

    osteosarcoma cell line (positive control) using antibody to CBFA1. CBFA1 was detected in all of these cell lines except the normal breast line HMEC...density in the M1 clone (Lane 9). The MG-63 human osteosarcoma cells (Lane 7) expressed the 60-65 kDa form as well as a prominent 46 kDa form that was...extracts. HMEC extracts failed to show CBFA1 activity. MG-63 osteosarcoma served as a positive control for CBFA1, and the EMSA assays showed the

  12. Metastatic Breast Cancer in Medication-Related Osteonecrosis Around Mandibular Implants

    PubMed Central

    Favia, Gianfranco; Tempesta, Angela; Limongelli, Luisa; Crincoli, Vito; Piattelli, Adriano; Maiorano, Eugenio

    2015-01-01

    Patient: Female, 66 Final Diagnosis: Breast cancer metastasis in medication-related osteonecrosis of the jaw Symptoms: — Medication: — Clinical Procedure: Clinical and radiological examination • surgical treatment Specialty: Dentistry Objective: Rare co-existance of disease or pathology Background: Many authors have considered dental implants to be unrelated to increased risk of medication-related osteonecrosis of the jaw (MRONJ). Nevertheless, more recently, more cases of peri-implant MRONJ (PI-MRONJ) have been described, thus becoming a challenging health problem. Also, metastatic cancer deposits are not infrequently found at peri-implant sites and this may represent an additional complication for such treatments. We present the case of a breast cancer patient with PI-MRONJ, presenting a clinically and radiologically undetected metastasis within the necrotic bone, and highlight the necessity of an accurate histopathological analysis. Case Report: A 66-year-old female patient, who had received intravenous bisphosphonates for bone breast cancer metastases, came to our attention for a non-implant surgery-triggered PI-MRONJ. After surgical resection of the necrotic bone, conventional and immunohistochemical examinations were performed, which showed breast cancer deposits within the necrotic bone. Conclusions: Cancer patients with metastatic disease, who are undergoing bisphosphonate treatment, may develop unusual complications, including MRONJ, which is a site at risk for hosting additional metastatic deposits that may be clinically and radiologically overlooked. Such risk is increased by previous or concomitant implant procedures. Consequently, clinicians should be prudent when performing implant surgery in cancer patients with advanced-stage disease and consider the possible occurrence of peri-implant metastases while planning adequate treatments in such patients. PMID:26371774

  13. The Glasgow Prognostic Score Predicts Response to Chemotherapy in Patients with Metastatic Breast Cancer.

    PubMed

    Wang, Dexing; Duan, Li; Tu, Zhiquan; Yan, Fei; Zhang, Cuicui; Li, Xu; Cao, Yuzhu; Wen, Hongsheng

    2016-01-01

    Breast cancer is one of the most common causes of cancer death in women worldwide. The Glasgow Prognostic Score (GPS), a cumulative prognostic score based on C-reactive protein and albumin, indicates the presence of a systemic inflammatory response. The GPS has been adopted as a powerful prognostic tool for patients with various types of malignant tumors, including breast cancer. The aim of this study was to assess the value of the GPS in predicting the response and toxicity in breast cancer patients treated with chemotherapy. Patients with metastatic breast cancers in a progressive stage for consideration of chemotherapy were eligible. The clinical characteristics and demographics were recorded. The GPS was calculated before the onset of chemotherapy. Data on the response to chemotherapy and progression-free survival (PFS) were also collected. Objective tumor responses were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Toxicities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC) version 3.0 throughout therapy. In total, 106 breast cancer patients were recruited. The GPS was associated with the response rate (p = 0.05), the clinical benefit rate (p = 0.03), and PFS (p = 0.005). The GPS was the only independent predictor of PFS (p = 0.005). The GPS was significantly associated with neutropenia, thrombocytopenia, anorexia, nausea and vomiting, fatigue, and mucositis (p = 0.05-0.001). Our data demonstrate that GPS assessment is associated with poor clinical outcomes and severe chemotherapy-related toxicities in patients with metastatic breast cancer who have undergone chemotherapy, without any specific indication regarding the type of chemotherapy applied. © 2016 S. Karger AG, Basel.

  14. Treatment of HER2-positive breast cancer.

    PubMed

    Figueroa-Magalhães, Maria Cristina; Jelovac, Danijela; Connolly, Roisin M; Wolff, Antonio C

    2014-04-01

    The human epidermal growth factor receptor 2 gene (HER2) is overexpressed and/or amplified in ~15% of breast cancer patients and was identified a quarter century ago as a marker of poor prognosis. By 1998, antibody therapy targeting the HER2 pathway was shown to demonstrably improve progression-free and overall survival in metastatic disease, and in 2005 evidence of improvement in disease-free and overall survival from the first generation of trastuzumab adjuvant trials became available. However, not all patients with HER2 overexpression benefit from trastuzumab. Second-generation studies in metastatic disease led to the approval of several new HER2-targeted therapies using small molecule tyrosine kinase inhibitors such as lapatinib, new HER2/HER3 antibodies such as pertuzumab, and the new antibody chemotherapy conjugate ado-trastuzumab emtansine. These successes supported the launch of second-generation adjuvant trials testing single and dual HER2-targeted agents, administered concomitantly or sequentially with chemotherapy that will soon complete accrual. HER2-positive breast cancer in the setting of HER2-targeted therapy is no longer associated with poor prognosis, and recent guidance by the US Food and Drug Administration suggests that pathologic response to HER2-targeted therapy given preoperatively may allow an earlier assessment of their clinical benefit in the adjuvant setting. An adjuvant trial of trastuzumab in patient whose tumors express normal levels of HER2 and trials of single/dual HER2-targeting without chemotherapy are also ongoing. In this article, we review the current data on the therapeutic management of HER2-positive breast cancer.

  15. Fluid Biopsy in Patients with Metastatic Prostate, Pancreatic and Breast Cancers

    PubMed Central

    Marrinucci, Dena; Bethel, Kelly; Kolatkar, Anand; Luttgen, Madelyn; Malchiodi, Michael; Baehring, Franziska; Voigt, Katharina; Lazar, Daniel; Nieva, Jorge; Bazhenova, Lyudmilda; Ko, Andrew H; Korn, W. Michael; Schram, Ethan; Coward, Michael; Yang, Xing; Metzner, Thomas; Lamy, Rachelle; Honnatti, Meghana; Yoshioka, Craig; Kunken, Joshua; Petrova, Yelena; Sok, Devin; Nelson, David; Kuhn, Peter

    2012-01-01

    Hematologic spread of carcinoma results in incurable metastasis; yet, the basic characteristics and travel mechanisms of cancer cells in the bloodstream are unknown. We have established a fluid phase biopsy approach that identifies circulating tumor cells (CTCs) without using surface protein-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. This “HD-CTC” assay finds >5 HD-CTCs/mL of blood in 80% of patients with metastatic prostate cancer (n=20), in 70% of patients with metastatic breast cancer (n=30), in 50% of patients with metastatic pancreatic cancer (n=18), and in 0% of normal controls (n=15). Additionally, it finds HD-CTC clusters ranging from 2 HDCTCs to greater than 30 HD-CTCs in the majority of these cancer patients. This initial validation of an enrichment-free assay demonstrates our ability to identify significant numbers of HD-CTCs in a majority of patients with prostate, breast and pancreatic cancers. PMID:22306768

  16. Systemic taxotere chemotherapy for metastatic tumor pleurisy in cats with spontaneous breast cancer.

    PubMed

    Yakunina, M N; Treshalina, E M

    2011-03-01

    Systemic and intrapleural chemotherapy for metastatic tumor pleurisy was carried out in cats with breast carcinoma. The animals (n=18) were divided into 2 groups. Cats of the systemic chemotherapy group received 3-6 courses of taxotere (30 mg/m(2); n=7) or 3 courses of taxotere (20 mg/m(2)) in combination with doxorubicin (20 mg/m(2)at 21-day intervals (n=5) during the adjuvant period of therapy for metastatic tumor pleurisy. Objective effect was attained in 10 (84.6%) cats: partial remission in 3 (25%) and complete remission in 7 (58.3%, p>0.05) cats. Metastatic pleurisy progressed in 2 (16.7%) cats. The median time to progression reached 1.79 months, median lifespan 2.8 months. The animals of intrapleural chemotherapy group (n=6) received 1-4 courses of cyclophosphamide (250 mg/m(2)) at 1-week interval during the adjuvant period without therapy for malignant pleurisy. Malignant pleurisy progressed in all cats. The median time to progression was equal to median lifespan (0.6 months). The therapy for malignant pleurisy in cats with breast cancer is regarded as the second-line chemotherapy with taxotere preferable as a monotherapy or in combination with doxorubicin.

  17. Horner's syndrome: An unusual presentation of metastatic disease in breast cancer.

    PubMed

    Vitale, Maria Giuseppa; Riccardi, Ferdinando; Carrillo, Giovanna; Trunfio, Martino; Mocerino, Carmela; Minelli, Salvatore; Barbato, Carmela; Ambrosio, Francesca; Cartenì, Giacomo

    2015-12-01

    Horner's syndrome (HS) is caused by an interruption of the cervical sympathetic pathway to the eye and the face. Acquired HS is mainly caused by benign or malignant neoplasms, and in patients with a history of cancer, it is almost always the result of tumor infiltration into the periphery or the central region of the cervical sympathetic chain.We present the case of a 52-year-old patient with long-term disease-free survival (6 years) after a radical mastectomy for breast cancer who presented with cervicobrachialgia and typical HS due to a left lateral-cervical and supraclavicular lymph nodal mass. Treatment of the metastatic disease with taxanes and concurrent trastuzumab resulted in a complete pain resolution, as well as long-term clinical and radiologic remission; however, the neurological cohort of HS remained as the expression of permanent damage to the sympathetic pathway.This report presents a highly rare case of HS as the first and solitary appearance of metastatic disease in a breast cancer patient. This neurologic involvement should always raise suspicion of metastatic infiltration, and the early recognition of the syndrome may prevent permanent nerve injury.

  18. Clinical roundtable monograph: effective management of quality of life in metastatic breast cancer.

    PubMed

    Christopher, Twelves; Gradishar, William J; O'Shaughnessy, Joyce A; Bramsen, Betsy; Lurie, Robert H

    2014-02-01

    Quality of life is accepted as an important consideration in the management of patients with metastatic breast cancer, which remains incurable. Recent clinical trials of newer agents, such as eribulin and trastuzumab emtansine, have incorporated quality of life analyses. Quality of life is impacted by multiple patient-related, disease-related, and treatment-related factors. Therapies most beneficial for maintaining or improving quality of life include those that can effectively reduce tumor burden and tumor-related symptoms, but have toxicity profiles that are well tolerated and easily managed. Overall outcomes of patients with metastatic breast cancer improve when therapy is focused not only on the disease itself, but also on the goals of minimizing diseaserelated and treatment-related symptoms. A paradigm shift now reflected in major guidelines is the incorporation of palliative care strategies earlier in the course of metastatic disease management. The selection and sequence of treatments should be made in cooperation with the patient and after consideration of her particular priorities.

  19. Additive enhancement of apoptosis by TRAIL and fenretinide in metastatic breast cancer cells in vitro.

    PubMed

    Ulukaya, Engin; Sarimahmut, Mehmet; Cevatemre, Buse; Ari, Ferda; Yerlikaya, Azmi; Dimas, Konstantinos

    2014-05-01

    Successful management of metastatic breast cancer still needs better chemotherapeutic approaches. The combination of fenretinide (4-HPR), a synthetic retinoid inducing apoptosis by ROS generation, and TRAIL, a cell death ligand inducing caspase-dependent apoptosis, might result in more powerful cytotoxic activity. We therefore investigated the cytotoxic activity and resulting cell death mode of this combination in MDA-MB-231 cell line as a representative of metastatic state. Cytotoxicity was assessed by the ATP viability assay while the mode of cell death was determined both morphologically using fluorescence microscopy and biochemically using Western blotting and ELISA. The combination resulted in an additive cytotoxic effect at the doses used. Fragmented and/or pyknotic nuclei, which is a feature of apoptosis, were observed after treatment with fenretinide or TRAIL. However, the combinatorial treatment further increased apoptotic figures. Confirming apoptosis, active caspase-3 and cleaved PARP were increased by fenretinide or TRAIL in both western blotting and ELISA. Again, apoptosis was further increased by the combination. The combination warrants further studies due to its superior cytotoxic activity in the metastatic setting of breast cancer. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. [Pertuzumab (Perjeta®) approval in HER2-positive metastatic breast cancers].

    PubMed

    Sabatier, Renaud; Gonçalves, Anthony

    2014-01-01

    Fifteen to 20% of breast cancers display HER2 amplification. Many therapeutic successes have been obtained for this subtype in the last decade since trastuzumab approval for metastatic and localized diseases. Pertuzumab, a new anti-HER2 antibody, has been approved in 2013 by the European Medicine Agency. This drug can be used in combination with trastuzumab and docetaxel for the first line treatment of metastatic or locally recurrent non resecable HER2-positive breast cancers not previously treated by chemotherapy or HER2-inhibitors in the metastatic setting. This approval has been done after the CLEOPATRA trial results. This was a randomized, double-blind, multicentre, phase III trial evaluating the standard treatment (trastuzumab plus docetaxel) associated to pertuzumab or placebo. The authors have reported a statistically significant and clinically relevant benefit for the pertuzumab-based treatment. Median progression-free survival was 18.4 for the pertuzumab arm versus 12.5 months for the control group (p<0.001). They also observed benefits concerning the secondary endpoints: overall response rate and overall survival. Patients receiving pertuzumab presented more frequent diarrhea and febrile neutropenia but no increase in cardiac events. This drug has already been evaluated in the neoadjuvant setting with a FDA approval recently obtained. Its use in the adjuvant setting is under evaluation.

  1. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers

    NASA Astrophysics Data System (ADS)

    Marrinucci, Dena; Bethel, Kelly; Kolatkar, Anand; Luttgen, Madelyn S.; Malchiodi, Michael; Baehring, Franziska; Voigt, Katharina; Lazar, Daniel; Nieva, Jorge; Bazhenova, Lyudmila; Ko, Andrew H.; Korn, W. Michael; Schram, Ethan; Coward, Michael; Yang, Xing; Metzner, Thomas; Lamy, Rachelle; Honnatti, Meghana; Yoshioka, Craig; Kunken, Joshua; Petrova, Yelena; Sok, Devin; Nelson, David; Kuhn, Peter

    2012-02-01

    Hematologic spread of carcinoma results in incurable metastasis; yet, the basic characteristics and travel mechanisms of cancer cells in the bloodstream are unknown. We have established a fluid phase biopsy approach that identifies circulating tumor cells (CTCs) without using surface protein-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. This 'HD-CTC' assay finds >5 HD-CTCs mL-1 of blood in 80% of patients with metastatic prostate cancer (n = 20), in 70% of patients with metastatic breast cancer (n = 30), in 50% of patients with metastatic pancreatic cancer (n = 18), and in 0% of normal controls (n = 15). Additionally, it finds HD-CTC clusters ranging from 2 HD-CTCs to greater than 30 HD-CTCs in the majority of these cancer patients. This initial validation of an enrichment-free assay demonstrates our ability to identify significant numbers of HD-CTCs in a majority of patients with prostate, breast and pancreatic cancers.

  2. Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer.

    PubMed

    Irelli, Azzurra; Cocciolone, Valentina; Cannita, Katia; Zugaro, Luigi; Di Staso, Mario; Lanfiuti Baldi, Paola; Paradisi, Stefania; Sidoni, Tina; Ricevuto, Enrico; Ficorella, Corrado

    2016-06-01

    Cancer cells can alter physiological mechanisms within bone resulting in high bone turnover, and consequently in skeletal-related events (SREs), causing severe morbidity in affected patients. The goals of bone targeted therapy, as bisphosphonates and denosumab, are the reduction of incidence and the delay in occurrence of the SREs, to improve quality of life and pain control. The toxicity profile is similar between bisphosphonates and denosumab, even if pyrexia, bone pain, arthralgia, renal failure and hypercalcemia are more common with bisphosphonates, while hypocalcemia and toothache are more frequently reported with denosumab. Osteonecrosis of the jaw (ONJ) occurred infrequently without statistically significant difference. The present review aims to provide an assessment on bone targeted therapies for preventing the occurrence of SREs in bone metastatic breast cancer patients, critically analyzing the evidence available so far on their effectiveness, in light of the different mechanisms of action. Thus, we try to provide tools for the most fitting treatment of bone metastatic breast cancer patients. We also provide an overview on the usefulness of bone turnover markers in clinical practice and new molecules currently under study for the treatment of bone metastatic disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Vinorelbine with or without Trastuzumab in Metastatic Breast Cancer: A Retrospective Single Institution Series

    PubMed Central

    Stravodimou, Athina; Zaman, Khalil; Voutsadakis, Ioannis A.

    2014-01-01

    Background. We report our experience with vinorelbine, a widely used chemotherapeutic, in unselected metastatic breast cancer patients treated in clinical routine. Patients and Methods. The data of all patients with metastatic breast cancer receiving vinorelbine with or without trastuzumab during a six year period were reviewed. Patients received vinorelbine intravenous 25–30 mg/m2 or 60–80 mg/m2 orally in days 1 and 8 of a 21 day cycle. Results. Eighty-seven women were included. Sixty-two patients received vinorelbine alone and 25 patients received vinorelbine in combination with trastuzumab. In 67 patients this was the first line treatment for metastatic disease and in 20 patients it was 2nd or later line of treatment. The median TTP was six months (range: 1–45). The median overall survival was 11.5 months (range: 1–83). Seventy patients were evaluable for response. In patients receiving first line treatment 44.4% had a response while in the second and subsequent lines setting 12.5% of patients responded (P = 0.001). Objective response was obtained in 63.6% of patients receiving concomitant trastuzumab and in 25% of patients receiving vinorelbine alone (P = 0.0002). Conclusion. This study confirms a high disease control rate. Response rate and TTP were superior in first line treatment compared to subsequent lines. PMID:25006504

  4. Concerns about Breast Cancer, Pain, and Fatigue in Non-Metastatic Breast Cancer Patients Undergoing Primary Treatment

    PubMed Central

    Amiel, Chelsea R.; Fisher, Hannah M.; Antoni, Michael H.

    2016-01-01

    Women diagnosed with breast cancer often endorse psychosocial concerns prior to treatment, which may influence symptom experiences. Among these, low perceived social support relates to elevated fatigue. Those with low social support perceptions may also experience a greater sense of rejection. We sought to determine if social rejection concerns post-surgery predict fatigue interference 12 months later in women with non-metastatic breast cancer. Depressive symptoms and pain severity after completion of adjuvant therapy (six months post-surgery) were examined as potential mediators. Women (N = 240) with non-metastatic breast cancer were recruited 2–10 weeks post-surgery. Multiple regression analyses examined relationships among variables adjusting for relevant covariates. Greater rejection concerns at study entry predicted greater fatigue interference 12 months later (p < 0.01). Pain severity after adjuvant therapy partially mediated the relationship between social rejection concerns and fatigue interference, with significant indirect (β = 0.06, 95% CI (0.009, 0.176)) and direct effects (β = 0.18, SE = 0.07, t(146) = 2.78, p < 0.01, 95% CI (0.053, 0.311)). Therefore, pain levels post-treatment may affect how concerns of social rejection relate to subsequent fatigue interference. Interventions targeting fears of social rejection and interpersonal skills early in treatment may reduce physical symptom burden during treatment and into survivorship. PMID:27571115

  5. Does hormonal therapy have a therapeutic role in metastatic primary small cell neuroendocrine breast carcinoma? Case report and literature review.

    PubMed

    Alkaied, Homam; Harris, Kassem; Brenner, Arnold; Awasum, Michael; Varma, Seema

    2012-06-01

    Primary neuroendocrine carcinoma of breast (NECB) is a very rare tumor; the World Health Organization(WHO) subcategorized these tumors into 3 major histologic subtypes: solid, small cell carcinoma (SMCC), and large cell NE carcinoma. The SMCC subtype is the least common and most aggressive and has been reported to be as aggressive as its pulmonary counterpart. SMCC is usually confirmed based on clinical, pathologic,and imaging studies. Local disease is usually managed in a fashion similar to that of the usual ductal breast cancer; in the metastatic SMCC setting, regimens that are implemented in small cell lung cancer are usually attempted, according to case reports and published small case series. Hormone receptors can be expressed in more than 90% of the solid tumor subtype; however its expression is manifested in about 50% of cases of SMCC. Although hormonal therapy can be used successfully to treat the usual metastatic ductal breast cancer,its utility in metastatic SMCC has not been reported. We report an impressive response to hormonal therapy in a patient with late relapse of breast carcinoma with a metastatic SMCC subtype that expressed hormone receptors. The response to hormonal therapy was sustained for about 12 months. The response to hormonal therapy is definitely an interesting finding that, to our knowledge, has not been described before in the setting of metastatic SMCC. We suggest considering adding hormonal therapy to the treatment pipeline for primary SMCC of the breast that express hormone receptors.

  6. Trends in presentation, management and survival of patients with de novo metastatic breast cancer in a Southeast Asian setting.

    PubMed

    Bhoo-Pathy, Nirmala; Verkooijen, Helena Marieke; Tan, Ern-Yu; Miao, Hui; Taib, Nur Aishah Mohd; Brand, Judith S; Dent, Rebecca A; See, Mee-Hoong; Subramaniam, ShriDevi; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har

    2015-11-05

    Up to 25% of breast cancer patients in Asia present with de novo metastatic disease. We examined the survival trends of Asian patients with metastatic breast cancer over fifteen years. The impact of changes in patient's demography, tumor characteristics, tumor burden, and treatment on survival trend were examined. Patients with de novo metastatic breast cancer from three hospitals in Malaysia and Singapore (N = 856) were grouped by year of diagnosis: 1996-2000, 2001-2005 and 2006-2010. Step-wise multivariable Poisson regression was used to estimate the contribution of above-mentioned factors on the survival trend. Proportions of patients presenting with metastatic breast cancer were 10% in 1996-2000, 7% in 2001-2005, and 9% in 2006-2010. Patients in 2006-2010 were significantly older, appeared to have higher disease burden, and received more chemotherapy, endocrine therapy, and surgery of primary tumor. The three-year relative survival in the above periods were 20·6% (95% CI: 13·9%-28·2%), 28·8% (95% CI: 23·4%-34·2%), and 33·6% (95% CI: 28·8%-38·5%), respectively. Adjustment for treatment considerably attenuated the relative excess risk of mortality in recent years, compared to other factors. Substantial improvements in survival were observed in patients with de novo metastatic breast cancer in this study.

