Beyond CDK4/6 Inhibition: Current Strategies in Hormone Receptor-Positive Metastatic Breast Cancer

Abstract

We focus our second-line treatment strategy on biomarker-defined resistance mechanisms that emerge after progression on CDK4/6 inhibitors. In our view, ESR1 mutation-mediated resistance constitutes a biologically distinct phenotype of endocrine resistance rather than a simple treatment escape. Therefore, in patients with ESR1-mutated tumors, we strongly favor incorporating next-generation oral selective estrogen receptor degraders (SERDs), given their targeted mechanism, favorable tolerability, and efficacy following CDK4/6 inhibition. For tumors harboring alterations in the PIK3CA-AKT-PTEN pathway, treatment selection is similarly biomarker driven. In patients with PIK3CA mutations, fulvestrant combined with alpelisib remains an effective option, though tolerability concerns often influence long-term adherence; accordingly, we increasingly prefer fulvestrant with capivasertib due to its activity across PIK3CA, AKT1, and PTEN alterations and its more manageable safety profile. When patients exhibit rapid progression, endocrine-independent biology, or aggressive visceral disease, we transition early to antibody-drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan, which demonstrate superior outcomes compared with conventional chemotherapy in appropriately selected cases. Overall, an individualized, biomarker-driven approach remains central to optimizing therapeutic sequencing in advanced HR+ breast cancer.