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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ETriple-negative breast cancer is a heterogeneous disease and therefore presents treatment challenges, as targetable characteristic molecular abnormalities have not yet been identified. As with BRCA1-associated breast cancer, defective DNA repair and homologous recombination are implicated in sporadic TNBC, engendering sensitivity to platinum chemotherapy and poly (ADP-ribose) polymerase.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Egenomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Etreatment challenges\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eadjuvant therapy\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eneoadjuvant therapy\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003ETriple-negative breast cancer (TNBC) lacks estrogen receptors (ER), progesterone receptors, and amplification of human epidermal growth factor receptor 2 (HER2) [Sikov WM. Breast Cancer Symposium. 2014]. TNBC accounts for 15% to 20% of breast cancer cases diagnosed in the United States alone.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003ENicholas Turner, PhD, Institute of Cancer Research, London, United Kingdom, discussed the heterogeneity in TNBC and the challenges it presents for effective treatment.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EFrom a global level, BC can be divided into 2 specific subtypes called BRCA luminal and BRCA basal-like. Basal-like BCs comprise the majority of TNBC subtypes (approximately 80%), while luminal-androgen receptor (AR) BC is clearly distinct [Weigelt B et al. \u003Cem\u003EJ Pathol.\u003C\/em\u003E 2010]. Luminal-AR TNBC, although ER- and progesterone-receptor-negative, has high expression of hormonal driven pathways [Lehmann BD et al. \u003Cem\u003EJ Clin Invest.\u003C\/em\u003E 2011]. They express the AR, and in vitro, they are sensitive to the AR antagonist bicalutamide. In a phase 2 trial of 28 patients with AR-positive, ER-negative metastatic BC, 19% had stable disease\u2009\u0026gt;\u20096 months when treated with bicalutamide [Gucalp A et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2013], showing proof of principle that AR is a potential target in this group of cancers, said Prof Turner.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe other key feature of luminal-AR TNBC is enrichment for mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) [Lehmann BD et al. \u003Cem\u003EBreast Cancer Res.\u003C\/em\u003E 2014]. PIK3CA mutation correlates in TNBC cell lines with activation of the pathway, and these cell lines are sensitive to PIK3 inhibitors. Luminal-AR TNBC has several similarities to HER2-amplified BC (eg, ER-negative, PIK3CA mutation, histologic grade 2\/3, and apocrine features), and both cell lines were found to be sensitive to cyclin D kinase 4\/6 inhibition [Finn RS et al. \u003Cem\u003EBreast Cancer Res.\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EA mesenchymal subtype of TNBC is characterized by expression of genes associated with epithelial-to-mesenchymal transition [Burstein MD et al. \u003Cem\u003EClin Can Res.\u003C\/em\u003E 2014]. Another subtype, mesenchymal stem-like TNBC, is enriched for stem cell-like phenotypes [Hennessy BT et al. \u003Cem\u003ECancer Res.\u003C\/em\u003E 2009], frequently has an immune infiltrate, has a lower proliferative rate than basal-like cancers, and has intermediate levels of PIK3CA mutation [Lehmann BD et al. \u003Cem\u003EJ Clin Invest.\u003C\/em\u003E 2011]. High lymphocytic infiltration is a subset of basal-like and mesenchymal stem-like TNBC; it represents a subtype of TNBC that has an excellent prognosis [Loi S et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2013].\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EApproximately 60% of patients with TNBC express epidermal growth factor receptor; they demonstrated some evidence of sensitivity to cetuximab but only at a low level that is insufficient to drive future clinical development [Baselga J et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2013].\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003ETNBC is complicated by intratumoral heterogeneity. TNBCs have been shown to vary widely in their clonal frequencies and display a complete spectrum of mutational and clonal evolution, leading to intrinsic resistance to targeted therapy [Shah SP et al. \u003Cem\u003ENature.