Immunotherapy for Triple-Negative Breast Cancer: A Focus on Immune Checkpoint Inhibitors

Introduction Triple-negative breast cancer (TNBC) is clinically defined as breast tumors lacking expression of estrogen receptor (ER) and progesterone receptor, with normal human epidermal growth factor receptor type 2 (HER2) gene copy number and expression. It accounts for approximately 15% to 20% of all breast cancers and is more prevalent in younger women and in African-American women. TNBC has an aggressive natural history, with an increased mortality rate during the first 5 years with most deaths occurring in the first 5 years. Typically, there is a high risk of early recurrence and this tends to occur within the first 4 years after diagnosis. Compared with other subtypes, visceral metastasis is more likely, involving the brain and lungs. TNBC is also characterized by molecular heterogeneity. There is diversity in the histologic patterns and transcriptional subtypes. The majority of TNBCs are high-grade invasive ductal carcinomas, but there is a small subset with distinct pathology and indolent biologic behavior, such as adenoid cystic carcinoma. Lehmann and colleagues proposed a classification that defined several molecular subtypes of TNBC; these include 2 basal-like (BL1 and BL2), an immunomodulatory, a mesenchymal, a mesenchymal stem-like, and a luminal androgen receptor subtype. Similarly, another gene expression analysis suggested the following subgroups: luminal/ androgen receptor, mesenchymal, BL/immune-suppressed, and BL/immune-activated. These classifications help to increase our understanding of the biology of TNBC and identify rational therapeutic strategies for TNBC subtypes. Chemotherapy is the current standard-of-care treatment of TNBC in the adjuvant, neoadjuvant, and metastatic settings. TNBCs are highly sensitive to chemotherapy, as evidenced by pathologic complete response (pCR) rates in the 30% to 40% range after neoadjuvant chemotherapy, compared with complete response (CR) rates for ER-positive breast cancer, which range from 10% to 25%. However, TNBC has higher rates of relapse, which has been referred to as the triple-negative paradox. The need to improve the outcomes of patients with TNBC drives large-scale clinical investigational efforts to evaluate novel therapeutic approaches. Immunotherapy, such as checkpoint inhibitors, represents a modality that has changed the treatment landscape for other solid tumors, especially melanoma and non– small cell lung cancer (NSCLC). The potential role of immune checkpoint blockade therapy in TNBC is the focus of this review.