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

This review focuses on estrogen receptor–positive early-stage breast cancer in younger premenopausal women (generally <40 years), a group with worse outcomes than older patients despite similar stage and subtype.

Key points:

• Prognostic gap in young women
  Younger premenopausal women with ER-positive disease have disproportionately higher recurrence and mortality rates. This is not fully explained by traditional clinicopathologic risk factors.

• Distinct tumor biology
  Emerging data show that tumors in this population often have:

• • Greater burden of copy number alterations
• • Higher frequency of homologous recombination deficiency
• • Distinct immune microenvironment patterns

These biological features may contribute to endocrine resistance and aggressive behavior and are not adequately addressed by current treatment algorithms.

• Evolving endocrine therapy strategies
  Endocrine therapy remains the mainstay of treatment, but approaches are shifting:

• • Ovarian function suppression (OFS) is increasingly recognized as standard in higher-risk patients, improving outcomes when added to tamoxifen or aromatase inhibitors.
• • Adding CDK4/6 inhibitors to standard endocrine therapy is emerging as a beneficial strategy for selected high-risk cases.
• • Molecular profiling is being used more often to tailor intensity of endocrine and systemic therapies.

• Rethinking chemotherapy–endocrine sequencing
  Traditional paradigms that prioritize chemotherapy based largely on age are being challenged. A more nuanced, biology-based approach may:

• • Avoid overtreatment with chemotherapy in biologically low-risk tumors.
• • Prompt treatment escalation (e.g., OFS + AI, CDK4/6 inhibitors) in biologically high-risk disease, irrespective of chronological age.

• Proposed framework for future trials and practice
  The authors argue that:

• • Trial eligibility should be driven by tumor biology (germline mutations, gene-expression profiles, immune signatures), not just age cutoffs.
• • OFS should be considered standard-of-care in control arms for appropriate premenopausal high-risk participants.
• • Biomarker-driven strategies should be used both for escalation (e.g., adding targeted agents) and de-escalation (avoiding unnecessary chemotherapy).

Overall, the review advocates for genomically and immunologically informed treatment decisions in premenopausal ER-positive early breast cancer, moving beyond age-based decisions toward biologically tailored care to close the outcome gap in this under-represented population.