Targeted Neoadjuvant Therapies in HR+/HER2-Breast Cancers: Challenges for Improving pCR

A strong association of pCR (pathological complete response) with disease-free survival or overall survival is clinically desirable. The association of pCR with disease-free survival or overall survival in ER+/HER2-breast cancers following neoadjuvant systemic therapy (NAT) or neoadjuvant endocrine therapy (NET) is relatively low as compared to the other two subtypes of breast cancers, namely triple-negative and HER2+ amplified. On the bright side, a neoadjuvant model offers a potential opportunity to explore the efficacy of novel therapies and the associated genomic alterations, thus providing a rare personalized insight into the tumor's biology and the tumor cells' response to the drug. Several decades of research have taught us that the disease's biology is a critical factor determining the tumor cells' response to any therapy and hence the final outcome of the disease. Here we propose two scenarios wherein apoptosis can be induced in ER+/HER2- breast cancers expressing wild type TP53 and RB genes following combinations of BCL2 inhibitor, MDM2 inhibitor, and cell-cycle inhibitor. The suggested combinations are contextual and based on the current understanding of the cell signaling in the ER+/HER2- breast cancers. The two combinations of drugs are (1) BCL2 inhibitor plus a cell-cycle inhibitor, which can prime the tumor cells for apoptosis, and (2) BCL2 inhibitor plus an MDM2 inhibitor.