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

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.

The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast Cancer

“…Luminal B tumors have a more aggressive phenotype, a higher histological grade, and a worse prognosis than those of the luminal A subtype [ 8 , 9 ]. Patients that are overexpressing HER2 are frequently treated with Trastuzumab (an humanized monoclonal antibody against this receptor) or, in most cases upon recurrence, lapatinib (an small molecular inhibitor of HER2 tyrosine kinase activity) [ 10 ]. Despite the implementation of these selective therapies against luminal and HER2 positive breast cancers, approximately 20–30% of the patients that are treated with endocrine therapy and 70% of patients that are treated with Trastuzumab develop resistance, and progress to a more advanced disease [ 11 ].…”

Investigation of the Anticancer Effect of α-Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect

“…Immunohistochemical examination of Bcl2 as antiapoptotic protein was carried out in breast tissue which showed increased expression in DMBA group. BCL2 is responsible for suppression of the mitochondrial pathway activation to apoptosis, and its expression is increased in most breast cancer cases [ 26 ]. Treatment with 7b mainly reduced BCL2 activity, thus induces apoptosis, and limits cancer progression [ 26 , 27 , 28 ].…”

“…BCL2 is responsible for suppression of the mitochondrial pathway activation to apoptosis, and its expression is increased in most breast cancer cases [ 26 ]. Treatment with 7b mainly reduced BCL2 activity, thus induces apoptosis, and limits cancer progression [ 26 , 27 , 28 ]. The reduction of cancer size may be explained by the downregulation of Bcl2 and up-regulation of BAX, which leads to a shift in the Bcl2/BAX ratio towards a pro-apoptotic signal in 7b -treated group.…”

The Role of the CDK4/6 Inhibitor Ribociclib in Locally Advanced and Oligometastatic Hormone Receptor Positive, Her2 Negative, Advanced Breast Cancer: Case Series and Review of the Literature

“…The recent phase II trial CORALLEEN in patients with high-risk luminal B breast cancer demonstrated response rates similar to multiagent chemotherapy with ribociclib/letrozole but with less toxicity ( 21 ). However, the demonstrated clinical efficacy of ribociclib and the other CDK4/6 inhibitors in metastatic settings cannot yet be translated in higher pathological complete response in neoadjuvant settings, where the role of targeted agents is still debated ( 22 ).…”