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

SIMPLE SUMMARY: A high pathological complete response in the neoadjuvant setting is directly associated with a better overall response. A favorable prognosis is achieved when preoperative chemo or endocrine therapy succeeds in achieving a high pathological complete response (total eradication of tumors in the breast and the lymph nodes). Approximately 70% of breast cancers are ER-positive. The growth and progression of ER-positive breast cancers are critically dependent on estrogen receptor signaling. Although endocrine therapies (tamoxifen, an aromatase inhibitor, and fulvestrant) in ER-positive breast cancers are the backbone of adjuvant setting, the efficacy of such therapies in terms of achieving a pathological complete response is not encouraging in the neoadjuvant setting. Similar results are observed following targeted therapies in a neoadjuvant setting. Reviewing the literature in the context of different therapies of ER-positive breast cancers in the neoadjuvant setting, here we propose two hypothetical strategies to induce apoptosis based on the background of genomic alterations in the tumor tissues. ABSTRACT: 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.