Tailoring targeted therapies for younger women with ER-positive early-stage breast cancer.

Younger premenopausal women (typically defined as those aged <40 years) diagnosed with oestrogen receptor (ER)-positive early-stage breast cancer have disproportionately poorer outcomes relative to older women, with age-related differences being especially pronounced in this subtype. Emerging evidence suggests that this age-related disparity is underpinned by distinct biological and genomic features - such as enrichment in copy number alterations, homologous recombination deficiency and unique immune microenvironments - that are not fully addressed by current therapeutic strategies. Endocrine therapy remains the cornerstone of treatment for premenopausal women with ER-positive early-stage breast cancer, yet strategies for its use continue to evolve. Clinical studies have highlighted the importance of ovarian function suppression (OFS) in improving the outcomes in patients with high-risk disease, as well as the benefit of adding CDK4/6 inhibitors to standard-of-care (SOC) endocrine therapies and the expanding role of molecular profiling in guiding treatment decisions. In this Review, we describe how treatment paradigms are now challenging the conventional sequencing of chemotherapy and endocrine therapy in younger women. A biology-driven approach - incorporating germline status, gene expression and immune signatures - will better guide therapy in this population and transform clinical decision-making beyond chronological age. We propose that future trials involving women with premenopausal ER-positive disease must prioritize biology over age in defining eligibility, incorporate OFS as a SOC in the control arm and expand biomarker-driven approaches to refine both treatment escalation and de-escalation. A genomically and immunologically informed strategy is essential to improve the outcomes in this under-represented population.