  7. Trends in presentation, management and survival of patients with de novo metastatic breast cancer in a Southeast Asian setting

    PubMed Central

    Bhoo-Pathy, Nirmala; Verkooijen, Helena Marieke; Tan, Ern-Yu; Miao, Hui; Taib, Nur Aishah Mohd; Brand, Judith S.; Dent, Rebecca A.; See, Mee-Hoong; Subramaniam, ShriDevi; Chan, Patrick; Lee, Soo-Chin; Hartman, Mikael; Yip, Cheng-Har

    2015-01-01

    Up to 25% of breast cancer patients in Asia present with de novo metastatic disease. We examined the survival trends of Asian patients with metastatic breast cancer over fifteen years. The impact of changes in patient’s demography, tumor characteristics, tumor burden, and treatment on survival trend were examined. Patients with de novo metastatic breast cancer from three hospitals in Malaysia and Singapore (N = 856) were grouped by year of diagnosis: 1996–2000, 2001–2005 and 2006–2010. Step-wise multivariable Poisson regression was used to estimate the contribution of above-mentioned factors on the survival trend. Proportions of patients presenting with metastatic breast cancer were 10% in 1996–2000, 7% in 2001–2005, and 9% in 2006–2010. Patients in 2006–2010 were significantly older, appeared to have higher disease burden, and received more chemotherapy, endocrine therapy, and surgery of primary tumor. The three-year relative survival in the above periods were 20·6% (95% CI: 13·9%–28·2%), 28·8% (95% CI: 23·4%–34·2%), and 33·6% (95% CI: 28·8%–38·5%), respectively. Adjustment for treatment considerably attenuated the relative excess risk of mortality in recent years, compared to other factors. Substantial improvements in survival were observed in patients with de novo metastatic breast cancer in this study. PMID:26536962

  8. H2Mab-77 is a Sensitive and Specific Anti-HER2 Monoclonal Antibody Against Breast Cancer.

    PubMed

    Itai, Shunsuke; Fujii, Yuki; Kaneko, Mika K; Yamada, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Saidoh, Noriko; Chang, Yao-Wen; Handa, Saori; Takahashi, Maki; Suzuki, Hiroyoshi; Harada, Hiroyuki; Kato, Yukinari

    2017-08-01

    Human epidermal growth factor receptor 2 (HER2) plays a critical role in the progression of breast cancers, and HER2 overexpression is associated with poor clinical outcomes. Trastuzumab is an anti-HER2 humanized antibody that leads to significant survival benefits in patients with HER2-positive metastatic breast cancers. In this study, we developed novel anti-HER2 monoclonal antibodies (mAbs) and characterized their efficacy in flow cytometry, Western blot, and immunohistochemical analyses. Initially, we expressed the full length or ectodomain of HER2 in LN229 glioblastoma cells and then immunized mice with ectodomain of HER2 or LN229/HER2, and performed the first screening by enzyme-linked immunosorbent assays using ectodomain of HER2. Subsequently, we selected mAbs according to their efficacy in flow cytometry (second screening), Western blot (third screening), and immunohistochemical analyses (fourth screening). Among 100 mAb clones, only three mAbs reacted with HER2 in Western blot, and clone H2Mab-77 (IgG1, kappa) was selected. Finally, immunohistochemical analyses with H2Mab-77 showed sensitive and specific reactions against breast cancer cells, warranting the use of H2Mab-77 to detect HER2 in pathological analyses of breast cancers.

  9. Evaluating the role of nab-paclitaxel (Abraxane) in women with aggressive metastatic breast cancer.

    PubMed

    Ciruelos, Eva; Jackisch, Christian

    2014-05-01

    Nab-paclitaxel (Abraxane(®)) is an albumin-bound form of paclitaxel that utilizes the natural properties of albumin to improve paclitaxel delivery to the tumor. It is licensed for use in metastatic breast cancer (MBC) at a dose of 260 mg/m(2) Q3W based on its superior therapeutic index versus conventional paclitaxel 175 mg/m(2) Q3W demonstrated in a Phase III study. In a post-hoc analysis, nab-paclitaxel treatment was associated with rapid and dramatic tumor responses in patients with poor prognostic factors (visceral dominant disease, ≥3 metastatic lesions), suggesting it may be a preferred treatment for these patients. Moreover, significant efficacy has been seen with nab-paclitaxel 100 and 150 mg/m(2) QW 3/4, suggesting it may be possible to tailor use of this agent in the future.

  10. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites.

    PubMed

    Gao, Hua; Chakraborty, Goutam; Lee-Lim, Ai Ping; Mo, Qianxing; Decker, Markus; Vonica, Alin; Shen, Ronglai; Brogi, Edi; Brivanlou, Ali H; Giancotti, Filippo G

    2012-08-17

    The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation.

  11. Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer.

    PubMed

    Mishra, Ameet K; Parish, Christopher R; Wong, Ma-Li; Licinio, Julio; Blackburn, Anneke C

    2017-01-01

    Epidemiological studies have shown obesity to be linked with poorer outcomes in breast cancer patients. The molecular mechanisms responsible for the increased risk of invasive/metastatic disease with obesity are complex, but may include elevated levels of adipokines such as leptin. Using physiological levels of leptin found in obesity in a novel chronic in vitro treatment model (≤200 ng/ml for 14 days), we confirmed the occurrence of leptin-mediated changes in growth, apoptosis and metastatic behavior, and gene expression changes representing epithelial-to-mesenchymal transition (EMT) and a cancer stem cell (CSC) like phenotype in breast epithelial and cancer cell lines (MCF10A, MCF10AT1, MCF7 and MDA-MB-231). Further, we have discovered that these effects were accompanied by increased expression of TGFB1, and could be significantly reduced by co-treatment with neutralizing antibody against TGFB1, indicating that the induction of these characteristics was mediated via TGFB1. Occurring in both MCF7 and MCF10AT1 cells, it suggests these actions of leptin to be independent of estrogen receptor status. By linking leptin signalling to the established TGFB1 pathway of metastasis / EMT, this study gives a direct mechanism by which leptin can contribute to the poorer outcomes of obese cancer patients. Inhibitors of TGFB1 are in currently in phase III clinical trials in other malignancies, thus identifying the connection between leptin and TGFB1 will open new therapeutic opportunities for improving outcomes for obese breast cancer patients.

  12. The Management of Early Stage and Metastatic Triple Negative Breast Cancer: A Review

    PubMed Central

    Anders, Carey K.; Zagar, Timothy M.; Carey, Lisa A.

    2013-01-01

    Triple negative breast cancer (TNBC) defined as lacking expression of the estrogen receptor, progesterone receptor and HER2, comprises approximately 15% of incident breast cancers and is over-represented among those with metastatic disease. It is increasingly clear that TNBC is heterogeneous and that there are several biologically distinct subtypes within TNBC, in particular the basal-like subtype but also the claudin-low, among others. While the incidence of BRCA mutations across all subsets of breast cancer is quite low (~5%), BRCA mutations are more common among those with TNBC (~20%) and may have therapeutic implications. The general principles guiding the use of chemotherapy and radiation therapy do not differ dramatically between early stage TNBC and non-TNBC. There is a trend, however, to treat TNBC at a lower stage with chemotherapy as this is the only way to systemically reduce recurrence risk. In the metastatic setting, while cytotoxic chemotherapy is the mainstay of treatment for advanced TNBC, there are many promising targeted therapies in development in both the preclinical and early phase clinical trial settings. While the treatment of TNBC remains a challenge, coordinated efforts between clinician/scientist partnerships providing a comprehensive understanding of TNBC genomic, proteomic and other biologic processes may result in individualized therapy for TNBC faster than other subtypes -- driven by both the heterogeneity we know exists within this clinical entity and the intense need for improved treatment. PMID:23915742

  13. Drug withdrawal in women with progressive metastatic breast cancer while on aromatase inhibitor therapy.

    PubMed

    Chavarri-Guerra, Y; Higgins, M J; Szymonifka, J; Cigler, T; Liedke, P; Partridge, A; Ligibel, J; Come, S E; Finkelstein, D; Ryan, P D; Goss, P E

    2014-11-25

    Acquiring resistance to endocrine therapy is common in metastatic hormone-receptor-positive breast cancer (MBC). These patients most often transition either to next-line endocrine therapy or to systemic chemotherapy. However, withdrawal of endocrine therapy and observation as is selectively practiced in prostate cancer is another potential strategy for breast cancer patients. A prospective, single-arm phase II trial of aromatase inhibitor (AI) withdrawal was performed in women with MBC, who had disease progression on AI therapy. The primary objective was to estimate the clinical benefit rate (defined as complete or partial response, or stable disease for at least 24 weeks, by RECIST criteria). Participants were monitored clinically and radiographically off all therapy at 8, 16 and 24 weeks after treatment and every 12 weeks thereafter until disease progression. Twenty-four patients (of 40 intended) were enrolled when the study was closed due to slow accrual. Clinical benefit rate overall was 46% (95% CI 26% to 67%). Median progression-free survival from time of AI withdrawal was 4 months. Two patients have remained progression free, off all treatment, for over 60 months. Despite suboptimal patient accrual, our results suggest that selected patients with metastatic breast cancer progressing on AI therapy can experience disease stabilisation and a period of observation after AI withdrawal. A randomised phase II trial is planned.

  14. Vaginal Dryness and Beyond: The Sexual Health Needs of Women Diagnosed With Metastatic Breast Cancer.

    PubMed

    McClelland, Sara I; Holland, Kathryn J; Griggs, Jennifer J

    2015-01-01

    While research on the sexual health of women with early stage cancer has grown extensively over the past decade, markedly less information is available to support the sexual health needs of women diagnosed with advanced breast cancer. Semistructured interviews were conducted with 32 women diagnosed with metastatic breast cancer (ages 35 to 77) about questions they had concerning their sexual health and intimate relationships. All participants were recruited from a comprehensive cancer center at a large Midwestern university. Three themes were examined: the role of sexual activity and intimate touch in participants' lives, unmet information needs about sexual health, and communication with medical providers about sexual concerns. Findings indicated that sexual activities with partners were important; however, participants worried about their own physical limitations and reported frequent physical (e.g., bone pains) and vaginal pain associated with intercourse. When women raised concerns about these issues in clinical settings, medical providers often focused exclusively on vaginal lubricants, which did not address the entirety of women's problems or concerns. In addition, women diagnosed with metastatic breast cancer reported needing additional resources about specialized vaginal lubricants, nonpenetrative and nongenitally focused sex, and sexual positions that did not compromise their physical health yet still provided pleasure.

  15. Palbociclib for the Treatment of Estrogen Receptor–Positive, HER2-Negative Metastatic Breast Cancer

    PubMed Central

    Morikawa, Aki; Henry, N. Lynn

    2015-01-01

    Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 that acts by reducing phosphorylation of the tumor suppressor gene Retinoblastoma. When added to the aromatase inhibitor letrozole in a randomized phase II trial for first-line therapy of estrogen receptor-positive, HER2-negative metastatic breast cancer, palbociclib significantly increased progression-free survival compared to letrozole alone (palbociclib + letrozole: 20.2 months (95% CI 13.8-27.5), letrozole:10.2 months (95% CI 5.7-12.6); hazard ratio 0.49 (95% CI 0.32-0.75), p=0.0004). Based on these results the drug was recently granted accelerated approval by the FDA, and confirmatory studies are ongoing. Since this drug has a rational target in an oncologic pathway, concurrent biomarker development is of interest. In breast cancer, the most useful predictive biomarkers identified thus far are estrogen receptor and HER2 receptor status, although additional studies are ongoing. In this article, we review the development of palbociclib and its use in treatment of hormone receptor-positive metastatic breast cancer in the context of other FDA-approved agents in this setting. PMID:26100274

  16. 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

  17. [Interest of biological documentation on brain metastatic disease in breast cancer: A case report].

    PubMed

    Boissonneau, S; Faguer, R; Joubert, C; Fuentes, S; Metellus, P

    2015-08-01

    Breast cancer, after lung cancer, is the second major cause of brain metastases. In breast cancer, the prognosis is closely linked to the molecular subtype of the primary tumor. Targeted therapies, with or without cytotoxic treatment, have significantly modified overall survival in these patients. We report, the case of a patient suffering from breast cancer with brain metastasis in whom the biological documentation of the metastatic disease permitted to tailor the systemic treatment. Analysis of the surgical specimen revealed an immunohistochemical HER2 positive staining, which was not found in the primary tumor and therefore warranted trastuzumab administration. Another interesting insight based on this case report was to underline the phenotypic heterogeneity of the metastatic disease and its potential dynamic course as illustrated by the dissociated response to trastuzumab on body TEP-TDM in this particular patient. This case report also highlights the new place of the neurosurgeon in brain metastases management, not only as a participant in local treatment but also as a physician who is in fact involved in the delineation of the global oncological strategy in these patients as well as medical oncologists and radiation oncologists.

  18. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.

    PubMed

    Nelson, Michaela; Yang, Ming; Millican-Slater, Rebecca; Brackenbury, William J

    2015-10-20

    Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis.

  19. A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer

    PubMed Central

    Tomao, Silverio; Romiti, Adriana; Tomao, Federica; Di Seri, Marisa; Caprio, Giuliana; Spinelli, Gian Paolo; Terzoli, Edmondo; Frati, Luigi

    2006-01-01

    Background Many emerging new drugs have recently been trialled for treatment of early and advanced breast cancer. Among these new agents paclitaxel and gemcitabine play a crucial role, mostly in patients with relapsed and metastatic disease after failure of chemotherapy with antracyclines. Methods A phase II study was started in order to evaluate the activity and toxicity of a combination of paclitaxel and gemcitabine in a biweekly schedule on metastatic breast cancer patients previously treated with antracyclines. Results Twenty-five patients received paclitaxel (150 mg/mq) by 3-hours infusion, followed by gemcitabine (2000 mg/mq) given as a 60 min i.v. infusion (day 1–14) for a maximum of eight cycles. In all patients treatment was evaluated for toxicity and efficacy; four patients (16%) achieved a complete response, 12 (48%) a partial response giving an overall objective response rate of 64%. Stable disease was documented in 5 patients (20%) and progressive disease occurred in 4 patients (16%). Conclusion The schedule of treatment was safe and tolerable from a haematological and non-haematological point of view. These data confirm that the combination of gemcitabine and paclitaxel on a biweekly basis is an effective and well-tolerated regimen in breast cancer patients with prior therapeutic exposure to antracyclines. PMID:16723016

  20. Exosomes enriched in stemness/metastatic-related mRNAS promote oncogenic potential in breast cancer

    PubMed Central

    Rodríguez, Marta; Silva, Javier; Herrera, Alberto; Herrera, Mercedes; Peña, Cristina; Martín, Paloma; Gil-Calderón, Beatriz; Larriba, María Jesús; Coronado, Mª José; Soldevilla, Beatriz; Turrión, Víctor S.; Provencio, Mariano; Sánchez, Antonio; Bonilla, Félix; García-Barberán, Vanesa

    2015-01-01

    Cancer cells efficiently transfer exosome contents (essentially mRNAs and microRNAs) to other cell types, modifying immune responses, cell growth, angiogenesis and metastasis. Here we analyzed the exosomes release by breast tumor cells with different capacities of stemness/metastasis based on CXCR4 expression, and evaluated their capacity to generate oncogenic features in recipient cells. Breast cancer cells overexpressing CXCR4 showed an increase in stemness-related markers, and in proliferation, migration and invasion capacities. Furthermore, recipient cells treated with exosomes from CXCR4-cells showed increased in the same abilities. Moreover, inoculation of CXCR4-cell-derived exosomes in immunocompromised mice stimulated primary tumor growth and metastatic potential. Comparison of nucleic acids contained into exosomes isolated from patients revealed a “stemness and metastatic” signature in exosomes of patients with worse prognosis. Finally, our data supported the view that cancer cells with stem-like properties show concomitant metastatic behavior, and their exosomes stimulate tumor progression and metastasis. Exosomes-derived nucleic acids from plasma of breast cancer patients are suitable markers in the prognosis of such patients. PMID:26528758

  1. Protein Profiles Associated with Anoikis Resistance of Metastatic MDA-MB-231 Breast Cancer Cells.

    PubMed

    Akekawatchai, Chareeporn; Roytrakul, Sittiruk; Kittisenachai, Suthathip; Isarankura-Na-Ayudhya, Patcharee; Jitrapakdee, Sarawut

    2016-01-01

    Resistance to anoikis, a cell-detachment induced apoptosis, is one of the malignant phenotypes which support tumor metastasis. Molecular mechanisms underlying the establishment of this phenotype require further investigation. This study aimed at exploring protein expression profiles associated with anoikis resistance of a metastatic breast cancer cell. Cell survival of suspension cultures of non-metastatic MCF-7 and metastatic MDA-MB-231 cells were compared with their adherent cultures. Trypan blue exclusion assays demonstrated a significantly higher percentage of viable cells in MDA-MB-231 than MCF-7 cell cultures, consistent with analysis of annexin V-7-AAD stained cells indicating that MDA-MB-231 possess anti-apoptotic ability 1.7 fold higher than MCF-7 cells. GeLC-MS/MS analysis of protein lysates of MDA-MB-231 and MCF-7 cells grown under both culture conditions identified 925 proteins which are differentially expressed, 54 of which were expressed only in suspended and adherent MDA-MB-231 but not in MCF-7 cells. These proteins have been implicated in various cellular processes, including DNA replication and repair, transcription, translation, protein modification, cytoskeleton, transport and cell signaling. Analysis based on the STITCH database predicted the interaction of phospholipases, PLC and PLD, and 14-3-3 beta/alpha, YWHAB, with the intrinsic and extrinsic apoptotic signaling network, suggesting putative roles in controlling anti-anoikis ability. MDA-MB-231 cells grown in the presence of inhibitors of phospholipase C, U73122, and phospholipase D, FIPI, demonstrated reduced ability to survive in suspension culture, indicating functional roles of PLC and PLD in the process of anti-anoikis. Our study identified intracellular mediators potentially associated with establishment of anoikis resistance of metastatic cells. These proteins require further clarification as prognostic and therapeutic targets for advanced breast cancer.

  2. Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway

    PubMed Central

    Gan, Lu; Qiu, Zhu; Huang, Jing; Li, Yunhai; Huang, Hongyan; Xiang, Tingxiu; Wan, Jingyuan; Hui, Tianli; Lin, Yong; Li, Hongzhong; Ren, Guosheng

    2016-01-01

    Tumor-associated macrophages (TAMs) promote cancer development and progression by releasing various cytokines and chemokines. Previously, we have found that the number of COX-2+ TAMs was associated with lymph node metastasis in breast cancer. However, the mechanism remains enigmatic. In this study, we show that COX-2 in breast TAMs enhances the metastatic potential of breast cancer cells. COX-2 in TAMs induces MMP-9 expression and promotes epithelial-mesenchymal transition (EMT) in breast cancer cells. In addition, COX-2/PGE2 induces IL-6 release in macrophages. Furthermore, we find that the activation of Akt pathway in cancer cells is crucial for the pro-metastatic effect of COX-2+ TAMs by regulating MMP-9 and EMT. These findings indicate that TAMs facilitate breast cancer cell metastasis through COX-2-mediated intercellular communication. PMID:27994517

  3. Triple-negative breast cancer: is there a treatment on the horizon?

    PubMed Central

    Yao, Hui; He, Guangchun; Yan, Shichao; Chen, Chao; Song, Liujiang; Rosol, Thomas J.; Deng, Xiyun

    2017-01-01

    Triple-negative breast cancer (TNBC), which accounts for 15–20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors. Although these patients respond to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis remains poor. A group of targeted therapies under investigation showed favorable results in TNBC, especially in cancers with BRCA mutation. The lipid-lowering statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors), including lovastatin and simvastatin, have been shown to preferentially target TNBC compared with non-TNBC. These statins hold great promise for the management of TNBC. Only with the understanding of the molecular basis for the preference of statins for TNBC and more investigations in clinical trials can they be reformulated into a clinically approved drug against TNBC. PMID:27765921

  4. Neoadjuvant Trials in ER(+) Breast Cancer: A Tool for Acceleration of Drug Development and Discovery.

    PubMed

    Guerrero-Zotano, Angel L; Arteaga, Carlos L

    2017-06-01

    Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery in breast cancer, particularly in triple-negative and HER2-overexpressing subtypes, where pathologic complete response is a good surrogate of long-term patient benefit. For estrogen receptor-positive (ER(+)) breast cancers, however, use of this strategy has been challenging because of the lack of validated surrogates of long-term efficacy and the overall good prognosis of the majority of patients with this cancer subtype. We review below the clinical benefits of neoadjuvant endocrine therapy for ER(+)/HER2-negative breast cancer, its use and limitations for drug development, prioritization of adjuvant and metastatic trials, and biomarker discovery.Significance: Neoadjuvant endocrine therapy is an excellent platform for the development of investigational drugs, triaging of novel combinations, biomarker validation, and discovery of mechanisms of drug resistance. This review summarizes the clinical and investigational benefits of this approach, with a focus on how to best integrate predictive biomarkers into novel clinical trial designs. Cancer Discov; 7(6); 561-74. ©2017 AACR. ©2017 American Association for Cancer Research.

  5. Efficacy of Exemestane in Korean Patients with Metastatic Breast Cancer after Failure of Nonsteroidal Aromatase Inhibitors

    PubMed Central

    Lee, June Koo; Lee, Daewon; Kim, Ji-Yeon; Lim, Yoojoo; Lee, Eunyoung; Moon, Hyeong-Gon; Kim, Tae-Yong; Han, Sae-Won; Oh, Do-Youn; Lee, Se-Hoon; Han, Wonshik; Kim, Dong-Wan; Kim, Tae-You; Noh, Dong-Young

    2013-01-01

    Purpose Exemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported. Methods Data on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months). Results The median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs. Conclusion Exemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment. PMID:23593084

  6. Epithelial Mesenchymal Transition (EMT) in Metastatic Breast Cancer in Omani Women.

    PubMed

    Lakhtakia, Ritu; Aljarrah, Adil; Furrukh, Muhammad; Ganguly, Shyam S

    2017-05-19

    Breast cancer (BC) in Oman affects younger women and has a more aggressive course. Clinical and biological variables like age, pregnancy, tumor size, type, grade, receptor expression and proliferation predict disease aggression but there is no direct predictor of metastasis except lymphovascular invasion. Epithelial-mesenchymal transition (EMT) is characterized by epithelial cells losing epithelial and acquiring mesenchymal morpho-immunophenotypic characteristics. In tumors, EMT-like transitions may signify a metastatic phenotype and have features in common with cancer stem cells (CSC) which show resistance to chemotherapy. This study aimed to identify EMT and CSC phenotypes in metastatic and non-metastatic breast cancer in Omani women and their association with conventional clinico-pathological predictors of BC. In a retrospective study of ninety-six Omani women with breast cancer, the association of age, pregnancy/lactation, tumor size, type, grade, ductal carcinoma insitu (DCIS), lymphovascular invasion, hormone/ HER2 receptor expression and Ki67 proliferation index (Ki67 PI) was tested with EMT/ CSC phenotype and metastasis. Young age ≤ 40 years, lymphovascular invasion and EMT had a strong association with metastasis; CSC approached significance. Vimentin expression in tumor cells, fibronectin and MMP-11 in stroma were reliable markers of EMT; dual EMT and CSC phenotype (Vim+/ CD44+/ CD 24-/low) had a strong association with apocrine variant, basal-like tumors and triple negative cancers. EMT had a strong association with Ki67 proliferation index (PI) and CSC with HER2-like tumors and distant metastasis. These select markers may be useful in metastasis-prediction in pre-treatment biopsies.