\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EAndrew Tutt, PhD, Kings College, London, United Kingdom, discussed the genome complexity of TNBC. BRCA1\/2 are involved in the repair of DNA damage; each plays an important role in homologous recombination (HR). Sporadic TNBC and BRCA1-associated breast cancer share features suggesting a common pathogenesis. TNBC also has significant subpopulations with defective DNA repair; BRCA1\/2 is mutated in about 15% of patients with TNBC [Sharma P et al. \u003Cem\u003EBreast Cancer Res Treat.\u003C\/em\u003E 2014], and HR deficiency has been implicated in sporadic TNBC. When HR fails, other DNA repair processes take over, driving a mutator phenotype. Defects in HR repair can engender sensitivity to platinum therapy and poly (ADP-ribose) polymerase (PARP).\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EBRCA1-deficient cells are especially vulnerable to the interstrand cross-linking agents cisplatin and mitomycin [Silver DP et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2010]. High rates of pathologic response were achieved with neoadjuvant platinum therapy in BRCA1 mutation carriers.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EA genomic scar\u2014a genomic aberration with a known origin\u2014are reporters of HR deficiency and drug response [Watkins JA et al. \u003Cem\u003EBreast Cancer Res.\u003C\/em\u003E 2014]. Tracing scars in a patient\u2019s tumor genome to particular drivers of the mutator phenotype that caused them may enable treatments that target these origins. A tumor with an allelic balance phenotype extending to the telomere had higher sensitivity to drugs that induce DNA crosslinks (eg, platinums) [Birkbak NJ et al. \u003Cem\u003ECancer Discov.\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EAn HR deficiency (HRD) score is a measure of the genomic HRD footprint in a tumor caused by defects in the HR pathway; it is derived by counting the number of regions with loss of heterozygosity of intermediate size in the tumor genome [Telli ML et al. SABCS 2012; (abstr PD09-04)]. The HRD score was found to be significantly correlated with pathologic response to platinum-based chemotherapy in early-stage TNBC (\u003Cem\u003EP\u003C\/em\u003E\u2009=\u2009.0003) and BRCA1\/2 mutation-associated BC (\u003Cem\u003EP\u003C\/em\u003E\u2009=\u2009.0006).\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EPARP inhibitors appear promising as treatment for BRCA-associated cancers and sporadic TNBC. Most studies of PARP inhibition thus far have focused on germline BRCA-mutated cancer. Combining HR-targeting chemotherapy with PARP inhibition attempts to inhibit the DNA damage caused by platinum therapy, increasing cytotoxicity. However, in one trial, adding low-dose rucaparib, a PARP inhibitor, did not improve 1-year disease-free survival (DFS) or impact the toxicity of cisplatin [Dwadasi S et al. ASCO 2014 (abstr 1019)].\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EEric P. Winer, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, discussed current and new approaches to adjuvant and neoadjuvant therapy. Combination chemotherapy remains effective adjuvant therapy for TNBC. For stage II\/III TNBC, standard adjuvant chemotherapy is considered to be an anthracycline\/taxane regimen, either adriamycin, cyclophosphamide, and paclitaxel (dose-dense weekly); docetaxel, adriamycin, and cyclophosphamide; or 5-fluorouracil, epirubicin, and cyclophosphamide therapy plus docetaxel.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003ENeoadjuvant therapy for TNBC can successfully downstage disease to facilitate less radical surgery while improving prognosis, although overall prognosis remains inferior to that of other breast cancer subtypes, said Dr Winer. As neoadjuvant therapy, a pathologic complete response (pCR) was achieved in 45% of patients with TNBC treated with 5-fluorouracil, doxorubicin, and cyclophosphamide [Rouzier R et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2005] and 36% with adriamycin, cyclophosphamide, and paclitaxel [Carey LA et al. \u003Cem\u003EClin Cancer Res.\u003C\/em\u003E 2007], and 5-year distant DFS was \u0026gt;\u200990% in those who achieved pCR. Failure to achieve pCR is associated with poorer event-free and overall survival (OS) in TNBC.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EIn 2 trials, carboplatin improved the rate of pCR [von Minckwitz G et al. \u003Cem\u003ELancet Oncology.\u003C\/em\u003E 2014; Sikov WM et al. \u003Cem\u003EJ Clin Oncol.\u003C\/em\u003E 2014]; however, a definitive study is needed showing improvement in DFS or OS before carboplatin can be considered a new standard.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/56\/23.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo8de\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}