Moving beyond endocrine therapy for luminal metastatic breast cancer in the precision medicine era: looking for new targets

ABSTRACT Introduction: Hormone receptor-positive (HR+) breast cancer (BC) is the most frequent BC subtype, for which estrogen receptor (ER)-signaling blockade still represents the cornerstone of treatments. Nevertheless, almost all HR+ BC patients develop resistance to endocrine therapy, a critical therapeutic unmet need for BC patients. Recent advances in genomic medicine allowed for a more detailed identification and better characterization of the mechanisms underlining endocrine resistance and led to the development of targeted agents potentially able to restore endocrine sensitivity, thus improving disease control and potentially survival. Areas covered: New drugs in the early phase of development for HR-positive metastatic BC (MBC) treatment are here outlined. PI3K/AKT/mTOR, FGFR, and IGFRs are the main pathways addressed, and evidences about HER2 blockade in triple-positive diseases are also reported. New hormonal agents active against estrogen receptor 1 (ESR1)-mutant MBC are presented. A brief mention of biological agents not targeting intracellular signaling hubs, such as histone-deacetylase inhibitors and immunotherapy drugs, is finally provided. Expert opinion: promising results have been reported for the majority of new drugs under development. Despite this, a ‘precision medicine approach’ still has to demonstrate a benefit in this disease. Identification of reliable predictive biomarkers should be a key objective of future researches.