  7. [An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy].

    PubMed

    Sato, Yasushi; Takayama, Tetsuji; Sagawa, Tamotsu; Sato, Tsutomu; Okamoto, Kumiko; Takahashi, Shou; Abe, Seiichiro; Iyama, Satoshi; Murase, Kazuyuki; Kato, Junji; Niitsu, Yoshiro

    2008-03-01

    We reported here a case of advanced breast cancer successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy. A 56-year-old male was referred to our hospital for treatment of recurrent metastatic breast cancer. When he was admitted, his general condition was poor due to massive intraperitoneal metastasis. We administered TAC chemotherapy (docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2), every 3 weeks). During chemotherapy, he showed no major adverse effects except grade 3 neutropenia, which could be easily managed with G-CSF administration. Metastatic lesions almost disappeared after 4 cycles of TAC. TAC therapy was considered to be acceptable as salvage therapy for a metastatic male breast cancer patient.

  8. Overcoming Tamoxifen Resistance of Human Breast Cancer by Targeted Gene Silencing Using Multifunctional pRNA Nanoparticles.

    PubMed

    Zhang, Yijuan; Leonard, Marissa; Shu, Yi; Yang, Yongguang; Shu, Dan; Guo, Peixuan; Zhang, Xiaoting

    2017-01-24

    Most breast cancers express estrogen receptor (ER) α, and the antiestrogen drug tamoxifen has been widely used for their treatment. Unfortunately, up to half of all ERα-positive tumors have intrinsic or acquired endocrine therapy resistance. Our recent studies revealed that the ER coactivator Mediator Subunit 1 (MED1) plays a critical role in tamoxifen resistance through cross-talk with HER2. Herein, we assembled a three-way junction (3-WJ) pRNA-HER2apt-siMED1 nanoparticle to target HER2-overexpressing human breast cancer via an HER2 RNA aptamer to silence MED1 expression. We found that these ultracompact RNA nanoparticles are very stable under RNase A, serum, and 8 M urea conditions. These nanoparticles specifically bound to HER2-overexpressing breast cancer cells, efficiently depleted MED1 expression, and significantly decreased ERα-mediated gene transcription, whereas point mutations of the HER2 RNA aptamer on these nanoparticles abolished such functions. The RNA nanoparticles not only reduced the growth, metastasis, and mammosphere formation of the HER2-overexpressing breast cancer cells but also sensitized them to tamoxifen treatment. These biosafe nanoparticles efficiently targeted and penetrated into HER2-overexpressing tumors after systemic administration in orthotopic xenograft mouse models. In addition to their ability to greatly inhibit tumor growth and metastasis, these nanoparticles also led to a dramatic reduction in the stem cell content of breast tumors when combined with tamoxifen treatment in vivo. Overall, we have generated multifunctional RNA nanoparticles that specifically targeted HER2-overexpressing human breast cancer, silenced MED1, and overcame tamoxifen resistance.

  9. Chemotherapy and Functional Medicine in a Patient With Metastatic Breast Cancer: A Case Report

    PubMed Central

    Taxman, Elliot T.; Conlon, Erin D.; Speers, Alex; Dismuke, Kristin L.; Heyman, Tonya S.; Taxman, Thomas L.

    2016-01-01

    More than one-half of all cancer patients use some combination of conventional and complementary medicine, but exactly how this is done and what the outcomes include are poorly understood. This case study reports the successful treatment of metastatic invasive ductal breast carcinoma by 2 physician groups with treatments that combined conventional chemotherapy with nutritional support guided by nutritional and digestive laboratory testing. The goal of minimizing side effects and enhancing outcomes was achieved in this patient who did not receive radiation therapy and is almost 3 y posttreatment with no evidence of recurrence. PMID:27053933

  10. Higher survival of refractory metastatizing breast cancer after thermotherapy and autologous specific antitumoral immunotherapy.

    PubMed

    Pontiggia, P; Rizzo, S; Cuppone-Curto, F; Sabato, A; Rotella, G; Silvotti, M G; Martano, F

    1996-01-01

    46 women (average 54.3 yrs) with refractory metastatizing breast cancer were treated with thermotherapy and autologous specific immunotherapy (rhIL-2 ex vivo activated cells). Metastases involved one organ in 69%; in particular, bone, lung, liver. The PS after treatment was satisfactory in 41%; the outcome was better in those cases with metastases to one site. The women remaining alive were 31/46; 67% of thermoimmunotherapy treated patients were alive after a maximum survival time of 85 months (median 24 months). The 36 months of control showed a 5-fold higher survival rate in our series when challenged with that of compared women undergoing only chemotherapy (p < .001).

  11. Multicenter phase II study of apatinib in non-triple-negative metastatic breast cancer.

    PubMed

    Hu, Xichun; Cao, Jun; Hu, Wenwei; Wu, Changping; Pan, Yueyin; Cai, Li; Tong, Zhongsheng; Wang, Shusen; Li, Jin; Wang, Zhonghua; Wang, Biyun; Chen, Xiaoyu; Yu, Hao

    2014-11-07

    Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). This study was conducted to assess the efficacy and safety of apatinib in patients with non-triple-negative metastatic breast cancer who had received prior chemotherapy for their metastatic disease. This multicenter, open-label, single arm study enrolled patients with non-triple-negative breast cancer, pretreated with anthracycline, taxanes and capecitabine, and who failed in the metastatic setting at least 1 and at most 4 prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients as well as at least one anti-Her2 drug for Her2-positive patients. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Apatinib was administered as 500 mg daily on days 1 through 28 of each 4-week cycle. 38 patients were enrolled with a median age of 49 years (range, 35 to 62 years) and received apatinib for a median of 4 cycles (range from 0 to 10 cycles). 18 (47.4%) patients experienced dose reduction during treatment. The median relative dose intensity (relative to assigned dose for each cycle) was 82% (range, 45.0% to 100.0%). Median follow-up time was 10.1 months. Median PFS of all 38 patients was 4.0 months (95% confidence interval (CI), 2.8 m - 5.2 m). 36 patients were eligible for efficacy analysis. ORR was 16.7% (6/36). DCR was 66.7% (24/36). Median OS was 10.3 months (95% CI, 9.1 m - 11.6 m). The most common grade 3/4 treatment-related AEs were hypertension (20.5%), hand-foot syndrome (10.3%), and proteinuria (5.1%). Of three possibly drug-related SAEs recorded in the study, 2 (3.4%) deaths occurred within 28 days of last treatment and were both considered to be the result of disease progression. The other one was grade 2 diarrhea needing hospitalization. Apatinib exhibited objective

  12. High tumor budding stratifies breast cancer with metastatic properties.

    PubMed

    Salhia, Bodour; Trippel, Mafalda; Pfaltz, Katrin; Cihoric, Nikola; Grogg, André; Lädrach, Claudia; Zlobec, Inti; Tapia, Coya

    2015-04-01

    Tumor budding refers to single or small cluster of tumor cells detached from the main tumor mass. In colon cancer high tumor budding is associated with positive lymph nodes and worse prognosis. Therefore, we investigated the value of tumor budding as a predictive feature of lymph node status in breast cancer (BC). Whole tissue sections from 148 surgical resection specimens (SRS) and 99 matched preoperative core biopsies (CB) with invasive BC of no special type were analyzed on one slide stained with pan-cytokeratin. In SRS, the total number of intratumoral (ITB) and peripheral tumor buds (PTB) in ten high-power fields (HPF) were counted. A bud was defined as a single tumor cell or a cluster of up to five tumor cells. High tumor budding equated to scores averaging >4 tumor buds across 10HPFs. In CB high tumor budding was defined as ≥10 buds/HPF. The results were correlated with pathological parameters. In SRS high PTB stratified BC with lymph node metastases (p ≤ 0.03) and lymphatic invasion (p ≤ 0.015). In CB high tumor budding was significantly (p = 0.0063) associated with venous invasion. Pathologists are able, based on morphology, to categorize BC into a high and low risk groups based in part on lymph node status. This risk assessment can be easily performed during routine diagnostics and it is time and cost effective. These results suggest that high PTB is associated with loco-regional metastasis, highlighting the possibility that this tumor feature may help in therapeutic decision-making.

  13. Role of gonadotropin-releasing hormone analogues in metastatic male breast cancer: results from a pooled analysis.

    PubMed

    Di Lauro, Luigi; Pizzuti, Laura; Barba, Maddalena; Sergi, Domenico; Sperduti, Isabella; Mottolese, Marcella; Amoreo, Carla Azzurra; Belli, Franca; Vici, Patrizia; Speirs, Valerie; Santini, Daniele; De Maria, Ruggero; Maugeri-Saccà, Marcello

    2015-05-17

    Male breast cancer is a rare malignancy. Despite the lack of prospectively generated data from trials in either the adjuvant or metastatic setting, patients are commonly treated with hormone therapies. Much controversy exists over the use of gonadotropin-releasing hormone analogues in metastatic male breast cancer patients. We conducted this study to provide more concrete ground on the use of gonadotropin-releasing hormone analogues in this setting. We herein present results from a pooled analysis including 60 metastatic male breast cancer patients treated with either an aromatase inhibitor or cyproterone acetate as a monotherapy (23 patients) or combined with a gonadotropin-releasing hormone analogue (37 patients). Overall response rate was 43.5% in patients treated with monotherapy and 51.3% with combination therapy (p = 0.6). Survival outcomes favored combination therapy in terms of median progression-free survival (11.6 months versus 6 months; p = 0.05), 1-year progression-free survival rate (43.2% versus 21.7%; p = 0.05), median overall survival (29.7 months versus 22 months; p = 0.05), and 2-year survival rate (64.9% versus 43.5%; p = 0.05). In metastatic male breast cancer patients, the combined use of gonadotropin-releasing hormone analogues and aromatase inhibitors or antiandrogens seems to be associated with greater efficacy, particularly in terms of survival outcomes, compared with monotherapy. Collectively, these results encourage considering these agents in the metastatic setting.

  14. An unusual case of metastatic male breast cancer to the nasopharynx-review of literature.

    PubMed

    Agrawal, Swati; Jayant, Kumar; Agarwal, Rajendra Kumar; Dayama, Kalyan G; Arora, Seema

    2015-10-01

    Metastatic breast carcinoma has been described to the various areas in the head and neck region. However, these metastases are rarely found in nasopharynx. Herein we are presenting the first case of male breast carcinoma with the longest survival secondary to distant metastases in right maxillary sinus and extending to the nasopharynx with extensive skeletal & lung metastases. Here we present a case of 65-year-old male with past medical history of right breast carcinoma, presented clinically with symptoms of recurrent sinusitis. Physical examination revealed a mass in the nasopharynx, which subsequently proved to be hormonal receptor positive high-grade adenocarcinoma secondary to metastasis of primary breast cancer on biopsy. The patient received three cycles of palliative chemotherapy based on Doxorubicin with Paclitaxel weekly. In spite of that, he developed pulmonary, liver and bone metastases. Later, treatment regimen was changed to Gemcitabine, Paclitaxel and injectable Zolendronate with calcium and vitamin D supplementation. Still he didn't show any improvement and later, he developed febrile neutropenia. Then, he refused further chemotherapy and died after 12 months of receiving the best hospice care. Breast cancer is one of the most common cancers in terms of incidence and mortality; breast cancer deserves extensive studies and research in different aspects. Breast cancer metastasizing to nasopharynx would be the last diagnosis that comes to mind for a male patient presenting with clinical features suggestive of recurrent sinusitis infection. As recurrent sinusitis is a very common ailment affecting human kind and is mostly due to benign causes. Metastasis, although rare, should be included in the differential diagnosis of nasopharyngeal lesion since it may clinically mimic a benign neoplasm or primary carcinoma. Based on our clinical experience and review of literature, although it is a very rare possibility in a patient with sinusitis, still we advise

  15. The use of research‐based theatre in a project related to metastatic breast cancer

    PubMed Central

    Gray, Ross; Sinding, Chris; Ivonoffski, Vrenia; Fitch, Margaret; Hampson, Ann; Greenberg, Marlene

    2008-01-01

    Research‐based theatre represents an innovative approach to disseminating the results of qualitative studies. In this paper, we provide a rationale for the importance of research‐based theatre and also review previous work that has been done in the area. We then describe our experience in transforming research data into a dramatic production, Handle with Care? This production was based on two studies – one with women with metastatic breast cancer, and the other with medical oncologists treating breast cancer patients. Results from ongoing assessment of the project are reported. We discuss some of the factors related to the success of Handle with Care? and reflect on what has been learned about the process of developing dramatic pieces related to serious illness. PMID:11281920

  16. EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer

    PubMed Central

    Alvarez-Cubero, Maria J.; Nadal, Rosa; Sanchez-Rovira, Pedro; Salido, Marta; Rodríguez, María; García-Puche, Jose L.; Delgado-Rodriguez, Miguel; Solé, Francisco; García, Maria A.; Perán, Macarena; Rosell, Rafael; Marchal, Juan A.; Lorente, Jose A.

    2014-01-01

    Circulating tumor cells (CTCs) are frequently associated with epithelialmesenchymal transition (EMT). The objective of this study was to detect EMT phenotype through Vimentin (VIM) and Slug expression in cytokeratin (CK)-negative CTCs in non-metastatic breast cancer patients and to determine the importance of EGFR in the EMT phenomenon. In CK-negative CTCs samples, both VIM and Slug markers were co-expressed in the most of patients. Among patients EGFR+, half of them were positive for these EMT markers. Furthermore, after a systemic treatment 68% of patients switched from CK- to CK+ CTCs. In our experimental model we found that activation of EGFR signaling by its ligand on MCF-7 cells is sufficient to increase EMT phenotypes, to inhibit apoptotic events and to induce the loss of CK expression. The simultaneous detection of both EGFR and EMT markers in CTCs may improve prognostic or predictive information in patients with operable breast cancer. PMID:25277187

  17. Bevacizumab in the Treatment of Metastatic Breast Cancer: Friend or Foe?

    PubMed Central

    Montero, Alberto J.; Escobar, Mauricio; Lopes, Gilberto; Glück, Stefan; Vogel, Charles

    2011-01-01

    Metastatic breast cancer (MBC) is a major cause of death among women worldwide. Progress has been made in treating MBC with the advent of anti-estrogen therapies, potent cytotoxic agents, and monoclonal antibodies. Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), which was approved in 2008 by the US Food and Drug Administration (FDA), for first-line treatment of HER-2 negative MBC in combination with paclitaxel. The FDA then reversed this decision in December 2010 by recommending removal of the MBC indication from bevacizumab, citing primarily safety concerns, and that these risks did not outweigh the ability of bevacizumab to significantly prolong progression-free survival. This decision was unexpected in the oncology community and remains controversial. This review looks at all available phase 3 data with bevacizumab in the MBC setting to determine whether the data support this decision by the FDA, and discusses the future of bevacizumab in breast cancer. PMID:22012632

  18. What to expect from high throughput genomics in metastatic breast cancers?

    PubMed

    Onesti, Concetta Elisa; Vicier, Cécile; André, Fabrice

    2015-11-01

    Breast cancer is a heterogeneous disease and its genomic characteristics have been widely studied in the last years. Although several progresses have been made, metastatic disease is still incurable in the majority of patients. Recent genomic studies have shown that a large number of candidate targets exist in breast cancer. Currently only two drivers have been validated (ER and HER2), but several others seem to be associated with objective response, such as PIK3CA mutations, FGFR1 amplifications, AKT1 mutations, EGFR amplifications and ERBB2 mutations. Beside driver identification, many other applications can be developed for genomics such as identification of lethal subclones, DNA repair defects or immune response against tumor. Most of the precision medicine programs currently use targeted sequencing. Nevertheless, whole exome sequencing, RNA sequencing, gene expression analysis, phosphoprotein detection, SNP arrays and ctDNA sequencing have been also proposed in clinical trials.

  19. Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer.

    PubMed

    Wagner, Anna Dorothea; Thomssen, Christoph; Haerting, Johannes; Unverzagt, Susanne

    2012-07-11

    Vascular-endothelial-growth-factor (VEGF) is a key mediator of angiogenesis. VEGF-targeting therapies have shown significant benefits and been successfully integrated in routine clinical practice for other types of cancer, such as metastatic colorectal cancer. By contrast, individual trial results in metastatic breast cancer (MBC) are highly variable and their value is controversial. To evaluate the benefits (in progression-free survival (PFS) and overall survival (OS)) and harms (toxicity) of VEGF-targeting therapies in patients with hormone-refractory or hormone-receptor negative metastatic breast cancer. Searches of CENTRAL, MEDLINE, EMBASE, the Cochrane Breast Cancer Group's Specialised Register, registers of ongoing trials and proceedings of conferences were conducted in January and September 2011, starting in 2000. Reference lists were scanned and members of the Cochrane Breast Cancer Group, experts and manufacturers of relevant drug were contacted to obtain further information. No language restrictions were applied. Randomised controlled trials (RCTs) to evaluate treatment benefit and non-randomised studies in the routine oncology practice setting to evaluate treatment harms. We performed data collection and analysis according to the published protocol. Individual patient data was sought but not provided. Therefore, the meta-analysis had to be based on published data. Summary statistics for the primary endpoint (PFS) were hazard ratios (HRs). We identified seven RCTs, one register, and five ongoing trials from a total of 347 references. The published trials for VEGF-targeting drugs in MBC were limited to bevacizumab. Four trials, including a total of 2886 patients, were available for the comparison of first-line chemotherapy, with versus without bevacizumab. PFS (HR 0.67; 95% confidence interval (CI) 0.61 to 0.73) and response rate were significantly better for patients treated with bevacizumab, with moderate heterogeneity regarding the magnitude of the

  20. Targeting of miR9/NOTCH1 interaction reduces metastatic behavior in triple-negative breast cancer.

    PubMed

    Mohammadi-Yeganeh, Samira; Mansouri, Ardalan; Paryan, Mahdi

    2015-11-01

    Many reports have indicated deregulation of a variety of microRNAs (miRNAs) in human cancers. In this study, we appraised miR-9 correlation with NOTCH1 involved in Notch signaling in metastatic breast cancer. The Notch signaling pathway has been approved to be associated with the development and progression of many human cancers, including breast cancer, but the precise mechanism has remained unknown. To the best of our knowledge, this is the first study that introduces miR-9 and NOTCH1 correlation as an effective factor in breast cancer. We found that miR-9 expression was decreased in MDA-MB-231 breast cancer cells compared with MCF-10A normal breast cell line. However, NOTCH1 was upregulated in the metastatic breast cancer cells. Furthermore, luciferase assay revealed a significant inverse correlation between miR-9 and NOTCH1. Overexpression of Notch signaling via Notch1 intracellular domain in MDA-MB-231 cell line was suppressed by lentiviruses expressing miR-9. Taken together, the results obtained by MTT, flow cytometry, migration, and wound healing assays showed that it is possible to inhibit metastasis and induce pro-apoptotic state by induction of miR-9 expression in MDA-MB-231 cells but with no effect on cell proliferation. These results shows that miR-9, by direct targeting of NOTCH1, can reveal a suppressor-like activity in metastatic breast cancer cells.

  1. The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential.

    PubMed

    Chiang, Kun-Chun; Yeh, Ta-Sen; Chen, Shin-Cheh; Pang, Jong-Hwei S; Yeh, Chun-Nan; Hsu, Jun-Te; Chen, Li-Wei; Kuo, Sheng-Fong; Takano, Masashi; Kittaka, Atsushi; Chen, Tai C; Sun, Chi-Chin; Juang, Horng-Heng

    2016-04-21

    Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃), the newly-synthesized 1α,25(OH)₂D₃ analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)₂D₃ and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)₂D₃ and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)₂D₃ induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)₂D₃ and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)₂D₃ and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC.

  2. The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential

    PubMed Central

    Chiang, Kun-Chun; Yeh, Ta-Sen; Chen, Shin-Cheh; Pang, Jong-Hwei S.; Yeh, Chun-Nan; Hsu, Jun-Te; Chen, Li-Wei; Kuo, Sheng-Fong; Takano, Masashi; Kittaka, Atsushi; Chen, Tai C.; Sun, Chi-Chin; Juang, Horng-Heng

    2016-01-01

    Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3), the newly-synthesized 1α,25(OH)2D3 analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)2D3 and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)2D3 and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)2D3 induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)2D3 and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)2D3 and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC. PMID:27110769

  3. Segmentation of HER2 protein overexpression in immunohistochemically stained breast cancer images using Support Vector Machines

    NASA Astrophysics Data System (ADS)

    Pezoa, Raquel; Salinas, Luis; Torres, Claudio; Härtel, Steffen; Maureira-Fredes, Cristián; Arce, Paola

    2016-10-01

    Breast cancer is one of the most common cancers in women worldwide. Patient therapy is widely supported by analysis of immunohistochemically (IHC) stained tissue sections. In particular, the analysis of HER2 overexpression by immunohistochemistry helps to determine when patients are suitable to HER2-targeted treatment. Computational HER2 overexpression analysis is still an open problem and a challenging task principally because of the variability of immunohistochemistry tissue samples and the subjectivity of the specialists to assess the samples. In addition, the immunohistochemistry process can produce diverse artifacts that difficult the HER2 overexpression assessment. In this paper we study the segmentation of HER2 overexpression in IHC stained breast cancer tissue images using a support vector machine (SVM) classifier. We asses the SVM performance using diverse color and texture pixel-level features including the RGB, CMYK, HSV, CIE L*a*b* color spaces, color deconvolution filter and Haralick features. We measure classification performance for three datasets containing a total of 153 IHC images that were previously labeled by a pathologist.

