Emerging Endocrine Doublets and Serial ESR1 Testing in HR+/HER2− mBC

The panel examines how emerging endocrine doublets and earlier biomarker monitoring could reshape treatment sequencing for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2− mBC). Dr. Erica Mayer reiterates her preference for combining a novel endocrine therapy with a targeted partner when appropriate, given the higher response and progression-free survival observed with doublet strategies compared with monotherapy. She then discusses the potential implications of SERENA-6, which used serial circulating tumor DNA (ctDNA) testing during first-line aromatase inhibitor plus CDK4/6 inhibitor therapy to identify emerging ESR1 mutations before clinical or radiographic progression. Patients with an emergent ESR1 mutation were randomized to switch to camizestrant while continuing the same CDK4/6 inhibitor or remain on their existing regimen, with the switch strategy improving progression-free survival and delaying deterioration in quality of life. Dr. Mayer highlights how this approach could shift biomarker testing from progression-based assessment toward serial monitoring during treatment. The panel also identifies an important unanswered question: how best to sequence subsequent endocrine doublets after progression on an earlier ESR1-directed combination.