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

OPINION STATEMENT: 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.