  4. The subjective experience of young women with non-metastatic breast cancer: the Young Women with Breast Cancer Inventory.

    PubMed

    Christophe, V; Duprez, C; Congard, A; Antoine, P; Lesur, A; Fournier, E; Vanlemmens, L

    2015-06-03

    The subjective experience of young women with breast cancer has some particular features linked to the impact of the disease and its treatment on their age-related issues (e.g. desire for a child, couple relationship, career management). Despite these specific concerns, no questionnaire currently targets the young breast cancer patient's quality of life, subjective experience or common problems when facing cancer. This study presents the psychometric validation of an inventory that aimed to measure the impact of breast cancer on the quality of life of young women (<45 years of age) with non-metastatic disease. 546 women aged <45 years when diagnosed with a non-metastatic breast cancer were recruited in 27 French cancer research and treatment centers. They answered a self-reported questionnaire created from verbatim collected by non-directive interviews carried out with 69 patients in a first qualitative study. Exploratory and confirmatory analyses were conducted in order to obtain the final structure of the scale. Internal consistency, test-retest reliability and concurrent validity with quality of life questionnaires currently used (QLQ-C30 and the QLQ-BR23 module) were then assessed. The YW-BCI36 contains 36 items and highlights 8 factors: 1) feeling of couple cohesion, 2) negative affectivity and apprehension about the future, 3) management of child(ren) and of everyday life, 4) sharing with close relatives, 5) body image and sexuality, 6) financial difficulties, 7) deterioration of relationships with close relatives, and 8) career management. Psychometric analyses indicated good internal consistency (Cronbach's alpha values ranging from 0.76 to 0.91) and temporal reliability (Bravais-Pearson correlations ranging from 0.66 to 0.85). As expected, there were quite strong correlations between the YW-BCI36 and the QLQ-C30 and QLQ-BR23 scores (r ranging from 0.20 to -0.66), indicating adequate concurrent validity. The YW-BCI36 was confirmed as a valid scale for

  5. Comparative study of receptor discordance between primary and corresponding metastatic lesions in breast cancer.

    PubMed

    Erdem, Gokmen U; Altundag, Kadri; Ozdemir, Nuriye Y; Sahin, Suleyman; Demirci, Nebi S; Karatas, Fatih; Bozkaya, Yakup; Aytekin, Aydin; Tasdemir, Vildan; Aslan, Alma C; Sever, Ali R; Zengin, Nurullah

    2017-01-01

    It is well-known that tumor phenotype may change during the progression of breast cancer (BC). The purpose in this study was to compare the discordance in estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) between primary and recurrent/metastatic lesions (RML) and also to evaluate the prognostic significance of change in tumor phenotype on survival in patients with metastatic BC. The medical records of 6638 patients with BC from two breast centers treated between 1992 and 2015 were retrospectively analyzed. Of the 6638 patients, 549 cases in whom recurrence was histologically proven by biopsy or by surgical resection were enrolled into this study. Our presentation 13.5% of the patients had metastatic disease. Biopsy on recurrence was obtained from distant metastasis sites in 250 (63.6%) patients or from locoregional soft tissues/lymph-nodes in 143 (36.4%). Receptor discordance in ER, PgR and HER2 expressions between primary and RML were 27.2% (p=0.32), 38.6% (p<0.001) and 14.4% (p=0.007), respectively. Subsequent gain of ER and PgR showed significantly higher overall survival (OS) and post-recurrence survival (PRS) compared to the corresponding concordant-negative patients (119 vs 57 months, p=0.001 and 56 vs 31 months, p=0.03 for ER, 148 vs 58 months, p=0.003 and 64 vs 31 months, p=0.01 for PgR, respectively), hormone receptor (HR) loss was associated with worse OS. Similarly, HER2-loss cases experienced poorer PRS and OS outcomes, compared with those having stable HER2 expression (median 26 vs 60 months, p=0.009 for PRS and median 60 vs 111 months, p=0.06 for OS, respectively). This study confirmed the receptor discordance in ER/PgR and HER2 receptor expressions between primary and RML in patients with metastatic BC. As the loss of receptor expression is the most responsible factor for the discordance, treatments of recurrent/metastatic tumors should be individualized on the basis of molecular and genomic

  6. Cost effectiveness of cytotoxic and targeted therapy for metastatic breast cancer: a critical and systematic review.

    PubMed

    Blank, Patricia R; Dedes, Konstantin J; Szucs, Thomas D

    2010-01-01

    Breast cancer is the leading cancer type diagnosed among women in Western countries. Despite great advances in cancer therapies, many of these patients develop non-curable metastases. The objective of cancer treatment in the metastatic setting is mainly to control symptoms and to prolong survival. The selection of the optimal chemotherapeutic regimen is affected by performance status, tumour biology, site and extent of the disease and the exposure to prior therapies. Recent developments in new kinds of cancer drugs have contributed not only to immense progress in clinical outcomes but also to dramatically increased treatment-related health costs. Cost-effectiveness analysis is a type of economic evaluation that compares costs and health outcomes of alternative intervention strategies in a systematic way. In this review, a systematic literature search was performed and the evidence on the cost effectiveness of conventional chemotherapy and targeted therapy for metastatic breast cancer was explored. Cost-effectiveness/-utility analysis of treatment regimens for metastatic breast cancer were identified using literature and reference searches (MEDLINE). Published reports on conventional and targeted cancer therapies were scrutinized and incremental cost-effectiveness ratios (ICERs) were abstracted. Furthermore, the quality of reporting, as well as methodological and modeling issues, were extensively discussed. From full-text article reviews, six cost-effectiveness analyses on conventional therapies and seven studies on targeted therapies were included. Eight analyses were conducted in European countries, three in the US and two in Canada. The economic models were primarily (69%) based on clinical trial data. Results from sensitivity analyses and study perspectives were reported by all studies. Discount rates were mentioned in five articles (39%). The methods of reporting costs and effects varied considerably, as did trial design across conventional chemotherapies

  7. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.

    PubMed

    Robson, Mark; Im, Seock-Ah; Senkus, Elżbieta; Xu, Binghe; Domchek, Susan M; Masuda, Norikazu; Delaloge, Suzette; Li, Wei; Tung, Nadine; Armstrong, Anne; Wu, Wenting; Goessl, Carsten; Runswick, Sarah; Conte, Pierfranco

    2017-08-10

    Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number

  8. Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells.

    PubMed

    Shumakovich, Marina A; Mencio, Caitlin P; Siglin, Jonathan S; Moriarty, Rebecca A; Geller, Herbert M; Stroka, Kimberly M

    2017-08-09

    Tumor cell metastasis to the brain involves cell migration through biochemically and physically complex microenvironments at the blood-brain barrier (BBB). The current understanding of tumor cell migration across the BBB is limited. We hypothesize that an interplay between biochemical cues and physical cues at the BBB affects the mechanisms of brain metastasis. We found that astrocyte conditioned medium (ACM) applied directly to tumor cells increased tumor cell velocity, induced elongation, and promoted actin stress fiber organization. Notably, treatment of the extracellular matrix with ACM led to even more significant increases in tumor cell velocity in comparison with ACM treatment of cells directly. Furthermore, inhibiting matrix metalloproteinases in ACM reversed ACM's effect on tumor cells. The effects of ACM on tumor cell morphology and migration also depended on astrocytes' activation state. Finally, using a microfluidic device, we found that the effects of ACM were abrogated in confinement. Overall, our work demonstrates that astrocyte-secreted factors alter migration and morphology of metastatic breast tumor cells, and this effect depends on the cells' mechanical microenvironment.-Shumakovich, M. A., Mencio, C. P., Siglin, J. S., Moriarty, R. A., Geller, H. M., Stroka, K. M. Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells. © FASEB.

  9. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers.

    PubMed

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis.

  10. [Two cases of effective weekly paclitaxel administration and concurrent radiation for metastatic breast cancer].

    PubMed

    Kokufu, Ikuo; Tanei, Tomonori; Taniguchi, Hirokazu; Kimura, Fumihiko; Fukuda, Kazuhiro; Yamamoto, Masayuki; Yano, Tokiharu; Yamada, Katsumi; Tamaoka, Koichi; Hosono, Masako

    2003-01-01

    We report two cases in which weekly paclitaxel (TXL) administration and concurrent radiation was effective for metastatic breast cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication. Case 1: A 50-year-old woman was found to have atelectasis of the middle lobe after treatment for brain metastasis. She was diagnosed with hilar, mediastinal and supraclavicular lymph nodes metastases. She received weekly TXL administration and concurrent radiation to the mediastinum and supraclavicular fossa. The metastatic lymph nodes had disappeared one month after the treatment. Case 2: A 31-year-old woman was diagnosed with advanced breast cancer with lung, pleural, bone and orbital metastases. She received weekly TXL administration and concurrent radiation to the orbit. The lung and pleural metastases had disappeared and the orbital metastasis was decreased by 75% one month after the treatment, and the case was assessed as a partial response. Leukopenia and other major adverse effects were not observed in either of the two cases.

  11. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers

    PubMed Central

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis. PMID:27625789

  12. Evaluation of intravenous 6-thioguanine as first-line chemotherapy in women with metastatic breast cancer.

    PubMed

    Ingle, J N; Twito, D I; Suman, V J; Krook, J E; Maillard, J A; Windschitl, H E; Marschke, R F

    1997-02-01

    6-Thioguanine (6-TG) is a purine analog that has marked variability in plasma concentration after oral administration. Following the development of a multiple-day i.v. regimen, we performed a phase II trial of this agent as first-line chemotherapy in women with metastatic breast cancer. Forty-one patients with measurable (31 patients) or evaluable (10 patients) disease were entered into this trial. 6-TG was administered i.v. over a 10 min period daily for 5 consecutive days, with a planned cycle length of 35 days. The daily dosage level was 55 mg/m2 in the first 15 patients, but this was increased to 65 mg/m2 in the remaining patients due to inadequate myelosuppression at the lower dose. Six patients, all with measurable disease, achieved a complete response (CR) (two patients) or a partial response (PR) (four patients). Three responses occurred at the 55 mg/m2 level and three at the 65 mg/m2 level. The 95% confidence interval (CI) for the true response rate among patients with measurable disease was 6-39%. The median time to progression was 140 days and median survival time was 460 days. The regimen was well tolerated. We conclude that 6-TG, as given in this study, has limited activity as first-line chemotherapy for women with metastatic breast cancer.

  13. Weekly pegylated liposomal doxorubicin and paclitaxel in patients with metastatic breast carcinoma: A phase II study

    PubMed Central

    LEONARDI, VITA; PALMISANO, VALENTINA; PEPE, ALESSIO; USSET, ANTONELLA; MANUGUERRA, GIOVANNA; SAVIO, GIUSEPPINA; DE BELLA, MANUELA TAMBURO; LAUDANI, AGATA; ALÙ, MASSIMO; CUSIMANO, MARIA PIA; SCIANNA, CATERINA; GIRESI, ARMANDO; AGOSTARA, BIAGIO

    2010-01-01

    Pegylated liposomal doxorubicin (PLD) has the advantage of delivering active anthracycline directly to the tumor site, while exposing the patient to a lesser degree of doxorubicin-associated toxicities. Recently, a regimen in which paclitaxel is infused weekly over 1 h produced substantial antitumor activity with little myelosuppression. We designed a phase II trial to study the efficacy and toxicity of 10 mg/m2 PLD on Days 1, 8 and 15, plus 70 mg/m2 paclitaxel weekly in patients with untreated metastatic breast cancer and a high risk of cardiotoxicity. The study included 35 patients, with 31 (88.5%) evaluable for efficacy and 35 (100%) for toxicity. A total of 28 patients (80%) had two or more sites of disease. Overall, 4 complete and 16 partial responses were noted with an overall response rate of 64.5%, with 6 cases of stable and 5 cases of progressive disease. Toxicity was found to be manageable in that the only grade 3–4 side effects recorded were palmar-plantar erythrodysesthesia, 8.5%; mucositis, 2.8%; leucopenia, 12.5%; anemia, 2.8% and AST/ALT, 2.8%. No cardiotoxicity was observed. In conclusion, weekly PLD plus paclitaxel appears to be a well-tolerated and effective approach for metastatic breast cancer patients with a high risk of cardiotoxicity. PMID:22966374

  14. Cotargeting of CYP-19 (aromatase) and emerging, pivotal signalling pathways in metastatic breast cancer

    PubMed Central

    Daldorff, Stine; Mathiesen, Randi Margit Ruud; Yri, Olav Erich; Ødegård, Hilde Presterud; Geisler, Jürgen

    2017-01-01

    Aromatase inhibition is one of the cornerstones of modern endocrine therapy of oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). The nonsteroidal aromatase inhibitors anastrozole and letrozole, as well as the steroidal aromatase inactivator exemestane, are the preferred drugs and established worldwide in all clinical phases of the disease. However, although many patients suffering from MBC experience an initial stabilisation of their metastatic burden, drug resistance and disease progression occur frequently, following in general only a few months on treatment. Extensive translational research during the past two decades has elucidated the major pathways contributing to endocrine resistance and paved the way for clinical studies investigating the efficacy of novel drug combinations involving aromatase inhibitors and emerging drugable targets like mTOR, PI3K and CDK4/6. The present review summarises the basic research that provided the rationale for new drug combinations involving aromatase inhibitors and the main findings of pivotal clinical trials that have already started to change our way to treat hormone-sensitive MBC. The challenging situation of oestrogen receptor-positive and human epidermal growth factor receptor 2-positive (HER2+) MBC is also shortly reviewed to underline the complexity of the clinical scenario in the heterogeneous subgroups of hormone receptor-positive breast cancer patients and the increasing need for personalised medicine. Finally, we summarise some of the promising findings made with the combination of aromatase inhibitors with other potent endocrine treatment options like fulvestrant, a selective oestrogen receptor downregulator. PMID:27923036

  15. ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients.

    PubMed

    Angus, Lindsay; Beije, Nick; Jager, Agnes; Martens, John W M; Sleijfer, Stefan

    2017-01-01

    Mutations in the gene coding for the estrogen receptor (ER), ESR1, have been associated with acquired endocrine resistance in patients with ER-positive metastatic breast cancer (MBC). Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of its ligand estrogen, conferring resistance against several endocrine agents. While recent clinical studies reported that the occurrence of ESR1 mutations is rare in primary breast cancer tumors, these mutations are more frequently observed in metastatic tissue and circulating cell-free DNA of MBC patients pretreated with endocrine therapy. Given the assumed impact that the presence of ESR1 mutations has on outcome to endocrine therapy, assessing ESR1 mutations in MBC patients is likely to be of significant interest to further individualize treatment for MBC patients. Here, ESR1 mutation detection methods and the most relevant pre-clinical and clinical studies on ESR1 mutations regarding endocrine resistance are reviewed, with particular interest in the ultimate goal of guiding treatment decision-making based on ESR1 mutations. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  16. Matrix Rigidity Induces Osteolytic Gene Expression of Metastatic Breast Cancer Cells

    PubMed Central

    Ruppender, Nazanin S.; Merkel, Alyssa R.; Martin, T. John; Sterling, Julie A.; Guelcher, Scott A.

    2010-01-01

    Nearly 70% of breast cancer patients with advanced disease will develop bone metastases. Once established in bone, tumor cells produce factors that cause changes in normal bone remodeling, such as parathyroid hormone-related protein (PTHrP). While enhanced expression of PTHrP is known to stimulate osteoclasts to resorb bone, the environmental factors driving tumor cells to express PTHrP in the early stages of development of metastatic bone disease are unknown. In this study, we have shown that tumor cells known to metastasize to bone respond to 2D substrates with rigidities comparable to that of the bone microenvironment by increasing expression and production of PTHrP. The cellular response is regulated by Rho-dependent actomyosin contractility mediated by TGF-ß signaling. Inhibition of Rho-associated kinase (ROCK) using both pharmacological and genetic approaches decreased PTHrP expression. Furthermore, cells expressing a dominant negative form of the TGF-ß receptor did not respond to substrate rigidity, and inhibition of ROCK decreased PTHrP expression induced by exogenous TGF-ß. These observations suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis, which is especially important in metastatic cancer since many cancers (such as those of the breast and lung) preferentially metastasize to bone. PMID:21085597

  17. Perceptions and needs of women with metastatic breast cancer: a focus on clinical trials.

    PubMed

    Nahleh, Zeina A; Lin, Nancy U; Wolff, Antonio C; Cardoso, Fatima

    2013-06-01

    Many patients are living longer with Metastatic Breast Cancer (MBC) than ever before. However, complete responses remain uncommon, and progression of disease is often inevitable. The experience of living with MBC exposes patients to a wide variety of clinical, psychological, social and spiritual issues. Although much research effort has focused on decision-making and coping strategies among women with early breast cancer, relatively little attention has been given to the needs, experiences, and perceptions of women living with MBC. Furthermore, there are major research gaps in understanding and prioritizing the types of psycho-social interventions that would make the most difference in the lives of these patients. Fortunately, the tide is turning. This communication represents a joint effort of the Breast International Group and the National Cancer Institute (NCI)-sponsored North American Breast Cancer Group (BIG-NABCG) to highlight perceptions and needs of patients living with MBC and current obstacles facing them, and recommends strategies for better addressing some of these unmet needs.

  18. Local microRNA delivery targets Palladin and prevents metastatic breast cancer

    PubMed Central

    Gilam, Avital; Conde, João; Weissglas-Volkov, Daphna; Oliva, Nuria; Friedman, Eitan; Artzi, Natalie; Shomron, Noam

    2016-01-01

    Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3′-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug. PMID:27641360

  19. Cushing's storm secondary to a rare case of ectopic ACTH secreting metastatic breast cancer

    PubMed Central

    Bucciarelli, Maura; Lee, Ya-Yu

    2015-01-01

    Summary Ectopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non-sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure. Learning points Cushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.Cushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.Etomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone. PMID:26525183

  20. Diagnosis and surgical management of breast cancer metastatic to the spine

    PubMed Central

    Ju, Derek G; Yurter, Alp; Gokaslan, Ziya L; Sciubba, Daniel M

    2014-01-01

    Breast cancer is the most common malignancy and the second leading cause of death in Western women. Breast cancer most commonly metastasizes to the bone and has a particular affinity with the spine, accounting for 2/3 of osseous metastases discovered. With significant improvements in cancer therapies, the number of patients at risk for symptomatic spinal metastases is likely to increase. Patients may suffer from intractable pain and neurological dysfunction, negatively influencing their quality of life. Timely diagnosis of patients is crucial and has been aided by several breakthrough advances in imaging techniques which aid in detection, staging, and follow-up of bone metastases. Breast metastases are usually responsive to hormonal therapy and pharmacologic interventions, but skeletal metastases often require surgical intervention. The treatments are palliative but goals include the preserving or restoring neurologic function, ensuring spinal stability, and relieving pain. Advances in surgical techniques and instrumentation have allowed more effective decompression and stabilization of the spine, and with the support of recent evidence the trend has shifted towards using more advanced surgical options in appropriately selected patients. In this review, the clinical presentation, diagnosis, patient selection, and surgical management of breast cancer metastatic to the spine are discussed. PMID:25114843

  1. Fine-needle aspiration cytology diagnosis of metastatic nonhaematological neoplasms of the breast: a series of seven cases.

    PubMed

    Rodríguez-Gil, Yolanda; Pérez-Barrios, Andrés; Alberti-Masgrau, Nuria; Garzón, Alfredo; de Agustín, Pedro

    2012-04-01

    Metastatic neoplasms of the breast are rare. Mammary metastases as the initial presentation are even more infrequent and can simulate a primary malignancy clinically and radiologically. Recognition of metastatic tumors in the breast is important because it would prevent unnecessary mutilating surgery and would lead to appropriate treatment of the primary tumor. There is a broad variety of cytological appearances reported about primary tumors and few reports about secondary breast malignancies, specially diagnosed by FNAC. This study was carried out to examine the clinical and cytomorphologic features of metastatic breast tumors found in 12 de Octubre University Hospital during a period of 20 years. It confirms the utility of FNAC and describes findings that can help in the differential diagnosis that sometimes can be very difficult. Seven cases of nonhematological metastatic neoplasms of the breast were identified from the files of the Department of Pathology of the 12 de Octubre University Hospital from a total of 64,000 aspirates. We included only metastatic tumors from extramammary nonhematological neoplasms. There were nine cases of hematological metastatic neoplasm that were excluded. They were diagnosed with FNAC and confirmed by histopathology, with at least three years of follow up. The breast lump was the first manifestation of malignancy in one case of synovial sarcoma. The other six cases had been previously diagnosed of cancer. These included one malignant melanoma, one alveolar rhabdomyosarcoma, one mixed müllerian tumor, one medullary carcinoma of thyroid, one colonic adenocarcinoma, and one gastric adenocarcinoma. The period of time between primary tumor and metastases ranged from one month to eight years. An accurate cytologic diagnosis was made in all the cases. Immunocytochemistry was available but diagnosis could be made with cytomorphology alone in the seven cases. Fine-needle aspiration cytology is an excellent first line diagnostic modality

  2. Prospective Study Evaluating the Impact of Tissue Confirmation of Metastatic Disease in Patients With Breast Cancer

    PubMed Central

    Amir, Eitan; Miller, Naomi; Geddie, William; Freedman, Orit; Kassam, Farrah; Simmons, Christine; Oldfield, Maria; Dranitsaris, George; Tomlinson, George; Laupacis, Andreas; Tannock, Ian F.; Clemons, Mark

    2012-01-01

    Purpose Decisions about treatment for women with metastatic breast cancer are usually based on the estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor 2 (HER2) status of the primary tumor. Retrospective data suggest that discordance between primary and metastatic lesions leads to detrimental outcome. This prospective study investigated receptor status of primary tumors and metastases in the same patient and assessed the impact of discordance on patient management and survival. Patients and Methods Biopsies of suspected metastases were analyzed for ER, PgR, and HER2. Primary tumors and metastases were analyzed using similar methodology. The treating oncologist indicated a treatment plan before and after biopsy to determine whether the result influenced management. Patients were followed up for progression or death. Results Of 121 women undergoing biopsy, 80% could be analyzed for receptor status. Discordance in ER, PgR, and HER2 between the primary and the metastasis was 16%, 40%, and 10%, respectively. Biopsy led to a reported change of management in 14% of women (95% CI, 8.4% to 21.5%). Fine-needle aspiration and biopsy of bone led to reduced ability to analyze receptors. After a median follow-up of 12 months, there were no trends for an association between receptor discordance and either time to treatment failure or overall survival. Conclusion Biopsy of metastases is technically feasible. Clinicians alter immediate management in one of seven patients on the basis of results of the biopsy, and discordance is not then associated with detrimental effects on outcome. Tissue confirmation should be considered in women with breast cancer and suspected metastatic recurrence. PMID:22124102

  3. Biweekly Pegylated Liposomal Doxorubicin (Caelyx) in Heavily Pretreated Metastatic Breast Cancer: A Phase 2 Study.

    PubMed

    Jehn, Christian F; Hemmati, Philipp; Lehenbauer-Dehm, Silvia; Kümmel, Sherko; Flath, Bernd; Schmid, Peter

    2016-12-01

    Pegylated liposomal doxorubicin (PLD) has shown to be as effective as conventional doxorubicin in the treatment of metastatic breast cancer but provides a lower risk of cardiotoxicity. This phase 2 study in heavily pretreated patients with metastatic breast cancer was initiated to evaluate a biweekly instead of a 4-week schedule of PLD in order to obtain a more flexible and tolerable regimen. A total of 25 patients with 2 or more prior lines of chemotherapy for metastatic disease were treated with PLD (25 mg/m(2)) at 2-week intervals for a maximum of 12 courses. Pretreatment with anthracyclines was allowed as long as the cumulative doxorubicin dose at study entry was below 400 mg/m(2). Most patients were pretreated with anthracyclines, taxanes, vinorelbine, alkylating agents, and capecitabine. The clinical benefit rate, ie, objective response or stable disease, for at least 6 months was 22.7% for all patients and 22.2% in anthracycline- and taxane-pretreated patients, respectively. Median duration of clinical benefit and median time to progression were 12.5 months (95% confidence interval [CI], 10.1-32.3) and 7 weeks (95% CI, 5.4-8.6), respectively. Median overall survival was 9.6 months (95% CI, 5.4-13.9). One- and 2-year survival rates were 38% and 4%, respectively. Myelosuppression was low, with no grade 3 or 4 neutropenia or thrombocytopenia. Most common nonhematologic toxicities were nausea, alopecia, asthenia, and hand-foot syndrome. The low rate of hematologic toxicity and hand-foot syndrome is clinically noteworthy. Biweekly PLD is an easily manageable schedule with a favorable toxicity profile. Efficacy was moderate in heavily pretreated patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Health-related Quality of Life in Metastatic and Adjuvant Breast Cancer Patients

    PubMed Central

    Wallwiener, M.; Simoes, E.; Sokolov, A. N.; Brucker, S. Y.; Fasching, P. A.; Graf, J.

