Triple negative breast cancer (TNBC), lacking expression of the hormone receptors (estrogen/ER, progesterone/PR) and without amplification or overexpression of HER2, is defined by what it isn’t, which fails to reflect the potential for targetability and improved outcomes now emerging. In spite of recent advances, TNBC continues to carry the worst prognosis of all the clinical subtypes, has the fewest therapeutic options, and affects young women and women of color most, so improving therapy in this subtype is among the biggest challenges in breast cancer oncology. Epidemiologic studies confirm the unique biology of the basal-like subtype, which comprises the majority of TNBC, its unique risk factors and metastatic patterns. However, TNBC (and the basal-like intrinsic subtype) molecular and immunologic heterogeneity is becoming clearer, as are the implications of this heterogeneity on treatment response and outcome. For example, the presence of tumor infiltrating lymphocytes (TILS) is consistently associated with better outcomes in nonmetastatic TNBC. Prognosis in this subtype, as with all other subtypes, is driven not only by biology but also by clinical variables. Unlike hormone receptor-positive, there are no effective genomic prognostic assays for TNBC, however as with all breast cancer clinical subtypes, small node-negative breast cancers do well and may not need chemotherapy. However these are the minority; in the remainder of early TNBC, standard chemotherapy includes both anthracyclines and taxanes, with some evidence of benefit of the incorporation of platinums. There have been advances for patients with nonmetastastic TNBC in the past few years. For example, in all but the smallest node-negative tumors, the use of the neoadjuvant, or preoperative, approach improves surgical outcomes and allows risk stratification based on pathologic response. In patients treated with neoadjuvant chemotherapy with residual disease at surgery, adjuvant capecitabine improves relapse and survival. In those with germline mutations of BRCA1 or 2, the addition of adjuvant PARP inhibition in intermediate and high risk TNBC improved outcomes. Immune checkpoint inhibition (ICI) added to neoadjuvant chemotherapy improves pathologic response to therapy, and more recently the ICI pembrolizumab has also been shown to improve relapse-free survival. In metastatic disease, ICI improves outcome when added to chemotherapy in first-line treatment of PDL1-positive TNBC, and the PARP inhibitors olaparib and talazoparib offer a non-chemotherapy option for those with germline BRCA1, BRCA2, or PALB2. However it remains true that metastatic TNBC remains dependent on chemotherapy-based treatment options. The antibody-drug conjugate (ADC) sacituzumab govitecan is an example of ways to deliver cytotoxic chemotherapy more safely and effectively, and has become a standard 2nd line or later option with examination of this ADC and others in earlier settings ongoing. Efforts to define TNBC in therapeutically targetable ways have not yet resulted in the goal of redefining this entity according to tumor and immune targets, but with greater biologic understanding and ongoing clinical and translational efforts, it is likely the term “triple negative” will become obsolete in the future.

Citation Format: LA Carey. Triple Negative Breast Cancer - Pitfalls and Progress [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PL2.