Review ArticlesTriple-Negative Breast Cancer Breast Tumors With an Identity CrisisNunnery, Sara E. MD∗,†,‡; Mayer, Ingrid A. MD, MSCI∗,†,‡; Balko, Justin M. PharmD, PhD∗,†,‡,§Author Information From the ∗Department of Medicine, Division of Hematology/Oncology †Breast Cancer Program ‡Vanderbilt-Ingram Cancer Center (VICC) §Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Reprints: Justin M. Balko, PharmD, PhD, Vanderbilt University Medical Center, 2220 Pierce Ave., 777 PRB, Nashville, TN 37232. E-mail: [email protected]. The Cancer Journal: 1/2 2021 - Volume 27 - Issue 1 - p 2-7 doi: 10.1097/PPO.0000000000000494 Buy Metrics Abstract Triple-negative breast cancer (TNBC) is pathologically defined by lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 amplification and portends an aggressive clinical course with worse outcomes compared with other breast cancers. Until recently, standard treatment options consisted of sequential cytotoxic chemotherapies for both early and metastatic disease. Advances in sequencing technology have led to the identification of 4 main subtypes of TNBC based on recurrent genetic alterations, transcriptional patterns, and molecular features: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), and luminal androgen receptor (LAR). Frequent alterations found in DNA damage response pathways, germline and somatic BRCA1/2 genes, PI3K signaling pathways, and the presence of androgen receptors and infiltrating immune cells could serve as actionable targets to optimize treatments and improve outcomes for patients with TNBC. Recent approvals for immune checkpoint inhibitors and the antibody-drug conjugate, sacituzumab govitecan-hziy, for advanced TNBC illustrate the advances in treatment that can result from these molecular discoveries. This review will explore the molecular subtypes of TNBC and their distinct characteristics, as well as highlight the molecular features and potential “drivers” that have been identified as promising targets for new treatment strategies. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.