    2016-01-01

    Introduction: When cancer patients have advanced disease and a primary cure is no longer possible, the focus is on maintaining the patientʼs quality of life. Recent therapeutic advances in breast cancer treatment mean that even patients with metastatic disease can remain stable for long periods of time. The aim of this study was to look at the health-related quality of life (HRQL) of these patients and compare it with data for the general population and to show the differences in outcomes for different survey instruments used to measure quality of life. Material and Methods: A total of 96 breast cancer patients with metastatic disesae or receiving adjuvant therapy were questioned about their quality of life. Patients were investigated using the established survey instruments EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L and EQ VAS. All patients filled out questionnaires. Statistical analysis was done using MS Excel and SPSS. Results: Although the questionnaires were completed at the same time, the different questionnaires showed significant differences with regard to the level of stress experienced by the patient. When the EQ VAS questionnaire was used, the patientʼs current state of health was assessed as significantly better than with the EORTC QLQ-C30. Overall, all aspects of patientsʼ quality of life were found to be in need of optimization and HRQL of patients was significantly poorer in all areas compared to the reference population. Conclusion: To improve the quality of life of patients with metastatic disease, it is necessary to continuously monitor the success of therapy. The choice of survey tools is highly relevant as assessments differ considerably depending on the choice of questionnaire. PMID:27761027

  5. Altering the Microenvironment to Promote Dormancy of Metastatic Breast Cancer Cell in a 3D Bone Culture System

    DTIC Science & Technology

    2015-04-01

    cytokines are critical for metastatic breast cancer cells to grow or remain dormant. This hypothesis is being tested using a 3D bioreactor of ECM...bone. Although we have not yet tested for cytokines, we hypothesize that the breast cancer-osteoblast inflammatory response may be exacerbated with...Scale bar = 100 μm. 7 a.2 Collagenous and non-collagenous proteins We tested whether estrogen in the medium affected the collagenous and non

  6. An Evaluation of Algorithms for Identifying Metastatic Breast, Lung, or Colorectal Cancer in Administrative Claims Data.

    PubMed

    Whyte, Joanna L; Engel-Nitz, Nicole M; Teitelbaum, April; Gomez Rey, Gabriel; Kallich, Joel D

    2015-07-01

    Administrative health care claims data are used for epidemiologic, health services, and outcomes cancer research and thus play a significant role in policy. Cancer stage, which is often a major driver of cost and clinical outcomes, is not typically included in claims data. Evaluate algorithms used in a dataset of cancer patients to identify patients with metastatic breast (BC), lung (LC), or colorectal (CRC) cancer using claims data. Clinical data on BC, LC, or CRC patients (between January 1, 2007 and March 31, 2010) were linked to a health care claims database. Inclusion required health plan enrollment ≥3 months before initial cancer diagnosis date. Algorithms were used in the claims database to identify patients' disease status, which was compared with physician-reported metastases. Generic and tumor-specific algorithms were evaluated using ICD-9 codes, varying diagnosis time frames, and including/excluding other tumors. Positive and negative predictive values, sensitivity, and specificity were assessed. The linked databases included 14,480 patients; of whom, 32%, 17%, and 14.2% had metastatic BC, LC, and CRC, respectively, at diagnosis and met inclusion criteria. Nontumor-specific algorithms had lower specificity than tumor-specific algorithms. Tumor-specific algorithms' sensitivity and specificity were 53% and 99% for BC, 55% and 85% for LC, and 59% and 98% for CRC, respectively. Algorithms to distinguish metastatic BC, LC, and CRC from locally advanced disease should use tumor-specific primary cancer codes with 2 claims for the specific primary cancer >30-42 days apart to reduce misclassification. These performed best overall in specificity, positive predictive values, and overall accuracy to identify metastatic cancer in a health care claims database.

  7. The Subclonal Architecture of Metastatic Breast Cancer: Results from a Prospective Community-Based Rapid Autopsy Program “CASCADE”

    PubMed Central

    Flensburg, Christoffer; Alsop, Kathryn; Mansour, Mariam; Francis, Prudence A.; Thorne, Heather A.; Silva, Maria Joao; Kanu, Nnennaya; Dietzen, Michelle; Bowtell, David D.; Speed, Terence P.; Swanton, Charles; Loi, Sherene

    2016-01-01

    Background Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. However, evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings Three patients with oestrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program (CASCADE). Cases represented a range of management problems in breast cancer, including late relapse after early stage disease, de novo metastatic disease, discordant disease response, and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism (SNP) arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing. Between cases, there were significant differences in mutational burden, driver mutations, mutational processes, and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross-seeding was found in each case, and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We

  8. Immunohistochemical distinction of primary sweat gland carcinoma and metastatic breast carcinoma: can it always be accomplished reliably?

    PubMed

    Mentrikoski, Mark J; Wick, Mark R

    2015-03-01

    Even with adequate history, the distinction of cutaneous metastatic breast carcinoma from primary sweat gland carcinoma can be difficult. Although previous studies have attempted to separate these tumors with various immunohistochemical panels, those series have been limited by small numbers of patients as well as the inclusion of benign sweat gland tumors. In this analysis, stains for p63, CK5/6, and D2-40 were included, as well as GATA3 and mammaglobin, in an evaluation of 21 primary sweat gland carcinomas and 33 examples of cutaneous metastatic breast carcinoma. Immunoreactivity for p63, CK5/6, D2-40, GATA3, and mammaglobin was respectively observed in 81%, 71%, 52%, 71%, and 5% of sweat gland carcinomas compared with 6%, 6%, 6%, 91%, and 45% of metastatic breast carcinomas. These differences were statistically significant for p63, CK5/6, and D2-40. For the diagnosis of metastatic breast carcinoma, GATA3 was the most sensitive marker (91%), but its sensitivity was substantially lower. Mammaglobin was 95% specific for breast carcinoma but again suffered from limited sensitivity (45%) in this context. These data suggest that p63 and CK5/6 are specific determinants for sweat gland carcinoma in the stated setting. In the absence of those analytes, metastatic breast carcinoma cannot always be identified to the exclusion of a primary tumor. This diagnostic scenario continues to require the procurement of a detailed clinical history regarding the number and duration of skin lesions in any given case. Copyright© by the American Society for Clinical Pathology.

  9. Detection of primary breast cancer presenting as metastatic carcinoma of unknown primary origin by 111In-pentetreotide scan.

    PubMed

    Lenzi, R; Kim, E E; Raber, M N; Abbruzzese, J L

    1998-02-01

    Women with isolated metastatic carcinoma or adenocarcinoma involving axillary lymph nodes are a well-recognized group of unknown primary carcinoma (UPC) patients with a favorable prognosis. This group of patients are generally treated based on the assumption that they have occult breast cancer. However, to facilitate patient access to the whole spectrum of therapies available for patients with breast cancer, including strategies involving the use of high-dose chemotherapy, a precise diagnosis is increasingly important. In this clinical case we report the detection of a primary breast cancer by 111In-pentetreotide scanning in a woman who presented with metastatic carcinoma in axillary nodes, no palpable breast lesion, a nondiagnostic mammogram, and negative breast ultrasonography. Previous outcomes analysis of patients with UPC have emphasized the value of identifying women with breast cancer. This report suggests that the 111In-pentetreotide scan can contribute specific, clinically useful information in the evaluation of women presenting with metastatic carcinoma in axillary nodes and an occult primary and deserves prospective study in women with UPC presenting with isolated axillary metastases.

  10. Pembrolizumab and Binimetinib in Treating Patients With Locally Advanced or Metastatic Triple Negative Breast Cancer

    ClinicalTrials.gov

    2017-09-27

    Breast Adenocarcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  11. Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity

    PubMed Central

    Sambi, Manpreet; Haq, Sabah; Samuel, Vanessa; Qorri, Bessi; Haxho, Fiona; Hill, Kelli; Harless, William; Szewczuk, Myron R

    2017-01-01

    One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current

  12. Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity.

    PubMed

    Sambi, Manpreet; Haq, Sabah; Samuel, Vanessa; Qorri, Bessi; Haxho, Fiona; Hill, Kelli; Harless, William; Szewczuk, Myron R

    2017-01-01

    One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current

  13. Minimal residual disease in bone marrow and peripheral blood of patients with metastatic breast cancer.

    PubMed

    Bischoff, Joachim; Rosenberg, Robert; Dahm, Michael; Janni, Wolfgang; Gutschow, Klaus

    2003-01-01

    The presence of occult micrometastases in bone marrow (BM) of patients with early breast cancer increases the risk of relapse. Detection of circulation tumor cells in peripheral blood (PB) may also influence the patient's prognosis. Few data are available on the correlation between tumor cell dissemination in BM and PB in solid epithelial tumors. Twenty-milliliter blood samples were collected from PB of 42 patients with advanced breast cancer and centrifuged using the density gradient OncoQuick (OncoQuick Greiner BioOne, Frickenhausen, Germany). The BM aspirates available from 11 of the 42 patients were centrifuged using density centrifugation Ficoll. Tumor cell detection was performed by microscopy after cytospin preparation and immunocytochemical staining with the monoclonal antibody A45-B/B3. Cytokeratin-positive cells were detected in 23 patients (55%) in the PB and in three patients (27%) in the BM. A cohort with bone lesions as the only metastatic side showed a correlation as follows: 7 of the 11 patients (64%) had negative findings in BM and PB, whereas cytokeratin-positive cells in PB were present in 3 of these 11 patients (27%). The presence of visceral metastases was associated with the detection of cytokeratin-positive cells in the PB in 20 of the 31 patients (65%) in this subgroup. The density gradient OncoQuick in combination with immunocytochemical staining allows the detection of cytokeratin-positive cells in PB of patients with advanced breast cancer. The immunocytochemical detection of cytokeratin-positive cells in PB seems to be associated with the site of metastatic manifestation.

  14. Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells.

    PubMed

    Mantena, Sudheer K; Baliga, Manjeshwar S; Katiyar, Santosh K

    2006-08-01

    The strategies available for the treatment of metastatic breast cancer are limited. Dietary botanicals may have a better protective effect on this disease. We therefore investigated the effects of grape seed proanthocyanidins (GSPs) on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of breast cancer cells, 4T1, MCF-7 and MDA-MB-468, with GSPs resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in 4T1 cells in a time- and dose-dependent manner. Further analysis indicated an alteration in the ratio of Bax/Bcl-2 proteins in favor of apoptosis, and the knockdown of Bax using Bax siRNA transfection of 4T1 cells resulted in blocking of GSPs-induced apoptosis. Induction of apoptosis was associated with the release of cytochrome c, increased expression of Apaf-1 and activation of caspase 3 and poly (ADP-ribose) polymerase. Treatment with the pan-caspase inhibitor (Z-VAD-FMK) resulted in partial but significant inhibition of apoptosis in 4T1 cells suggesting the involvement of both caspase activation-dependent and activation-independent pathways in the apoptosis of 4T1 cells induced by GSPs. The effects of dietary GSPs were then examined using an in vivo model in which 4T1 cells were implanted subcutaneously in Balb/c mice. Dietary GSPs (0.2 and 0.5%, w/w) significantly inhibited the growth of the implanted 4T1 tumor cells and increased the ratio of Bax:Bcl-2 proteins, cytochrome c release, induction of Apaf-1 and activation of caspase 3 in the tumor microenvironment. Notably, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggest that GSPs possess chemotherapeutic efficacy against breast cancer including inhibition of metastasis.

  15. Eribulin in heavily pretreated metastatic breast cancer patients and clinical/biological feature correlations: impact on the practice.

    PubMed

    Fabi, Alessandra; Moscetti, Luca; Ciccarese, Mariangela; Caramanti, Miriam; Salesi, Nello; La Verde, Nicla; Russillo, Michelangelo; Generali, Daniele; Scandurra, Giuseppina; Vari, Sabrina; Pacetti, Umberto; Cognetti, Francesco; Giannarelli, Diana

    2015-01-01

    This multicenter study describes the effectiveness of eribulin in current practice. In total, 78 patients with advanced metastatic breast cancer, previously treated with two or more chemotherapy lines were enrolled. The median duration of response and disease stability were 7.5 (5.4-9.5) and 8.9 (6.2-11.6) months, respectively, with a clinical benefit (CB) at 6 months in 41% of patients. CB in visceral and nonvisceral metastases were 72.7 and 88.9%, respectively. Eribulin was active also in brain metastases, with 47% CB. The activity was shown in all biological subtypes. Toxicities were manageable. Our study confirms the effectiveness of eribulin mesylate in the treatment of patients with metastatic breast cancer and two or more lines of chemotherapy, in particular in the good disease control at the different metastatic sites.

  16. Detection of Metastatic Breast and Thyroid Cancer in Lymph Nodes by Desorption Electrospray Ionization Mass Spectrometry Imaging

    NASA Astrophysics Data System (ADS)

    Zhang, Jialing; Feider, Clara L.; Nagi, Chandandeep; Yu, Wendong; Carter, Stacey A.; Suliburk, James; Cao, Hop S. Tran; Eberlin, Livia S.

    2017-06-01

    Ambient ionization mass spectrometry has been widely applied to image lipids and metabolites in primary cancer tissues with the purpose of detecting and understanding metabolic changes associated with cancer development and progression. Here, we report the use of desorption electrospray ionization mass spectrometry (DESI-MS) to image metastatic breast and thyroid cancer in human lymph node tissues. Our results show clear alterations in lipid and metabolite distributions detected in the mass spectra profiles from 42 samples of metastatic thyroid tumors, metastatic breast tumors, and normal lymph node tissues. 2D DESI-MS ion images of selected molecular species allowed discrimination and visualization of specific histologic features within tissue sections, including regions of metastatic cancer, adjacent normal lymph node, and fibrosis or adipose tissues, which strongly correlated with pathologic findings. In thyroid cancer metastasis, increased relative abundances of ceramides and glycerophosphoinisitols were observed. In breast cancer metastasis, increased relative abundances of various fatty acids and specific glycerophospholipids were seen. Trends in the alterations in fatty acyl chain composition of lipid species were also observed through detailed mass spectra evaluation and chemical identification of molecular species. The results obtained demonstrate DESI-MSI as a potential clinical tool for the detection of breast and thyroid cancer metastasis in lymph nodes, although further validation is needed. [Figure not available: see fulltext.

  17. Detection of Metastatic Breast and Thyroid Cancer in Lymph Nodes by Desorption Electrospray Ionization Mass Spectrometry Imaging

    NASA Astrophysics Data System (ADS)

    Zhang, Jialing; Feider, Clara L.; Nagi, Chandandeep; Yu, Wendong; Carter, Stacey A.; Suliburk, James; Cao, Hop S. Tran; Eberlin, Livia S.

    2017-02-01

    Ambient ionization mass spectrometry has been widely applied to image lipids and metabolites in primary cancer tissues with the purpose of detecting and understanding metabolic changes associated with cancer development and progression. Here, we report the use of desorption electrospray ionization mass spectrometry (DESI-MS) to image metastatic breast and thyroid cancer in human lymph node tissues. Our results show clear alterations in lipid and metabolite distributions detected in the mass spectra profiles from 42 samples of metastatic thyroid tumors, metastatic breast tumors, and normal lymph node tissues. 2D DESI-MS ion images of selected molecular species allowed discrimination and visualization of specific histologic features within tissue sections, including regions of metastatic cancer, adjacent normal lymph node, and fibrosis or adipose tissues, which strongly correlated with pathologic findings. In thyroid cancer metastasis, increased relative abundances of ceramides and glycerophosphoinisitols were observed. In breast cancer metastasis, increased relative abundances of various fatty acids and specific glycerophospholipids were seen. Trends in the alterations in fatty acyl chain composition of lipid species were also observed through detailed mass spectra evaluation and chemical identification of molecular species. The results obtained demonstrate DESI-MSI as a potential clinical tool for the detection of breast and thyroid cancer metastasis in lymph nodes, although further validation is needed.

  18. Inoculated Cell Density as a Determinant Factor of the Growth Dynamics and Metastatic Efficiency of a Breast Cancer Murine Model

    PubMed Central

    Gregório, Ana C.; Fonseca, Nuno A.; Moura, Vera; Lacerda, Manuela; Figueiredo, Paulo; Simões, Sérgio; Dias, Sérgio; Moreira, João Nuno

    2016-01-01

    4T1 metastatic breast cancer model have been widely used to study stage IV human breast cancer. However, the frequent inoculation of a large number of cells, gives rise to fast growing tumors, as well as to a surprisingly low metastatic take rate. The present work aimed at establishing the conditions enabling high metastatic take rate of the triple-negative murine 4T1 syngeneic breast cancer model. An 87% 4T1 tumor incidence was observed when as few as 500 cancer cells were implanted. 4T1 cancer cells colonized primarily the lungs with 100% efficiency, and distant lesions were also commonly identified in the mesentery and pancreas. The drastic reduction of the number of inoculated cells resulted in increased tumor doubling times and decreased specific growth rates, following a Gompertzian tumor expansion. The established conditions for the 4T1 mouse model were further validated in a therapeutic study with peguilated liposomal doxorubicin, in clinical used in the setting of metastatic breast cancer. Inoculated cell density was proven to be a key methodological aspect towards the reproducible development of macrometastases in the 4T1 mouse model and a more reliable pre-clinical assessment of antimetastatic therapies. PMID:27820870

  19. Endomedullary radiofrequency ablation of metastatic lesion of the right femur 5 years after primary breast carcinoma: a case report.

    PubMed

    Majerović, Mate; Augustin, Goran; Jelincić, Zeljko; Buković, Damir; Burcar, Ivan; Smud, Dubravko; Kekez, Tihomir; Kinda, Emil; Matosević, Petar; Turcić, Josip

    2008-12-01

    Metastatic tumors of the long bones usually present with severe pain refractory to analgesic therapy. Pathologic fractures of the bone may lead to the significant decrease of patient's quality of life and necessitate further surgical therapy. We present 66 year old female with metastatic left breast carcinoma (T2N0M0) diagnosed 5 years before presentation of the metastatic lesion of the right femur causing severe pain in the middle of the right upper leg. Pain persisted after palliative irradiation therapy. We performed radiofrequency ablation of the metastatic lesion of the right femur using R.I.TA. Medical System Generator. This resulted in total necrosis of the tumor mass that caused osteolysis of the internal part of the femoral cortex. First three months after RFA procedure, the pain and tenderness were absent and normal daily activities were performed without restrictions.

  20. Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer

    PubMed Central

    Weber, Günther; Chamorro, Clara Ibel; Granath, Fredrik; Liljegren, Annelie; Zreika, Sami; Saidak, Zuzana; Sandstedt, Bengt; Rotstein, Samuel; Mentaverri, Romuald; Sánchez, Fabio; Pivarcsi, Andor; Ståhle, Mona

    2009-01-01

    Introduction Human cathelicidin antimicrobial protein, hCAP18, and its C-terminal peptide LL-37 is a multifunctional protein. In addition to being important in antimicrobial defense, it induces chemotaxis, stimulates angiogenesis and promotes tissue repair. We previously showed that human breast cancer cells express high amounts of hCAP18, and hypothesised that hCAP18/LL-37 may be involved in tumour progression. Methods hCAP18 mRNA was quantified in 109 primary breast cancers and compared with clinical findings and ERBB2 mRNA expression. Effects of exogenous LL-37 and transgenic overexpression of hCAP18 on ErbB2 signalling were investigated by immunoblotting using extracts from breast cancer cell lines ZR75-1 and derivatives of MCF7. We further analysed the impact of hCAP18/LL-37 on the morphology of breast cancer cells grown in soft agar, on cell migration and on tumour development in severe combined immunodeficiency (SCID) mice. Results The expression of hCAP18 correlated closely with that of ERBB2 and with the presence of lymph node metastases in oestrogen receptor-positive tumours. hCAP18/LL-37 amplified Heregulin-induced mitogen-activated protein kinase (MAPK) signalling through ErbB2, identifying a functional association between hCAP18/LL-37 and ErbB2 in breast cancer. Treatment with LL-37 peptide significantly stimulated the migration of breast cancer cells and their colonies acquired a dispersed morphology indicative of increased metastatic potential. A truncated version of LL-37 competitively inhibited LL-37 induced MAPK phosphorylation and significantly reduced the number of altered cancer cell colonies induced by LL-37 as well as suppressed their migration. Transgenic overexpression of hCAP18 in a low malignant breast cancer cell line promoted the development of metastases in SCID mice, and analysis of hCAP18 transgenic tumours showed enhanced activation of MAPK signalling. Conclusions Our results provide evidence that hCAP18/LL-37 contributes to breast

  1. OBP-401-GFP telomerase-dependent adenovirus illuminates and kills high-metastatic more effectively than low-metastatic triple-negative breast cancer in vitro.

