TREATMENT OF TRIPLE-NEGATIVE BREAST CANCER

Abstract

Breast cancer is the most commonly diagnosed cancer in female population worldwide. Advances in understanding tumor biology, particularly signaling pathways, have led to the development and approval of novel therapeutic agents, especially in HER2 positive and hormone receptor positive subtypes. Triplenegative breast cancer (TNBC) is defined by lack of expression of estrogen receptor, progesteron receptor and HER-2 amplification and accounts for approximately 15-20% of breast cancers. It is also a heterogeneous group of tumors which tend to have an aggressive phenotype with higher recurrence rates and lower survival rates. This subtype lacks unifying molecular alterations that can guide therapy decisions. To date, there are no approved targeted therapies specifically for this subtype; however, many are in development. The most important future strategies will be those for targeting triple-negative breast cancers through novel receptors, harnessing the immune system, and new ways of targeting angiogenesis. Ongoing research is investigating targetable novel cell surface receptors, the use checkpoint inhibitors, and identifying subgroups likely to benefit from platinum-based therapies and poly(adenosine diphosphate-ribose) polymerase inhibitors. The androgen receptor (AR) has been identified as a possible predictive biomarker for antiandrogen therapy in ER- breast cancer. AR positivity has been associated with more favorable prognoses in TNBC. There are several studies that show AR is associated with lower Ki-67 proliferative marker, lower mitotic score, lower histologic grade and lower clinical stage. Since the presence of residual disease after completion of neoadjuvant therapy predicts poor prognosis, numerous clinical trials are designed to test the value of further adjuvant therapy in TNBC patients with residual disease. Preliminary results of the CREATE-X (JBCRG-04) trial by the Japan Breast Cancer Research Group were presented at the 2015 San Antonio Breast Cancer Symposium. Two ongoing US studies examine the value of more chemotherapy or immunotherapy as adjuvant treatment for patients with residual TNBC after neoadjuvant chemotherapy. While numerous studies investigating anti-vascular endothelial growth factor (VEGF) therapy in the neoadjuvant sett ing suggest improved pathologic complete response rates, especially in TNBC, studies to date have not demonstrated a survival benefit in the adjuvant sett ing or metastatic sett ing. A promising field of clinical research in breast cancer is the use of immune checkpoint inhibitors. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to enhance pre-existing anti-cancer immune responses. Several studies investigating checkpoint inhibitors are currently enrolling breast cancer patients. Approximately 20% of TNBCs express PD-L1, and expression of PD-L1 is associated with poor prognosis, thus making this aggressive phenotype att ractive subtype in which to investigate PD-L1 blockade.