Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges

Abstract

Triple negative breast cancer (TNBC) is an aggressive breast cancer with historically poor outcomes, primarily due to the lack of effective targeted therapies. The tumor molecular heterogeneity of TNBC has been well recognized, yet molecular subtype driven therapy remains lacking. While neoadjuvant anthracycline and taxane-based chemotherapy remains the standard of care for early stage TNBC, the optimal chemotherapy regimen is debatable. The addition of carboplatin to anthracycline, cyclophosphamide, and taxane (ACT) regimen is associated with improved complete pathologic response (pCR). Immune checkpoint inhibitor (ICI) combinations significantly increase pCR in TNBC. Increased tumor infiltrating lymphocyte (TILs) or the presence of DNA repair deficiency (DRD) mutation is associated with increased pCR. Other targets, such as poly-ADP-ribosyl polymerase inhibitors (PARPi) and Phosphatidylinositol-3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K-AKT-mTOR) pathway inhibitors, are being evaluated in the neoadjuvant setting. This review examines recent progress in neoadjuvant therapy of TNBC, including platinum, ICI, PARPi, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) pathway targeted therapies, and novel tumor microenvironment (TME) targeted therapy, in addition to biomarkers for the prediction of pCR.

Keywords: Triple negative breast cancer; neoadjuvant treatment; targeted treatment.

Figure 1

Mechanisms of PI3K/AKT/mTOR pathway activation and targeted therapies. Activating mutations in the α catalytic domain of PI3K and/or PTEN mutation lead to pathway activation. PI3K signaling pathway linking RTK signaling leads to downstream activation of PI3K/AKT/mTOR, promoting cell proliferation and survival. RTK receptor tyrosine kinase, PI3K phosphatidylinositol-3-kinase, PTEN phosphatase and tensin homolog, AKT Protein Kinase B, mTORC mechanistic target of rapamycin complex.