    PubMed

    Yano, S; Takehara, K; Kishimoto, H; Tazawa, H; Urata, Y; Kagawa, S; Bouvet, M; Fujiwara, T; Hoffman, R M

    2017-02-01

    We previously described the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared with 2 of 12 of the parental cell line. OBP-401 is a telomerase-dependent cancer-specific, green fluorescent protein (GFP)-expressing adenovirus. OBP-401 was used to infect parental MDA-MB-231P cells and high-metastatic MDA-MB-231H and MDA-MB-231HLN isolated from a lymph node metastasis and MDA-MB-231HLM isolated from a lung metastasis. Time-course imaging showed that OBP-401 labeled MDA-MB-231HP, MDA-MB-231HLN, and MDA-MB-231HLM cells more brightly than MDA-MB-231 parental cells. OBP-401 killed MDA-MB-231H, MDA-MB-231HLN, and MDA-MB-231HLM cells more efficiently than MDA-MB-231P parental cells. These results indicate that OBP-401 could infect, label and then kill high-metastatic MDA-MB-231 more efficiently than low-metastatic MDA-MB-231.

  2. Methyl Sulfone Blocked Multiple Hypoxia- and Non-Hypoxia-Induced Metastatic Targets in Breast Cancer Cells and Melanoma Cells

    PubMed Central

    Caron, Joan McIntyre; Caron, Jane McIntyre

    2015-01-01

    Metastatic cancer causes 90% of cancer deaths. Unlike many primary tumors, metastatic tumors cannot be cured by surgery alone. Metastatic cancer requires chemotherapy. However, metastatic cells are not easily killed by chemotherapy. These problems with chemotherapy are caused in part by the metastatic cell niche: hypoxia. Here we show that the molecule, methyl sulfone, normalized metastatic metabolism of hypoxic breast cancer and melanoma cells by altering several metabolic functions of the cells. Under hypoxia, methyl sulfone decreased expression of the master regulator of hypoxia, HIF-1α, and reduced levels of the glycolytic enzymes, PKM2, LDHA, GLUT1, the pro-angiogenic protein, VEGF, and the iron-sulfur metabolism molecules, miR-210 and transferrin, all of which promote metastasis. Conversely, methyl sulfone increased levels of ISCU1/2 and ferroportin, proteins associated with iron-sulfur cluster biogenesis and iron homeostasis in normal cells. These data identify methyl sulfone as a multi-targeting molecule that blocks the survival/proliferative effect of hypoxia on metastatic cells and brings normality back to cellular metabolism. PMID:26536104

  3. Genomic profiling of isolated circulating tumor cells from metastatic breast cancer patients

    PubMed Central

    Magbanua, Mark Jesus M.; Sosa, Eduardo V.; Roy, Ritu; Eisenbud, Lauren E.; Scott, Janet H.; Olshen, Adam; Pinkel, Dan; Rugo, Hope; Park, John W.

    2014-01-01

    Molecular characterization of circulating tumor cells (CTCs) from blood is technically challenging because cells are rare and difficult to isolate. We developed a novel approach to isolate CTCs from blood via immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS). Isolated CTCs were subjected to genome-wide copy number analysis via array comparative genomic hybridization (aCGH). In clinical studies, CTCs were isolated from 181 patients with metastatic breast cancer, 102 of which were successfully profiled, including matched archival primary tumor from five patients. CTCs revealed a wide range of copy number alterations including those previously reported in breast cancer. Comparison with two published aCGH datasets of primary breast tumors revealed similar frequencies of recurrent genomic copy number aberrations. In addition, serial testing of CTCs confirmed reproducibility and indicated genomic change over time. Comparison of CTCs with matched archival primary tumors confirmed shared lineage with notable divergence. We demonstrate that it is feasible to isolate CTCs away from hematopoietic cells with high purity via IE/FACS and profile them via aCGH analysis. Our approach may be utilized to explore genomic events involved in cancer progression and to monitor therapeutic efficacy of targeted therapies in clinical trials in a relatively non-invasive manner. PMID:23135909

  4. Role of bone and liver scans in surveying patients with breast cancer for metastatic disease

    SciTech Connect

    Evans, D.M.; Wright, D.J.

    1987-10-01

    The objective of this study is to correlate the presence of bone and liver metastases in patients with breast cancer with respect to the results of bone and liver scans, axillary nodal status, and serum alkaline phosphatase levels. One hundred ninety-seven patients with breast cancer treated by modified radical mastectomy between the years 1978 and 1981 were studied. Fifty-nine (30%) of the total group had distant metastases during the course of observation of 60 to 96 months; of 35 patients in whom bone metastases developed, 30 had normal preoperative bone scan results. Of 21 patients who had liver metastases, 19 had normal preoperative liver scans. Nineteen (70%) of the 27 patients with abnormal bone scans had normal alkaline phosphatase levels. Seven (63%) of the 11 patients who had abnormal liver scans had a normal alkaline phosphatase. The study supports the concept that preoperative bone and liver scans are ineffective indicators of metastatic involvement. Selection of patients for screening by bone and liver scans according to alkaline phosphatase determinations was not supported by this study. The appropriate use of bone scans for screening in patients with breast carcinoma is suggested as a follow-up device in patients with positive lymph nodes.

  5. Low-temperature plasma needle effects on cultured metastatic breast cancer cells

    NASA Astrophysics Data System (ADS)

    Knecht, Sean; Bilen, Sven; Micci, Michael; Brubaker, Timothy; Wilson, Michael; Cook, Ian; Czesak, Nicholas; Hipkins, Garret

    2015-11-01

    The Penn State Low-Temperature Plasma group is presently investigating the applications of low-temperature plasma for biomedical applications, including the effects on MDA-MB-231 metastatic breast cancer cells. A plasma needle system has been designed and constructed that consists of a 22-gauge stainless steel syringe needle, which acts as the high-voltage electrode, covered with PEEK tubing as the dielectric with a ring ground electrode on the outside. The system is driven by a low-frequency AC voltage amplifier, with typical operating conditions of 2-5 kV peak voltage at 5 kHz. Helium is used as the working fluid and produces a plasma jet with ~ cm's visible extent. Cultured breast cancer cells were provided by our collaborator and exposed to the plasma needle for varying doses and detachment of cells was observed. The effects are attributed to reactive oxygen and nitrogen species generation and transport through the cell culture medium. Plasma needle characterization and the results of the breast cancer experiments will be presented.

  6. Interplay between YB-1 and IL-6 promotes the metastatic phenotype in breast cancer cells

    PubMed Central

    Castellana, Bàrbara; Aasen, Trond; Moreno-Bueno, Gema; Dunn, Sandra E.; Ramón y Cajal, Santiago

    2015-01-01

    Epithelial to mesenchymal transition (EMT) induces cell plasticity and promotes metastasis. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) and the pleiotropic cytokine interleukin 6 (IL-6) have both been implicated in tumor cell metastasis and EMT, but via distinct pathways. Here, we show that direct interplay between YB-1 and IL-6 regulates breast cancer metastasis. Overexpression of YB-1 in breast cancer cell lines induced IL-6 production while stimulation with IL-6 increased YB-1 expression and YB-1 phosphorylation. Either approach was sufficient to induce EMT features, including increased cell migration and invasion. Silencing of YB-1 partially reverted the EMT and blocked the effect of IL-6 while inhibition of IL-6 signaling blocked the phenotype induced by YB-1 overexpression, demonstrating a clear YB-1/IL-6 interdependence. Our findings describe a novel signaling network in which YB-1 regulates IL-6, and vice versa, creating a positive feed-forward loop driving EMT-like metastatic features during breast cancer progression. Identification of signaling partners or pathways underlying this co-dependence may uncover novel therapeutic opportunities. PMID:26512918

  7. A phase I study of ixabepilone in combination with epirubicin in patients with metastatic breast cancer.

    PubMed

    Roché, Henri; De Benedictis, Elena; Cottura, Ewa; Govi, Silvia; Dalenc, Florence; Locatelli, Alberta; Deslandres, Marion; Zambetti, Milvia; Gladieff, Laurence; Messina, Marianne; Gianni, Luca

    2012-06-01

    In this phase I trial, 42 women with metastatic breast cancer were treated with a fixed dose of epirubicin (75 mg/m2) and escalating doses of ixabepilone (25, 30, and 35 mg/m2). The maximum-tolerated dose of ixabepilone in combination with epirubicin was 30 mg/m2 (the recommended dose for phase II evaluation), and the dose-limiting toxicity dose was 35 mg/m2 with grade 4 neutropenia. The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer. Patients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m(2)) and escalating doses of ixabepilone (25, 30, and 35 mg/m(2)). Forty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m(2) (n = 6) in combination with 75 mg/m(2) epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m(2) was 30 mg/m(2), and the DLT dose was 35 mg/m(2) with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels. The combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m(2), followed by ixabepilone 30 mg/m(2) every 3 weeks. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer

    PubMed Central

    Kim, Min Soo; Jeong, Joon; Seo, Jeongbeob; Kim, Hae-Suk; Kim, Seong-Jin; Jin, Wook

    2016-01-01

    Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer. PMID:27654855

  9. Evidence for a Role of Tumor-Derived Laminin-511 in the Metastatic Progression of Breast Cancer

    PubMed Central

    Chia, Jenny; Kusuma, Nicole; Anderson, Robin; Parker, Belinda; Bidwell, Bradley; Zamurs, Laura; Nice, Edouard; Pouliot, Normand

    2007-01-01

    Most studies investigating laminins (LMs) in breast cancer have focused on LM-111 or LM-332. Little is known, however, about the expression and function of α5 chain-containing LM-511/521 during metastatic progression. Expression of LM-511/521 subunits was examined in genetically related breast tumor lines and corresponding primary tumors and metastases in a syngeneic mouse model using real-time quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. The results from our investigation indicate that LM-511 rather than LM-111, -332, or -521 correlates with metastatic potential in mouse mammary tumors. LM-511 was a potent adhesive substrate for both murine and human breast carcinoma cells and promoted strong haptotactic responses in metastatic lines. Haptotaxis was mediated by α3 integrin in both MCF-7 and MDA-MB-231 cells and was strongly inhibited by blocking antibodies against this integrin subunit. However, whereas nonmetastatic MCF-7 cells migrated toward LM-511 primarily via α3β1 integrin, results from antibody perturbation experiments and flow cytometry analysis suggest that this response is mediated by an as yet unidentified α3β integrin heterodimer (other than α3β1) in MDA-MB-231 cells. These results are consistent with earlier reports implicating α3 integrins in breast cancer progression and support the role of LM-511 as a functional substrate regulating breast cancer metastasis. PMID:17525279

  10. Activity of Nanobins Loaded with Cisplatin and Arsenic Trioxide in Primary and Metastatic Breast Cancer

    NASA Astrophysics Data System (ADS)

    Swindell, Elden Peter, III

    Despite recent advances in breast cancer screening and detection, the disease is still a leading cause of death for women of all ages. Young, African-American women are disproportionally affected with a type of breast cancer, triple-negative breast cancer, which is particularly difficult to treat and has the worst prognosis of any breast cancer subtype. These tumors often spread to the lungs, liver, bones and brains of patients, which is ultimately fatal. This dissertation presents results from a series of in vivo and in vitro experiments that investigate the clinical utility of a novel nanoparticulate formulation of cisplatin and arsenic trioxide, NB(Pt,As) for treating primary and metastatic triple-negative breast cancer. These nanobins consist of a solid, crystalline metal nanoparticle surrounded by a lipid bilayer with 80-90 nm diameter. This drug payload is extremely stable, and so NB(Pt,As) is extremely well tolerated in mice. Furthermore, NB(Pt,As) is effective in two different mouse models of breast cancer, one of primary tumor growth an another of lung metastases. A discovery presented here, that thiol containing compounds are required for drug release, may explain these seemingly incongruous results. The large amount of intracellular thiol can trigger drug release, while the low concentration of free thiols in blood is insufficient to cause drug release. To improve the treatment of brain tumors with this unique drug, we added transferrin to the surface of the nanobin using copper-catalyzed "click" chemistry, which preserves protein activity. The addition of transferrin to the nanobins enables 10 fold greater uptake in the brains of mice treated with the transferrin-targeted nanobins Tf-NB(Pt,A) compared to NB(Pt,As). By penetrating the blood brain barrier, the Tf-NB(Pt,As) was able to reduce breast cancer metastases in the brains of mice, whereas NB(Pt,As) had no effect. Taken together, these results demonstrate the intricate balance of drug release

  11. Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells.

    PubMed

    Joosse, Simon A; Hannemann, Juliane; Spötter, Julia; Bauche, Andreas; Andreas, Antje; Müller, Volkmar; Pantel, Klaus

    2012-02-15

    Circulating tumor cells (CTC) might function as early markers for breast cancer metastasis or monitoring therapy efficacy. Enrichment and identification of CTCs are based on epithelial markers that might be modulated during epithelial-mesenchymal transition. Little is known about the expression of keratins in CTCs and whether all CTCs can be detected with antibodies directed against a limited panel of keratins. Protein expression of keratin 2, 4-10, 13-16, 18, and 19 were assessed by a cocktail of antibodies (C11, AE1, AE3, and K7) and keratin antibodies C11 and A45-B/B3 alone in 11 breast cancer cell lines and 50 primary breast carcinomas and their lymph node metastases. Furthermore, CTCs were assessed in blood of 70 metastatic breast cancer patients. Claudin-low cell lines did not show expression of normal breast epithelial keratins but were positive for K14 and K16, detected by the cocktail only. Primary breast carcinomas showed changes in keratin expression during metastatic progression to the lymph nodes. In 35 of 70 patients CTCs were identified, of which 83%, 40%, and 57% were identified by the cocktail, C11 and A45-B/B3, respectively. Identification of CTCs by the cocktail was associated with shorter survival (P < 0.01). In silico analyses revealed association between KRT16 expression and shorter relapse-free survival in metastatic breast cancer. Breast cancer cells show a complex pattern of keratin expression with potential biologic relevance. Individual keratin antibodies recognizing only a limited set of keratins inherit the risk to miss biologically relevant CTCs in cancer patients, and antibody cocktails including these keratins are therefore recommended. ©2012 AACR.

  12. Nursing perspectives on fulvestrant for the treatment of postmenopausal women with metastatic breast cancer.

    PubMed

    Litsas, Georgia

    2011-12-01

    Fulvestrant is an estrogen receptor antagonist indicated for the treatment of hormone receptor-positive metastatic breast cancer (MBC) in postmenopausal women with disease progression following antiestrogen therapy. Fulvestrant has a different mechanism of action than other hormonal therapies, including aromatase inhibitors and tamoxifen. In clinical trials of postmenopausal women with MBC, fulvestrant was effective and well tolerated compared to anastrozole after failure of tamoxifen. The monthly injection regimen of fulvestrant provides nurses with an additional opportunity to improve patient adherence to hormonal therapy, reinforce patient education, and monitor side effects. Several ongoing trials will elucidate the role of fulvestrant in the treatment of MBC. Issues that are being addressed in those trials include alternative doses and schedules, efficacy and safety in other patient populations, and the development of novel treatment combinations. This article provides oncology nurses with the knowledge needed to educate patients on the use of fulvestrant, to effectively administer this medication, and to prevent and manage potential side effects.

  13. Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer.

    PubMed

    Pernin, Victor; Belin, Lisa; Cottu, Paul; Bontemps, Patrick; Lemanski, Claire; De La Lande, Brigitte; Baumann, Pierre; Missohou, Fernand; Levy, Christelle; Peignaux, Karine; Bougnoux, Pierre; Denis, Fabrice; Bollet, Marc; Dendale, Rémi; Vago, Nora Ady; Campana, François; Fourquet, Alain; Kirova, Youlia M

    2014-12-01

    The purpose of this multicenter prospective and descriptive study was to determine late toxicities and outcomes among patients with non-metastatic breast cancer receiving concurrent bevacizumab (BV) and radiation therapy (RT) in the clinical trials. Early and late toxicities were assessed and evaluation was available for 63 patients (pts) at 12 months. Acute radiation dermatitis was observed in 48 (76%): grade 1 for 27, grade 2 for 17 and grade 3 for 4 pts. Grade 2 acute oesophagitis was observed in one patient (2%). Little toxicity was described 1 year after the completion of RT: 7 pts (12%): grade 1-2 pain, 3 (5%) presented grade 1 fibrosis, and 2 pts (4%) - telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1-2 lymphoedema occurred. Only one patient experienced a LEVF value less than 50% one year after the end of RT. In conclusion, the concurrent BV with locoregional RT provides acceptable toxicities.

  14. Randomized Trial of Expressive Writing for Distressed Metastatic Breast Cancer Patients

    PubMed Central

    Mosher, Catherine E.; DuHamel, Katherine N.; Lam, Joanne; Dickler, Maura; Li, Yuelin; Massie, Mary Jane; Norton, Larry

    2011-01-01

    Women with metastatic breast cancer and significant psychological distress (N = 87) were assigned randomly to engage in four home-based sessions of expressive writing or neutral writing. Women in the expressive writing group wrote about their deepest thoughts and feelings regarding their cancer, whereas women in the neutral writing group wrote about their daily activities in a factual manner. No statistically significant group differences in existential and psychological well-being, fatigue, and sleep quality were found at 8-weeks post-writing. However, the expressive writing group reported significantly greater use of mental health services during the study than the neutral writing group (55% vs. 26%, respectively; p < .05). Findings suggest that expressive writing may improve uptake of mental health services among distressed cancer patients, but is not broadly effective as a psychotherapeutic intervention. PMID:21678181

  15. Randomised trial of expressive writing for distressed metastatic breast cancer patients.

    PubMed

    Mosher, Catherine E; Duhamel, Katherine N; Lam, Joanne; Dickler, Maura; Li, Yuelin; Massie, Mary Jane; Norton, Larry

    2012-01-01

    Women with metastatic breast cancer and significant psychological distress (N = 87) were assigned randomly to engage in four home-based sessions of expressive writing or neutral writing. Women in the expressive writing group wrote about their deepest thoughts and feelings regarding their cancer, whereas women in the neutral writing group wrote about their daily activities in a factual manner. No statistically significant group differences in existential and psychological well-being, fatigue and sleep quality were found at 8-weeks post-writing. However, the expressive writing group reported significantly greater use of mental health services during the study than the neutral writing group (55% vs. 26%, respectively; p < 0.05). Findings suggest that expressive writing may improve the uptake of mental health services among distressed cancer patients, but is not broadly effective as a psychotherapeutic intervention.

  16. The Use of Triethylenethiophosphoramide (Thio-TEPA) in the Treatment of Metastatic Carcinoma of the Breast

    PubMed Central

    Kuwayti, Kamal; Hilton, James H. B.

    1963-01-01

    Twenty-two patients with metastatic breast cancer were treated by a combination of testosterone and N,N′,N″, triethylenethiophosphoramide (Thio-TEPA). All had undergone mastectomy and received radiation; six had had an oophorectomy and 12 had had oophorectomy and adrenalectomy. For its marrow-stimulating effect testosterone was given intramuscularly, 100 mg. daily for five days; then 100 mg. of depo-testosterone was given intramuscularly once a week. On the sixth day of treatment, 15 mg. of Thio-TEPA was given intramuscularly and repeated daily or every second day until a definite depression of the leukocyte and/or platelet counts occurred. To 15 patients a total dose of 200 mg. or more of triethylenethiophosphoramide was given. Thirteen patients improved subjectively and five of these improved objectively. The duration of improvement varied between one and 12 months. Treatment was most effective in patients with bony metastases. PMID:13927682

  17. Metronomic Chemotherapy for Metastatic Breast Cancer – a Systematic Review of the Literature

    PubMed Central

    Banys-Paluchowski, M.; Schütz, F.; Ruckhäberle, E.; Krawczyk, N.; Fehm, T.

    2016-01-01

    Conventional chemotherapy is generally administered in high doses followed by a treatment-free period to give the body needful time to recover. This “maximum tolerated dose” approach results in high response rates. However, long periods between therapy cycles can lead to development of resistance mechanisms and consequently disease progression. One of the most interesting alternative strategies is metronomic chemotherapy. This concept relies on the continuous administration of chemotherapy at low doses and aims at targeting endothelial cells in the tumor bed as well. Recently, metronomic chemotherapy has been incorporated into the recommendations issued by the German AGO expert panel (www.ago-online.de). A systematic review of PubMed/Medline, ClinicalTrials.gov, the European Clinical Trials Database (EudraCT) and the Cochrane Database was conducted. In the present review, we discuss the current evidence on metronomic chemotherapy in metastatic breast cancer. PMID:27239061

  18. Patient Management with Eribulin in Metastatic Breast Cancer: A Clinical Practice Guide

    PubMed Central

    Cheng, Fiona Tsui-Fen; Sriuranpong, Virote; Villalon, Antonio; Smruti, B. K; Tsang, Janice; Yap, Yoon Sim

    2016-01-01

    Eribulin, an antimicrotubule chemotherapeutic agent, is approved for the treatment of pretreated metastatic breast cancer (mBC) based on the positive outcomes of phase II and phase III clinical trials, which enrolled mainly Western patients. Eribulin has recently been approved in an increasing number of Asian countries; however, there is limited clinical experience in using the drug in certain countries. Therefore, we established an Asian working group to provide practical guidance for eribulin use based on our clinical experience. This paper summarizes the key clinical trials, and the management recommendations for the reported adverse events (AEs) of eribulin in mBC treatment, with an emphasis on those that are relevant to Asian patients, followed by further elaboration of our eribulin clinical experience. It is anticipated that this clinical practice guide will improve the management of AEs resulting from eribulin treatment, which will ensure that patients receive the maximum treatment benefit. PMID:27066091

  19. Patient Management with Eribulin in Metastatic Breast Cancer: A Clinical Practice Guide.

    PubMed

    Ro, Jungsil; Cheng, Fiona Tsui-Fen; Sriuranpong, Virote; Villalon, Antonio; Smruti, B K; Tsang, Janice; Yap, Yoon Sim

    2016-03-01

    Eribulin, an antimicrotubule chemotherapeutic agent, is approved for the treatment of pretreated metastatic breast cancer (mBC) based on the positive outcomes of phase II and phase III clinical trials, which enrolled mainly Western patients. Eribulin has recently been approved in an increasing number of Asian countries; however, there is limited clinical experience in using the drug in certain countries. Therefore, we established an Asian working group to provide practical guidance for eribulin use based on our clinical experience. This paper summarizes the key clinical trials, and the management recommendations for the reported adverse events (AEs) of eribulin in mBC treatment, with an emphasis on those that are relevant to Asian patients, followed by further elaboration of our eribulin clinical experience. It is anticipated that this clinical practice guide will improve the management of AEs resulting from eribulin treatment, which will ensure that patients receive the maximum treatment benefit.

