Next-generation endocrine therapy in HR+/HER2 - breast cancer: oral SERDs, ER-targeting innovations, and ctDNA-driven ESR1 mutation-guided switching

Endocrine therapy (ET) is the backbone of HR+/HER2 - breast cancer management, yet acquired resistance commonly emerges despite aromatase inhibitors (AIs) and CDK4/6 inhibitors. A key actionable mechanism is treatment-selected ESR1 mutation, detectable in circulating tumor DNA (ctDNA) before radiographic progression.

This narrative review summarizes (i) next-generation estrogen receptor (ER)-targeting agents (oral SERDs and novel ER degraders), (ii) the rationale for ESR1-guided endocrine switching, and (iii) practical considerations for implementing a ctDNA-enabled "monitor-trigger-switch" strategy in routine care.

Oral SERDs are moving from late-line salvage toward earlier settings, supported by post-CDK4/6 efficacy signals in ESR1-mutant disease and by prospective molecular switching trials. PADA-1 and SERENA-6 provide prospective evidence that intervention at molecular progression can delay radiographic progression in selected patients. However, available SERENA-6 data remain interim, OS is immature, and implementation outside trial settings requires careful attention to assay validity, monitoring burden, cost, and risk of overtreatment from ambiguous low-level ctDNA findings. We also discuss early-stage implications, including emerging signals that adjuvant oral SERDs may improve invasive disease-free survival, raising questions regarding patient selection and integration with existing escalation strategies.

ctDNA-enabled, ESR1-guided switching has the potential to shift endocrine management from reactive treatment changes at clinical progression toward earlier molecular interception of resistance in selected patients.