ESR1 and neoplasm: In this setting, the optimal therapeutic strategy following progression during ET plus CDK4/6i treatment remains unclear, with limited data available to guide subsequent treatment choices.15 Current guidelines recommend assessing for actionable mutations (eg, PIK3CA, ESR1, AKT, PTEN) and conducting germline testing for BRCA1/2 or PALB2 mutations on tumor progression during ET plus CDK4/6i therapy.16,17 Therapeutic options include ET with or without targeted agents (eg, alpelisib, capivasertib, everolimus), PARP inhibitors for patients with germline BRCA1/2 mutations, and chemotherapy (CT).