  20. Cytotoxic chemotherapy: Still the mainstay of clinical practice for all subtypes metastatic breast cancer.

    PubMed

    Twelves, Chris; Jove, Maria; Gombos, Andrea; Awada, Ahmad

    2016-04-01

    Cytotoxic chemotherapy remains central to the treatment of all subtypes of metastatic breast cancer (MBC). We review evidence-based chemotherapy options for women with MBC after an anthracycline and a taxane including re-challenge with anthracycline or taxane, capecitabine, eribulin and ixabepilone as a single agent or combination with capecitabine (not approved in the EU); and the vinca alkaloid vinflunine as single agent or combined with either capecitabine/gemcitabine (also not approved EU or USA). Etirinotecan pegol, comprising irinotecan bound to polyethylene glycol by a biodegradable linker, is a new cytotoxic agent for patients with MBC that has achieved encouraging response rates in phase II studies; it has been further evaluated in the phase III BEACON trial. New cytotoxics should address novel targets or modes of delivery, achieve meaningful improvements in outcomes and seek to identify predictive biomarker(s).

  1. Complete responders to chemotherapy in metastatic breast cancer. Characterization and analysis.

    PubMed

    Decker, D A; Ahmann, D L; Bisel, H F; Edmonson, J H; Hahn, R G; O'Fallon, J R

    1979-11-09

    Four hundred thirty-eight patients with metastatic breast cancer treated with nine prospective randomized trials were reviewed to analyze, characterize, and compare those with complete regression (CR) (N=49 [11%]) with those with noncomplete regression (non-CR) (N=389 [89%]). Site of dominant disease was identical in the CR and non-CR patients. However, CR was statistically more likely when the disease-free interval and the postmenopausal status was five years or less. Survival and time to progression occurred at sites of prior dominant disease, except that relapses occurred in the CNS in 14%. Six CR patients received prolonged chemotherapy and were believed to be "cured" when treatment was discontinued; however, all except one have had relapses.

  2. 2’-Behenoyl-Paclitaxel Conjugate Containing Lipid Nanoparticles for the Treatment of Metastatic Breast Cancer

    PubMed Central

    Ma, Ping; Benhabbour, S. Rahima; Feng, Lan; Mumper, Russell J

    2012-01-01

    The aim of these studies was to develop a novel 2’-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in-vitro and in-vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation. PMID:22902506

  3. Development of Raman spectral markers to assess metastatic bone in breast cancer

    NASA Astrophysics Data System (ADS)

    Ding, Hao; Nyman, Jeffry S.; Sterling, Julie A.; Perrien, Daniel S.; Mahadevan-Jansen, Anita; Bi, Xiaohong

    2014-11-01

    Bone is the most common site for breast cancer metastases. One of the major complications of bone metastasis is pathological bone fracture caused by chronic bone loss and degeneration. Current guidelines for the prediction of pathological fracture mainly rely on radiographs or computed tomography, which are limited in their ability to predict fracture risk. The present study explored the feasibility of using Raman spectroscopy to estimate pathological fracture risk by characterizing the alterations in the compositional properties of metastatic bones. Tibiae with evident bone destruction were investigated using Raman spectroscopy. The carbonation level calculated by the ratio of carbonate/phosphate ν1 significantly increased in the tumor-bearing bone at all the sampling regions at the proximal metaphysis and diaphysis, while tumor-induced elevation in mineralization and crystallinity was more pronounced in the metaphysis. Furthermore, the increased carbonation level is positively correlated to bone lesion size, indicating that this parameter could serve as a unique spectral marker for tumor progression and bone loss. With the promising advances in the development of spatially offset Raman spectroscopy for deep tissue measurement, this spectral marker can potentially be used for future noninvasive evaluation of metastatic bone and prediction of pathological fracture risk.

  4. Development of Raman spectral markers to assess metastatic bone in breast cancer

    PubMed Central

    Ding, Hao; Nyman, Jeffry S.; Sterling, Julie A.; Perrien, Daniel S.; Mahadevan-Jansen, Anita; Bi, Xiaohong

    2014-01-01

    Abstract. Bone is the most common site for breast cancer metastases. One of the major complications of bone metastasis is pathological bone fracture caused by chronic bone loss and degeneration. Current guidelines for the prediction of pathological fracture mainly rely on radiographs or computed tomography, which are limited in their ability to predict fracture risk. The present study explored the feasibility of using Raman spectroscopy to estimate pathological fracture risk by characterizing the alterations in the compositional properties of metastatic bones. Tibiae with evident bone destruction were investigated using Raman spectroscopy. The carbonation level calculated by the ratio of carbonate/phosphate ν1 significantly increased in the tumor-bearing bone at all the sampling regions at the proximal metaphysis and diaphysis, while tumor-induced elevation in mineralization and crystallinity was more pronounced in the metaphysis. Furthermore, the increased carbonation level is positively correlated to bone lesion size, indicating that this parameter could serve as a unique spectral marker for tumor progression and bone loss. With the promising advances in the development of spatially offset Raman spectroscopy for deep tissue measurement, this spectral marker can potentially be used for future noninvasive evaluation of metastatic bone and prediction of pathological fracture risk. PMID:24933683

  5. Impact of immunohistological subtypes on the long-term prognosis of patients with metastatic breast cancer.

    PubMed

    Kobayashi, Kokoro; Ito, Yoshinori; Matsuura, Masaaki; Fukada, Ippei; Horii, Rie; Takahashi, Shunji; Akiyama, Futoshi; Iwase, Takuji; Hozumi, Yasuo; Yasuda, Yoshikazu; Hatake, Kiyohiko

    2016-07-01

    Although improved long-term prognoses for patients with metastatic breast cancer (MBC) have been demonstrated, few reports address overall survival (OS) with sufficient follow-up. Furthermore, the relevance of immunohistological subtypes to OS in MBC has not been clarified. We evaluated, retrospectively, the OS of patients who had been initiated on systemic therapy for MBC between 2000 and 2008. The subjects of this study were 527 patients with MBC treated by systemic therapy. The median survival time (MST) was 55.5 months. The MST for each immunohistological subtype was as follows: luminal, 59.9 months; luminal-HER2, not reached; triple-negative, 18.6 months; and HER2-enriched, 49.9 months. According to multivariate analysis, metastasis-free intervals of ≥2 years and treatment with anthracycline for MBC were predictive of better OS. The predictors of shorter OS included disease progression after first-line treatment for MBC, triple-negative, and all histological factors, except papillotubular carcinoma, with liver metastasis, and having three or more initial metastatic sites. The prognosis of the patients with MBC in this series was better than that reported before 2000, which is probably attributable to the use of novel, improved pharmacological agents. For example, luminal-HER2 tumors can be treated using both aromatase inhibitors and trastuzumab. Because of the lower toxicities, it is now possible to administer these agents for longer periods, resulting in better prognoses.

  6. [Efficacy and Safety of Pertuzumab for HER2-Positive Metastatic Breast Cancer].

    PubMed

    Yamamura, Jun; Kamigaki, Shunji; Hamakawa, Takuya; Hoshino, Hiromitsu; Nakata, Ken; Yamamoto, Tameyoshi; Ikeda, Naoki; Kawase, Tomono; Tsujie, Masaki; Kimura, Yutaka; Ozato, Hiroki

    2015-06-01

    The CLEOPATRA trial showed a significant improvement in the progression-free survival (PFS) and overall survival of patients with HER2-positive first-line metastatic breast cancer (MBC) who were treated with pertuzumab (PER), trastuzumab (TRA), and docetaxel (DTX), compared to those treated with placebo, TRA, and DTX. PER was approved in 2013 for treating HER2-positive MBC in Japan. Herein, we present the retrospective review of data from 10 HER2-positive MBC patients who received PER in our hospital between September 2013 and August 2014.T he median age was 52 years (range, 45-66 years), and 7 patients were positive for ER.Six patients had not received any previous chemotherapy for their metastatic disease, while the others had received comparatively heavy pretreatment doses of chemotherapy.Our patients received the PER, TRA, and DTX regimen, although 2 patients were treated without DTX. Four patients experienced a partial response, 6 patients experienced stable disease (SD), and 3 patients experienced SD for ≥6 months. The response rate was 40%, and the clinical benefit rate was 70%.The median PFS was 7.3 months (range, 2.5-11.5 months). Grade 3 neutropenia and allergic reactions were observed in 1 and 2 patients, respectively; no Grade 4 adverse events were observed, and thus, the regimen was well tolerated. Further clinical research seems to be warranted for developing new treatment strategies involving PER for HER2-positive MBC.

  7. Color-Coded Imaging of Breast Cancer Metastatic Niche Formation in Nude Mice.

    PubMed

    Suetsugu, Atsushi; Momiyama, Masashi; Hiroshima, Yukihiko; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Bouvet, Michael; Hoffman, Robert M

    2015-12-01

    We report here a color-coded imaging model in which metastatic niches in the lung and liver of breast cancer can be identified. The transgenic green fluorescent protein (GFP)-expressing nude mouse was used as the host. The GFP nude mouse expresses GFP in all organs. However, GFP expression is dim in the liver parenchymal cells. Mouse mammary tumor cells (MMT 060562) (MMT), expressing red fluorescent protein (RFP), were injected in the tail vein of GFP nude mice to produce experimental lung metastasis and in the spleen of GFP nude mice to establish a liver metastasis model. Niche formation in the lung and liver metastasis was observed using very high resolution imaging systems. In the lung, GFP host-mouse cells accumulated around as few as a single MMT-RFP cell. In addition, GFP host cells were observed to form circle-shaped niches in the lung even without RFP cancer cells, which was possibly a niche in which future metastasis could be formed. In the liver, as with the lung, GFP host cells could form circle-shaped niches. Liver and lung metastases were removed surgically and cultured in vitro. MMT-RFP cells and GFP host cells resembling cancer-associated fibroblasts (CAFs) were observed interacting, suggesting that CAFs could serve as a metastatic niche.

  8. Immunoadjuvants in treatment of metastatic breast tumors using selective laser photothermal interaction

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Lucroy, Michael D.; Liu, Hong; Bartels, Kenneth E.; Jassemnejad, Baha; Barker, Shawn L.; Gandhi, Punit; Nordquist, Robert E.

    2001-07-01

    A novel immunoadjuvant, glycated chitosan, has been used in combinations with a near-infrared laser and a laser- absorbing dye to treat metastatic tumors in rats. The laser-dye combination provides selective photothermal tumor destruction. The addition of the in situ immunoadjuvant works in tandem with the photothermal interaction to induce a host antitumor immunity. Our previous experiments have shown the efficacy of this novel modality against a metastatic breast cancer in rat model, using the three components. The current study is to investigate the roles of different components, namely, the laser, the dye and the immunoadjuvant. Firs, the selective photothermal laser- tissue interactions are studied in vivo using rat leg muscles and rat tumors. Our results showed that with appropriate combination of laser parameter and dye does, an optimal selective photothermal tissue interaction could be achieved. The immune response is crucial in control of tumor metastasis and the immunoadjuvant has played pivotal role in the induction of the immunity in our experiment. Therefore, the role of immunoadjuvants in the laser cancer treatment is also investigated in the current study. Specifically, three different concentrations of glycated chitosan solutions - 0.5%, 1% and 2% - were used. In comparison, the 1% solution provided the best treatment outcome. Two additional immunoadjuvants, incomplete Freund's adjuvant and complete Freund's adjuvant were also used in the same laser-dye-adjuvant treatment protocol. The functions of different adjuvants are compared.

  9. Clinical predictors of long-term survival in HER2-positive metastatic breast cancer.

    PubMed

    Murthy, Pooja; Kidwell, Kelley M; Schott, Anne F; Merajver, Sofia D; Griggs, Jennifer J; Smerage, Jeffrey D; Van Poznak, Catherine H; Wicha, Max S; Hayes, Daniel F; Henry, N Lynn

    2016-02-01

    Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be "exceptional responders" with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. A retrospective, single-institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Median overall survival from the time of breast cancer recurrence was 3.9 years (95 % CI 3.4-5.2). From the time of diagnosis of MBC, 56 (33 %) survived for 5 or more years and 12 (7 %) survived more than 10 years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14 %) survived more than 5 years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2-12.0) since stopping therapy. In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7 % of patients were "exceptional responders." Combining these clinical factors with molecular determinants of prolonged survival may provide insights for individualizing treatment selection.

  10. Clinical outcomes based on multigene profiling in metastatic breast cancer patients

    PubMed Central

    Ueno, Naoto T.; Wathoo, Chetna; Chen, Huiqin; Shariati, Maryam; Wei, Caimiao; Alvarez, Ricardo H.; Moulder, Stacy L.; Sahin, Aysegul A.; Roy-Chowdhuri, Sinchita; Chavez-MacGregor, Mariana; Litton, Jennifer K.; Valero, Vincent; Luthra, Raja; Zeng, Jia; Shaw, Kenna R.; Mendelsohn, John; Mills, Gordon B.; Tripathy, Debu; Meric-Bernstam, Funda

    2016-01-01

    BACKGROUND Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis. PMID:27806348

  11. Clinical Predictors of Long-term Survival in HER2-positive Metastatic Breast Cancer

    PubMed Central

    Murthy, Pooja; Kidwell, Kelley M.; Schott, Anne F.; Merajver, Sofia D.; Griggs, Jennifer J.; Smerage, Jeffrey D.; Van Poznak, Catherine H.; Wicha, Max S.; Hayes, Daniel F.; Henry, N. Lynn

    2016-01-01

    Purpose Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be “exceptional responders” with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. Methods A retrospective, single institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Results Median overall survival from the time of breast cancer recurrence was 3.9 years (95% CI 3.4–5.2). From the time of diagnosis of MBC, 56 (33%) survived for 5 or more years and 12 (7%) survived more than 10 years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14%) survived more than 5 years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2–12.0) since stopping therapy. Conclusions In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7% of patients were “exceptional responders”. Combining these clinical factors associated with molecular determinants of prolonged survival with may provide insights for individualizing treatment selection. PMID:26875184

  12. The efficacy and toxicity profile of metronomic chemotherapy for metastatic breast cancer: A meta-analysis

    PubMed Central

    Liang, Jinyan; Dai, Xiaomeng; Wan, Chao; Hong, Xiaohua; Zhang, Kai; Liu, Li

    2017-01-01

    Purpose The current meta-analysis aimed to summarize the available evidence for the efficacy and serious adverse events (AEs) associated with use of metronomic chemotherapy (MCT) in patients with metastatic breast cancer (MBC). Method Electronic databases (PubMed, EMBASE database, Web of Knowledge, and the Cochrane database) were systematically searched for articles related to the use of MCT in MBC patients. Eligible studies included clinical trials of MBC patients treated with MCT that presented sufficient data related to tumor response, progression-free survival (PFS), overall survival (OS), and grade 3/4 AEs. A meta-analysis was performed using a random effects model. Results This meta-analysis consists of 22 clinical trials with 1360 patients. The pooled objective response rate and clinical benefit rate of MCT were 34.1% (95% CI 27.4–41.5) and 55.6% (95% CI 49.2–61.9), respectively. The overall 6-month PFS, 12-month OS, and 24-month OS rates were 56.8% (95% CI 48.3–64.9), 70.3% (95% CI 62.6–76.9), and 40.0% (95% CI 30.6–50.2), respectively. The pooled incidence of grade 3/4 AEs was 29.5% (95% CI 21.1–39.5). There was no statistically significant difference observed in any endpoint between subgroups defined by concomitant anti-cancer therapies or chemotherapy regimens. After excluding one controversial study, we observed a trend showing lower toxicity rates with the use of MCT alone compared to use of MCT with other anti-cancer therapies (P = 0.070). Conclusions Metronomic chemotherapy may be effective for use in patients with metastatic breast cancer. MCT used alone is possibly equally effective and less toxic than combination therapies. Well-designed RCTs are needed to obtain more evidence. PMID:28296916

  13. Eribulin Monotherapy in Patients Aged 70 Years and Older With Metastatic Breast Cancer

    PubMed Central

    Cortes, Javier; Vahdat, Linda T.; Cardoso, Fatima; Twelves, Chris; Wanders, Jantien; Dutcus, Corina E.; Yang, Jay; Seegobin, Seth; O’Shaughnessy, Joyce

    2014-01-01

    Purpose. Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients. Methods. Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m2 as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), and incidence of adverse events (AEs) was calculated for four age groups (<50 years, 50–59 years, 60–69 years, ≥70 years). Results. Overall, 827 patients were included in the analysis (<50 years, n = 253; 50–59 years, n = 289; 60–69 years, n = 206; ≥70 years, n = 79). Age had no significant impact on OS (11.8 months, 12.3 months, 11.7 months, and 12.5 months, respectively; p = .82), PFS (3.5 months, 2.9 months, 3.8 months, and 4.0 months, respectively; p = .42), ORR (12.7%, 12.5%, 6.3%, and 10.1%, respectively), or CBR (20.2%, 20.8%, 20.4%, and 21.5%, respectively). Although some AEs had higher incidence in either the youngest or the oldest subgroup, there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia). Conclusion. Eribulin monotherapy in these selected older patients with good baseline performance status led to OS, PFS, ORR, CBR, and tolerability similar to those of younger patients with metastatic breast cancer. The benefits and risks of eribulin appear to be similar across age groups. PMID:24682463

  14. Pamidronate in prevention of bone complications in metastatic breast cancer: a cost-effectiveness analysis.

    PubMed

    Hillner, B E; Weeks, J C; Desch, C E; Smith, T J

    2000-01-01

    Pamidronate is effective in reducing bony complications in patients with metastatic breast cancer who have known osteolytic lesions. However, pamidronate does not increase survival and is associated with additional financial costs and inconvenience. We conducted a post-hoc evaluation of the cost-effectiveness of pamidronate using the results of two randomized trials that evaluated pamidronate 90 mg administered intravenously every month versus placebo. The trials differed only in the initial systemic therapy administered (hormonal or chemotherapy). Total skeletal related events (SREs), including surgery for pathologic fracture, radiation for fracture or pain control, conservatively treated pathologic fracture, spinal cord compression, or hypercalcemia, were taken directly from the trials. Using a societal perspective, direct health care costs were assigned to each SRE. Each group's monthly survival was equal and was projected to decline using observed median survivals. The cost of pamidronate reflected the average wholesale price of the drug plus infusion. The value or disutility of an adverse event per month was evaluated using a zero value (events avoided) or an assigned one (range, 0.2 to 0.8). The cost of pamidronate therapy exceeded the cost savings from prevented adverse events. The difference between the treated and placebo groups was larger with hormonal systemic therapy than with chemotherapy (additional $7,685 compared with $3,968 per woman). The projected net cost per SRE avoided was $3,940 with chemotherapy and $9,390 with hormonal therapy. The cost-effectiveness ratios were $108,200 with chemotherapy and $305, 300 with hormonal therapy per quality-adjusted year. Although pamidronate is effective in preventing a feared, common adverse outcome in metastatic breast cancer, its use is associated with high incremental costs per adverse event avoided. The analysis is most sensitive to the costs of pamidronate and pathologic fractures that were asymptomatic

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

    ClinicalTrials.gov

    2017-02-27

    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

  16. Loco-regional treatment in metastatic breast cancer patients: is there a survival benefit?

    PubMed

    Ly, Bevan H; Nguyen, Nam P; Vinh-Hung, Vincent; Rapiti, Elisabetta; Vlastos, Georges

    2010-02-01

    A number of studies have recently demonstrated a survival benefit in stage IV breast cancer patients following surgical resection of the primary tumor. Here, we investigate the relationship between loco-regional treatment and survival in patients with metastatic breast cancer and evaluate the impact of different loco-regional treatments. We conducted a systematic review of the literature using PubMed to analyze studies with the following criteria: Type of loco-regional treatment (surgery alone or combined with radiation, radiotherapy), overall survival, progression-free survival, selection factors for local treatment, and complication rates. Thirteen studies evaluated the effect of loco-regional treatment on overall survival with overall median survival increasing from a range of 12.6-28.3 months among patients without surgery to a range of 25-42 months among patients with surgery. In addition, six studies reported a 3-year survival benefit of 28-95% and 17-79% in women with and without locoregional therapy respectively. Two studies did not find any improvement in overall survival. One study found an improvement in 5-year breast cancer-specific survival of 27% with negative surgical margins versus 12% with no surgery. Three studies reported an advantage in progression-free survival in the treatment group compared with the non-treatment group. Loco-regional treatment for breast cancer patients with distant metastases at diagnosis is an important issue because of possible improvement of survival or disease-free survival. The possibility of surgery and/or radiotherapy following induction chemotherapy should be weighed and left to individual practice. Participation in randomized controlled trials should be encouraged.

  17. Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer.

    PubMed

    Assadipour, Yasmine; Zacharakis, Nikolaos; Crystal, Jessica S; Prickett, Todd D; Gartner, Jared J; Somerville, Robert P T; Xu, Hui; Black, Mary A; Jia, Li; Chinnasamy, Harshini; Kriley, Isaac; Lu, Lily; Wunderlich, John R; Zheng, Zhili; Lu, Yong-Chen; Robbins, Paul F; Rosenberg, Steven A; Goff, Stephanie L; Feldman, Steven A

    2017-08-01

    Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer.Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized.Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4(+) and HLA-DRB1*1501-restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples.Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer. Clin Cancer Res; 23(15); 4347-53. ©2017 AACR. ©2017 American Association for Cancer Research.

