Selective estrogen receptor degraders in premenopausal breast cancer: Biological activity and endpoint relevance in window of opportunity trials.

Selective estrogen receptor degraders (SERDs) have emerged as a key therapeutic class in hormone receptor-positive (HR+) breast cancer, combining estrogen receptor (ER) antagonism with direct receptor degradation. Despite this dual mechanism, pivotal trials of SERDs in premenopausal patients-across both metastatic and adjuvant settings-have mandated concurrent ovarian function suppression (OFS). Mechanistically, because ER undergoes continuous synthesis, both receptor antagonism and degradation require sustained occupancy of the ligand-binding domain. The central question is therefore one of competitive target engagement-whether oral SERDs can achieve and maintain adequate receptor occupancy in a high-estrogen premenopausal environment, independent of their intrinsic degradation efficiency. Reframing the debate around this competitive binding dynamic, rather than degradation capacity alone, offers a more mechanistically complete basis for evaluating OFS necessity in premenopausal patients. Window-of-opportunity (WOO) trials have offered an early opportunity to probe this question, consistently demonstrating rapid ER downregulation and antiproliferative activity with SERD monotherapy. Yet interpretation of these findings is complicated by substantial heterogeneity across trials in patient selection, comparator design, treatment duration, tissue sampling strategy, and endpoint definition. Moreover, the endpoints most used to gauge pharmacodynamic response-Ki67 suppression and complete cell cycle arrest (CCCA)-were validated in postmenopausal populations treated with aromatase inhibitors or tamoxifen, agents that act primarily through estrogen deprivation or competitive antagonism rather than receptor degradation. Their applicability to SERDs, and to the distinct estrogen milieu of premenopausal patients, remains under investigation. This narrative review critically summarizes the development of oral SERDs in metastatic HR+ breast cancer, review findings from window-of-opportunity trials, discuss emerging evidence in premenopausal women and addresses the methodological variability, underlying biological considerations, and limitations of conventional pharmacodynamic endpoints.