NATURE REVIEWS | CLINICAL ONCOLOGY ADVANCE ONLINE PUBLICATION | 1 University of North Carolina, 170 Manning Drive, Chapel Hill, NC 27599–7305, USA (L. Carey). Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA (E. Winer). European Institute of Oncology, University of Milan, Via Ripamonti 435, 20141 Milan, Italy (G. Viale). Edinburgh University Cancer Center, Crewe Road South, Edinburgh EH4 2XU, UK (D. Cameron). Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy (L. Gianni). Correspondence to: L. Gianni luca.gianni@ istitutotumori.mi.it Triple-negative breast cancer: disease entity or title of convenience? Lisa Carey, Eric Winer, Giuseppe Viale, David Cameron and Luca Gianni Abstract | This Review outlines the understanding and management of triple-negative breast cancer (TNBC). TNBC shares morphological and genetic abnormalities with basal-like breast cancer (BLBC), a subgroup of breast cancer defined by gene-expression profiling. However, TNBC and BLBC tumors are heterogeneous and overlap is incomplete. Breast cancers found in BRCA1 mutation carriers are also frequently triple negative and basal like. TNBC and BLBC occur most frequently in young women, especially African Americans, and tend to exhibit aggressive, metastatic behavior. These tumors respond to conventional chemotherapy but relapse more frequently than hormone receptor-positive, luminal subtypes and have a worse prognosis. New systemic therapies are urgently needed as most patients with TNBC and/or BLBC relapse with distant metastases, and hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in patients with TNBC and/or BRCA1- associated tumors. Increased understanding of the genetic abnormalities involved in the pathogenesis of TNBC, BLBC and BRCA1-associated tumors is opening up new therapeutic possibilities for these hard-to-treat breast cancers. Carey, L. et al. Nat. Rev. Clin. Oncol. advance online publication 28 September 2010; doi:10.1038/nrclinonc.2010.154 Introduction In April 2009, the Fondazione Michelangelo and the Fondazione IRCCS Istituto Nazionale dei Tumori orga- nized the ninth in a series of seminars on recent advances and controversies in breast cancer. This seminar was designed to update practicing clinicians on ‘triple- negative’ breast cancer (TNBC)—that is the subgroup of tumors that do not express clinically significant levels of the estrogen receptor (ER), progesterone receptor (PgR) and HER2. In particular, the seminar addressed the ques- tion of whether TNBC is a distinct pathological subtype of breast cancer or a pragmatic category for determining eligibility for clinical trials and guiding individual patient treatment. In addition, emerging treatment strategies were discussed because patients with TNBC are not eligible for hormonal therapies or HER2-targeted agents and, there- fore, have no established systemic therapy options other than chemotherapy. What is TNBC? TNBC is a diagnosis of exclusion, based on lack of ER and PgR expression by immunohistochemistry (IHC), and of HER2 overexpression or gene amplification by IHC or in situ hybridization, respectively. 1 The frequency of this cluster of findings therefore depends to some extent on the methods and thresholds used (which have evolved over time), but generally 10–24% of invasive breast cancers fall into this category. 2–5 TNBCs are typically high- grade tumors, although low-grade tumors do occur. 2,6–10 Furthermore, although most TNBCs are of ductal (not otherwise specified) type, other rarer tumors (for example, metaplastic, medullary and adenoid cystic tumors) may be triple negative and these may have a better prognosis than the usually poor one of TNBCs in general. 1,7,11 As described in further detail below, molecular-profiling studies suggest that although most TNBCs (about 70%) fall into the basal-like subtype, the remainder consist of a variety of molecular subtypes that are biologically dis- tinct. 12 These findings suggest that TNBC is not a single disease but includes additional tumor types, making it a heterogeneous entity. Apart from lacking ER, PgR and HER2 expression, TNBCs are associated with a number of other patho- logical features (Table 1). TNBCs frequently express basal cytokeratins (particularly cytokeratin 5, 14 and 17) and the EGFR HER1, 2,7–10,13–15 features that are associated with a poor prognosis in breast cancer. 2,16–18 Compared with other tumor types, TNBCs are also more likely to express myoepithelial markers, such as caveolins (CAV) 1 and 2, 8 c-kit, 10,15 and P-cadherin, 7 and less likely to express epi- thelial markers, such as E-cadherin. 7 They also have high expression of genes associated with proliferation (Ki67 Competing interests E. Winer declares an association with the following company: Genentech. D. Cameron declares associations with the following companies: Pfizer, Roche, Sanofi-Aventis. L. Gianni declares associations with the following companies: Biogen Idec, Eisai, Genentech, GlaxoSmithKline, Millennium Pharmaceuticals, Novartis, Roche, Sanofi-Aventis. See the article online for full details of the relationships. L. Carey and G. Viale declare no competing interests. FOCUS ON BREAST CANCER © 20 Macmillan Publishers Limited. All rights reserved 10