  18. Comparing medical cost of care for patients with metastatic breast cancer receiving taxane therapy: claims analysis.

    PubMed

    Force, Rex W; Pugmire, Brooke A; Culbertson, Vaughn L

    2010-07-01

    It has been estimated that more than $8 billion is spent annually on the management of breast cancer in the United States. The taxane chemotherapeutic agents are cornerstones in the treatment of breast cancer, yet no study has assessed whether the choice of a taxane affects the economic outcomes of metastatic breast cancer treatment. To determine if differences exist in the medical cost of care in patients receiving taxane-based chemotherapy for metastatic breast cancer, and to compare the use of ancillary medications (for neutropenia, anemia, and nausea and vomiting) and their associated costs among taxanes. We identified women with metastatic breast cancer based on diagnosis codes and the women's previous adjuvant chemotherapeutic regimens. Paid medical insurance claims were captured for the 24-month study period, from January 1, 2006, through December 31, 2007. The groups were determined according to the specific taxane administered. Total medical costs were captured from the date of first taxane administration to the end of data availability. Outpatient pharmacy costs were not available. A multivariate analysis was used to evaluate the total medical costs in each group. Median total medical costs per patient per month during the study period were adjusted using a multiple regression analysis. Utilization and cost of medications administered in the office or hospital for chemotherapy-induced adverse effects were captured and adjusted with Tobit models. Of the 2245 study participants, 1035 received docetaxel, 997 received generic paclitaxel, and 213 received nab-paclitaxel. On average, patients in the nab-paclitaxel group received more doses (9.6) than those in the generic paclitaxel (6.0) or docetaxel (4.8) groups. The multivariate analysis was robust, explaining 72% of the variability in total medical costs across the 3 taxane groups. Median per-patient per-month total medical costs for study participants were within approximately $800 of each other among the

  19. Photo-nano immunotherapy for metastatic breast cancer using synergistic single-walled carbon nanotubes and glycated chitosan

    NASA Astrophysics Data System (ADS)

    Zhou, Feifan; Hasanjee, Aamr; Doughty, Austin; West, Connor; Liu, Hong; Chen, Wei R.

    2015-03-01

    In our previous work, we constructed a multifunctional nano system, using single-walled carbon nanotube (SWNT) and glycated chitosan (GC), which can synergize photothermal and immunological effects. To further confirm the therapy efficacy, with a metastatic mouse mammary tumor model (4T1), we investigate the therapy effects and immune response induced by SWNT-GC, under laser irradiation. Laser+SWNT-GC treatment not only suppressed the prime tumor, but also induced antitumor immune response. It could be developed into a promising treatment modality for the metastatic breast cancer.

  20. Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole.

    PubMed

    Carlson, Robert W; Henderson, I Craig

    2003-01-01

    The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that

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

    PubMed

    Park, Yeon Hee; Shin, Hyun-Tae; 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

    2015-10-13

    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.

  2. A stopping rule for standard chemotherapy for metastatic breast cancer: lessons from a survey of Maryland medical oncologists.

    PubMed

    Benner, S E; Fetting, J H; Brenner, M H

    1994-01-01

    The sequential administration of standard chemotherapy regimens to treat metastatic breast cancer may keep patients and oncologists from considering other important, but more psychologically difficult, issues such as the patient's declining health or approaching death. This practice also utilizes health care resources for ever-decreasing individual patient benefit. If generally agreed-upon rules or guidelines were developed about stopping standard chemotherapy after a limited number of regimens, oncologists could recommend treatment discontinuation with greater confidence. Also, resources could be redirected. To inform the development of guidelines on when to stop chemotherapy for metastatic breast cancer, we surveyed fully trained Maryland medical oncologists about their knowledge and beliefs about chemotherapy for metastatic breast cancer. The survey instrument included open-ended questions and clinical vignettes. There was consensus about the value of first-line chemotherapy. Even though oncologists employed second-line chemotherapy, they were unenthusiastic about it. The frequent utilization of second-line regimens probably reflects an effort to offer marginal regimens to patients who want them. Based on these data, it is suggested that standard chemotherapy be stopped after breast cancer fails to stabilize or respond on a standard regimen. Patients who wish further treatment could be referred for investigational therapy if it is available and if they are eligible.

  3. Generation of Organ-conditioned Media and Applications for Studying Organ-specific Influences on Breast Cancer Metastatic Behavior.

    PubMed

    Piaseczny, Matthew M; Pio, Graciella M; Chu, Jenny E; Xia, Ying; Nguyen, Kim; Goodale, David; Allan, Alison

    2016-06-13

    Breast cancer preferentially metastasizes to the lymph node, bone, lung, brain and liver in breast cancer patients. Previous research efforts have focused on identifying factors inherent to breast cancer cells that are responsible for this observed metastatic pattern (termed organ tropism), however much less is known about factors present within specific organs that contribute to this process. This is in part because of a lack of in vitro model systems that accurately recapitulate the organ microenvironment. To address this, an ex vivo model system has been established that allows for the study of soluble factors present within different organ microenvironments. This model consists of generating conditioned media from organs (lymph node, bone, lung, and brain) isolated from normal athymic nude mice. The model system has been validated by demonstrating that different breast cancer cell lines display cell-line specific and organ-specific malignant behavior in response to organ-conditioned media that corresponds to their in vivo metastatic potential. This model system can be used to identify and evaluate specific organ-derived soluble factors that may play a role in the metastatic behavior of breast and other types of cancer cells, including influences on growth, migration, stem-like behavior, and gene expression, as well as the identification of potential new therapeutic targets for cancer. This is the first ex vivo model system that can be used to study organ-specific metastatic behavior in detail and evaluate the role of specific organ-derived soluble factors in driving the process of cancer metastasis.

  4. Differential expression of the α2,3-sialic acid residues in breast cancer is associated with metastatic potential.

    PubMed

    Cui, Hongxia; Lin, Yu; Yue, Liling; Zhao, Xuemei; Liu, Jicheng

    2011-05-01

    Aberrant sialylation is closely associated with the malignant phenotype of cancer cells and metastatic potential. However, the precise nature of the molecules in breast cancers has not been unveiled. In this study, we investigated the expression levels of α2,3-sialic acid residues of 50 primary tumor cases, 50 pair-matched lymph node metastasis tumor samples and in the MDA-MB-231, T-47D and MCF-7 breast cancer cell lines with different metastatic potential. The expression of α2,3-sialic acid residues was analyzed by histochemistry, cytochemistry and flow cytometry with Maackia amurensis lectin (MAL). The invasion and migration abilities of cells were examined using cell adhesion and transwell in vitro assays. Pair-matched lymph node metastasis tumor samples exhibited higher levels of expression of α2,3-sialic acid residues compared to that of primary tumors (P=0.0432). Furthermore, of 38 tumors cases in T1/T2 stages, 31 (81.58%) had weak staining for MAL, which specifically binds to α2,3-sialic acid residues, whereas of 12 tumor cases in T3/T4 stages, only 1 (8.33%) had weak reactions for MAL. The highly metastatic breast cancer cell line MDA-MB-231 exhibited the strongest binding to MAL and the highest expression levels of α2,3-sialic acid residues among the selected cell lines, depending on mRNA expression levels of α2,3-sialyltransferase gene. The adhesion, invasion and migration activities confirmed that MDA-MB-231 exhibited the greater cell adhesion to, migration toward and invasion to Matrigel. Taken together, the high expression of α2,3-sialic acid residues in breast cancer was associated with metastatic potential. This property may be important for developing new therapeutic approaches for breast cancer.

  5. Current and emerging therapies of HER2-positive metastatic breast cancer.

    PubMed

    Hernández-Blanquisett, Abraham; Touya, Diego; Strasser-Weippl, Kathrin; Ruiz, Rossana; St Louis, Jessica; Goss, Paul

    2016-10-01

    The HER2 receptor as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is overexpressed in 15-20% of all breast cancers and traditionally represents adverse biology and a guarded prognosis, particularly in HER2 positive metastatic breast cancer (MBC). Trastuzumab and newer anti-HER2 targeting agents have significantly improved the clinical outcomes of patients with HER2 positive MBC. The development of new techniques has led to discovery of promising biomarkers that can lead to more precise selection of patients for anti-HER2 therapies. This paper summarizes these new biomarkers, useful in selecting patients for treatment with new and emerging therapies for HER2 positive MBC. Emerging next generation sequencing techniques have truly changed the landscape of HER2 positive MBC. Deployment of multiple anti-HER2 therapies in combination is a strategy which has yielded additive or even synergistic effects and has led to markedly improved patient outcomes in HER2+ MBC. In the future, in order to further improve the treatment of these patients and to reduce toxicities, we need to improve our understanding of HER2-dependent pathways and their function, and to develop further treatment combinations while optimizing selection of patients by identifying new biomarkers. The results of prospective studies using CTCs, cDNA and other promising new biomarkers are awaited with great interest.

  6. Olive secoiridoids and semisynthetic bioisostere analogues for the control of metastatic breast cancer.

    PubMed

    Busnena, Belnaser A; Foudah, Ahmed I; Melancon, Tina; El Sayed, Khalid A

    2013-04-01

    (-)-Oleocanthal (1) and ligstroside aglycone (2) are common bioactive olive oil secoiridoids. Secoiridoid 1 has been previously reported as a c-MET inhibitor. Chemically, (-)-oleocanthal is the elenolic acid ester of the common olive phenolic alcohol tyrosol. Therefore, several analogues (4-13) were synthesized by esterification and carbamoylation of tyrosol using diverse phenolic naturally occurring in olive and heterocyclic acids as elenolic acid bioisosteres to assess the effect of replacing the acid moiety of (-)-oleocanthal. Their c-MET inhibitory activity as well as their antiproliferative, antimigratory, and anti-invasive activities against the highly metastatic human breast cancer cell line MDA-MB231 has been assessed. Ligstroside aglycone (2) showed the best antimigratory activity. Generally, tyrosol esters showed better activities versus carbamate analogues. Tyrosol sinapate (5) showed the best c-MET phosphorylation inhibitory activity in Z'-LYTE kinase assay. Both 1 and 5 competitively inhibited the ATP binding into its pocket in the c-MET catalytic domain. Compound 5 showed selective activities against tumor cells without toxicity to the non-tumorigenic human breast MCF10A epithelial cell line. Tyrosol esters with a phenolic acid containing hydrogen bond donor and/or acceptor groups at the para-position have better anticancer and c-MET inhibitory activities. Olive oil secoiridoids are excellent scaffolds for the design of novel c-MET inhibitors.

  7. Ixabepilone: a new treatment option for the management of taxane-resistant metastatic breast cancer

    PubMed Central

    Cobham, Marta Vallee; Donovan, Diana

    2009-01-01

    Ixabepilone (Ixempra®; Bristol-Myers Squibb) is a novel microtubule stabilizing agent recently approved for the treatment of metastatic breast cancer (MBC). This article focuses on considerations for ixabepilone administration and adverse event (AE) management, drawing from the biomedical literature indexed in PubMed, published abstracts from the American Society of Clinical Oncology annual meetings, and the manufacturer’s prescribing information for ixabepilone. Administered as monotherapy or in combination with capecitabine in clinical studies, ixabepilone demonstrated positive clinical response rates, prolonged progression-free survival, and a favorable safety profile in patients with MBC. Treatment-related AEs were predictable and manageable with dose modification, treatment interruption, and active management. As ixabepilone undergoes development in earlier lines of breast cancer therapy and in other solid tumors, oncology nurses will encounter more and more patients receiving ixabepilone therapy. If nurses are acquainted with the unique management strategies associated with ixabepilone treatment, as detailed herein, patients are more likely to receive the full benefit of therapy. PMID:21188125

  8. Ixabepilone: a new treatment option for the management of taxane-resistant metastatic breast cancer.

    PubMed

    Cobham, Marta Vallee; Donovan, Diana

    2009-06-29

    Ixabepilone (Ixempra(®); Bristol-Myers Squibb) is a novel microtubule stabilizing agent recently approved for the treatment of metastatic breast cancer (MBC). This article focuses on considerations for ixabepilone administration and adverse event (AE) management, drawing from the biomedical literature indexed in PubMed, published abstracts from the American Society of Clinical Oncology annual meetings, and the manufacturer's prescribing information for ixabepilone. Administered as monotherapy or in combination with capecitabine in clinical studies, ixabepilone demonstrated positive clinical response rates, prolonged progression-free survival, and a favorable safety profile in patients with MBC. Treatment-related AEs were predictable and manageable with dose modification, treatment interruption, and active management. As ixabepilone undergoes development in earlier lines of breast cancer therapy and in other solid tumors, oncology nurses will encounter more and more patients receiving ixabepilone therapy. If nurses are acquainted with the unique management strategies associated with ixabepilone treatment, as detailed herein, patients are more likely to receive the full benefit of therapy.

  9. [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.

  10. Posttraumatic Growth and Diurnal Cortisol Slope among Women with Metastatic Breast Cancer

    PubMed Central

    Diaz, Michael; Aldridge-Gerry, Arianna; Spiegel, David

    2014-01-01

    Background A cancer diagnosis leads to increased psychological and emotional distress. However, in the aftermath of a traumatic event, such as being diagnosed with breast cancer, an individual may also experience beneficial changes in life perspective, relationships with others, and more. These changes are collectively known as posttraumatic growth (PTG). Studies have demonstrated that cortisol levels have been linked with cancer survival, yet an investigation of the relationship between PTG and cortisol has yet to be conducted among cancer patients. Methods The relationship of PTG to cortisol levels was examined among 99 metastatic breast cancer patients. Results We found a significant correlation between PTG and diurnal cortisol slope (Spearman’s rho = −0.21, p < 0.05), indicating a link between positive psychological changes and healthier endocrine functioning in cancer patients. Conclusions PTG in response to the stress of cancer was related to more normal (i.e., steeper) diurnal cortisol patterns. Longitudinal studies are recommended to investigate these mechanisms in relationship to cancer survival. PMID:24767622

  11. Expression of Cadherin-17 Promotes Metastasis in a Highly Bone Marrow Metastatic Murine Breast Cancer Model

    PubMed Central

    Kurabayashi, Atsushi; Furihata, Mutsuo

    2017-01-01

    We previously established 4T1E/M3 highly bone marrow metastatic mouse breast cancer cells through in vivo selection of 4T1 cells. But while the incidence of bone marrow metastasis of 4T1E/M3 cells was high (~80%) when injected intravenously to mice, it was rather low (~20%) when injected subcutaneously. Therefore, using 4T1E/M3 cells, we carried out further in vitro and in vivo selection steps to establish FP10SC2 cells, which show a very high incidence of metastasis to lungs (100%) and spines (85%) after subcutaneous injection into mice. qRT-PCR and western bolt analysis revealed that cadherin-17 gene and protein expression were higher in FP10SC2 cells than in parental 4T1E/M3 cells. In addition, immunostaining revealed the presence of cadherin-17 at sites of bone marrow and lung metastasis after subcutaneous injection of FP10SC2 cells into mice. Suppressing cadherin-17 expression in FP10SC2 cells using RNAi dramatically decreased the cells' anchorage-independent growth and migration in vitro and their metastasis to lung and bone marrow in vivo. These findings suggest that cadherin-17 plays a crucial role in mediating breast cancer metastasis to bone marrow. PMID:28197418

  12. Hepar lobatum carcinomatosum revealing an occult metastatic lobular carcinoma of the breast.

    PubMed

    Graber, Ivan; Dumortier, Jérôme; Poncet, Gilles; Queneau, Pierre-Edouard; Mathevet, Patrice; Scoazec, Jean-Yves

    2010-12-01

    Hepar lobatum carcinomatosum is an unusual cause of chronic liver failure, usually maskerading as cirrhosis. The pathogenesis of this syndrome is unclear. We report a case of liver failure revealing an occult lobular carcinoma of the breast, which offers the opportunity to gain further insight into the mechanisms of this rare cause of chronic liver disease. A 57-year-old woman, without history of malignancy, presented with hepatomegaly, ascites and altered liver tests (serum transaminase activity >5 N and hyperbilirubinemia). The transjugular liver biopsy performed at diagnosis showed an extensive fibrosis, containing scattered tumor cells, typical of metastatic lobular carcinoma of the breast. Four months later, after discovery of a rectal adenocarcinoma, a laparoscopy was performed; peritoneal carcinomatosis was discovered. A surgical biopsy of the liver was taken during the procedure: it showed histological features suggestive of chronic Budd-Chiari syndrome, with venocentric fibrosis and reversed lobulation. Intraluminal invasion of small hepatic veins and sinusoidal obstruction by neoplastic cells were observed. A small focus of lobular carcinoma was eventually discovered in the left mammary gland. The present case report expands the spectrum of clinical presentations associated with hepar lobatum carcinomatosum and points out to the importance of vascular injury in the pathogenesis of this rare cause of chronic liver disease.

  13. Expression of WT1, CA 125, and GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary.

    PubMed

    Tornos, Carmen; Soslow, Robert; Chen, Shirley; Akram, Muzaffar; Hummer, Amanda J; Abu-Rustum, Nadeen; Norton, Larry; Tan, Lee K

    2005-11-01

    Metastatic breast carcinoma to the ovary is sometimes difficult to differentiate from primary ovarian carcinoma. This problem is often encountered in breast carcinoma patients who develop adnexal masses. ER and PR can be positive in a high percentage of breast and ovarian carcinomas, and therefore cannot be used in the differential diagnosis of these entities. WT1 and CA125 have been identified as possible markers for ovarian cancer. However, no studies have been done that specifically compare the immunophenotype of breast carcinoma metastatic to ovary with that of primary ovarian cancer. Thirty-nine cases of metastatic breast carcinoma to the ovary, 36 primary breast carcinomas, and 42 primary ovarian carcinomas were examined immunohistochemically for the expression of WT1, CA125, carcinoembryonic antigen, MUC2, MUC1, and GCDFP. The percentage of cells stained and the intensity of staining were recorded. Thirty-two ovarian carcinomas (76%) were positive for WT1, including 31 of 33 (94%) serous carcinomas. Most of them had strong and diffuse staining. None of the breast cancers either primary or metastatic to the ovary expressed WT1. Thirty-eight (90%) ovarian carcinomas were positive for CA125, most of them with strong and diffuse staining. Most breast carcinomas were negative for CA125, with only 6 (16%) of the primary ones and 5 (12%) of the metastatic showing weak and focal positivity. All ovarian carcinomas were negative for GCDFP. Five primary breast cancers (14%) and 17 (43%) metastatic to the ovary were positive for GCDFP. Nine (21%) ovarian carcinomas, 8 (22%) primary breast carcinomas, and 13 (33%) metastatic to the ovary were positive for carcinoembryonic antigen. Almost all tumors examined were positive for MUC1 (100% ovarian carcinomas, 100% primary breast carcinomas, and 95% metastatic breast carcinomas to ovary). MUC2 was positive in 10 (24%) ovarian carcinomas, 3 (8%) primary breast cancers, and 12 (30%) metastases to the ovary. The presence of

  14. p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading.

    PubMed

    Guerra, Emanuela; Cimadamore, Alessia; Simeone, Pasquale; Vacca, Giovanna; Lattanzio, Rossano; Botti, Gerardo; Gatta, Valentina; D'Aurora, Marco; Simionati, Barbara; Piantelli, Mauro; Alberti, Saverio

    2016-08-18

    Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study. A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse. p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases

  15. Phase II Trial of Trastuzumab in Combination With Cytotoxic Chemotherapy for Treatment of Metastatic Osteosarcoma With Human Epidermal Growth Factor Receptor 2 Overexpression: A Report From the Children's Oncology Group

    PubMed Central

    Ebb, David; Meyers, Paul; Grier, Holcombe; Bernstein, Mark; Gorlick, Richard; Lipshultz, Steven E.; Krailo, Mark; Devidas, Meenakshi; Barkauskas, Donald A.; Siegal, Gene P.; Ferguson, William Shay; Letson, George Douglas; Marcus, Karen; Goorin, Allen; Beardsley, Peter; Marina, Neyssa

    2012-01-01

    Purpose Despite efforts to intensify chemotherapy, survival for patients with metastatic osteosarcoma remains poor. Overexpression of human epidermal growth factor receptor 2 (HER2) in osteosarcoma has been shown to predict poor therapeutic response and decreased survival. This study tests the safety and feasibility of delivering biologically targeted therapy by combining trastuzumab with standard chemotherapy in patients with metastatic osteosarcoma and HER2 overexpression. Patients and Methods Among 96 evaluable patients with newly diagnosed metastatic osteosarcoma, 41 had tumors that were HER2-positive by immunohistochemistry. All patients received chemotherapy with cisplatin, doxorubicin, methotrexate, ifosfamide, and etoposide. Dexrazoxane was administered with doxorubicin to minimize the risk of cardiotoxicity from treatment with trastuzumab and anthracycline. Only patients with HER2 overexpression received concurrent therapy with trastuzumab given for 34 consecutive weeks. Results The 30-month event-free and overall survival rates for patients with HER2 overexpression treated with chemotherapy and trastuzumab were 32% and 59%, respectively. For patients without HER2 overexpression, treated with chemotherapy alone, the 30-month event-free and overall survival rates were 32% and 50%, respectively. There was no clinically significant short-term cardiotoxicity in patients treated with trastuzumab and doxorubicin. Conclusion Despite intensive chemotherapy plus trastuzumab for patients with HER2-positive disease, the outcome for all patients was poor, with no significant difference between the HER2-positive and HER2-negative groups. Although our findings suggest that trastuzumab can be safely delivered in combination with anthracycline-based chemotherapy and dexrazoxane, its therapeutic benefit remains uncertain. Definitive assessment of trastuzumab's potential role in treating osteosarcoma would require a randomized study of patients with HER2-positive disease

  16. Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis

    SciTech Connect

    Wang, Yifan; Li, Shu Jie; Pan, Juncheng; Che, Yongzhe; Yin, Jian; Zhao, Qing

    2011-08-26

    Highlights: {yields} Hv1 is specifically expressed in highly metastatic human breast tumor tissues. {yields} Hv1 regulates breast cancer cytosolic pH. {yields} Hv1 acidifies extracellular milieu. {yields} Hv1 exacerbates the migratory ability of metastatic cells. -- Abstract: The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT-PCR and immunocytochemistry showed that the expression levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells.

  17. Defining the optimal sequence for the systemic treatment of metastatic breast cancer.

    PubMed

    Mestres, J A; iMolins, A B; Martínez, L C; López-Muñiz, J I C; Gil, E C; de Juan Ferré, A; Del Barco Berrón, S; Pérez, Y F; Mata, J G; Palomo, A G; Gregori, J G; Pardo, P G; Mañas, J J I; Hernández, A L; de Dueñas, E M; Jáñez, N M; Murillo, S M; Bofill, J S; Auñón, P Z; Sanchez-Rovira, P

    2017-02-01

    Metastatic breast cancer is a heterogeneous disease that presents in varying forms, and a growing number of therapeutic options makes it difficult to determine the best choice in each particular situation. When selecting a systemic treatment, it is important to consider the medication administered in the