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  • Review Article
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Tailoring targeted therapies for younger women with ER-positive early-stage breast cancer

Nature Reviews Clinical Oncology (2026)Cite this article

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Abstract

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.

Key points

  • Younger premenopausal women (<40 years) with oestrogen receptor (ER)-positive early breast cancer have consistently inferior outcomes compared with older women, reflecting a biologically distinct form of the disease.

  • Germline mutations (such as those in BRCA2 or PALB2) and genomic alterations (such as copy number amplifications and homologous recombination deficiency) are enriched in ER-positive breast tumours from younger women, and could influence response to treatment and recurrence risk.

  • Molecular profiling can help to refine risk stratification in premenopausal women with breast cancer. Ongoing trials are evaluating the safety of omitting chemotherapy in those with low-risk genomic profiles, in favour of maximal endocrine therapy with ovarian function suppression (OFS), potentially redefining treatment strategies.

  • OFS can improve survival outcomes in premenopausal women with high-risk ER-positive early-stage breast cancer, particularly when combined with aromatase inhibitors and CDK4/6 inhibitors, such as abemaciclib and ribociclib, in appropriately selected patients.

  • Immunogenic tumour subsets (such as ER-low, basal-like or high-grade) are enriched in younger women with breast cancer, and are characterized by high levels of lymphocyte infiltration and PD-L1 expression, providing potential opportunities for future biomarker-guided immunotherapy strategies.

  • Emerging treatment paradigms are challenging the conventional sequencing of chemotherapy and endocrine therapy. A biology-driven approach, rather than an age-based model, might better guide treatment decisions for younger women with ER-positive breast cancer.

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Fig. 1: Biological characterization of ER-positive early-stage breast cancer in younger women.
Fig. 2: Evolution of endocrine therapy approaches for premenopausal women with breast cancer.
Fig. 3: Endocrine therapy pathways for premenopausal women with ER-positive breast cancer and becoming postmenopausal.
Fig. 4: Key trials testing endocrine therapy with or without OFS.
Fig. 5: Adjuvant therapies for ER-positive, HER2-negative early-stage breast cancer.

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Author notes

  1. These authors contributed equally: Soraia Lobo-Martins, Stephen J. Luen.

Authors and Affiliations

  1. Academic Trials Promoting Team (ATPT), Hôpital Universitaire de Bruxelles (H.U.B), Institut Jules Bordet, Université libre de Bruxelles (ULB), Bruxelles, Belgium

    Soraia Lobo-Martins

  2. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Stephen J. Luen & Sherene Loi

  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    Stephen J. Luen & Sherene Loi

  4. Hôpital Universitaire de Bruxelles (H.U.B), Institut Jules Bordet, Université libre de Bruxelles (ULB), Bruxelles, Belgium

    Martine Piccart

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All authors researched data for the article and contributed substantially to discussions of the content. S.L.-M. and S.J.L. wrote the article. M.P. and S.L. reviewed and edited the manuscript before submission.

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Competing interests

S.L.-M. has received honoraria from and/or has been an adviser for AstraZeneca, BMS, Gilead Sciences, MSD, Novartis, Pfizer and Roche; has received support for attending medical conferences from Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche and Sanofi; and has participated as a medical research fellow in studies institutionally funded by AstraZeneca, F. Hoffmann-La Roche and Novartis. S.J.L. receives research funding to his institution from AstraZeneca, Beigene, Novartis, Roche and SpringWorks Therapeutics; and has received honoraria or consultation fees from AstraZeneca, Daiichi Sankyo and Novartis. M.P. is a member of the scientific board of Oncolytics; has received honoraria as a consultant from AstraZeneca, Gilead, Lilly, Menarini, Mersana, MSD, Novartis, Pfizer, Roche–Genentech, Seattle Genetics, Seagen, NBE Therapeutics and Summit Therapeutics; and has received institutional research grants from AstraZeneca, Gilead, Lilly, Menarini, MSD, Novartis, Pfizer, Roche–Genentech and Servier. S.L. receives institutional research funding from AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Nektar Therapeutics, Novartis, Pfizer and Roche–Genentech; has been a consultant for Adanate, Amaroq Therapeutics, AstraZeneca, Bicycle Therapeutics, BioNTech, BMS, Daiichi Sankyo, Domain Therapeutics, Eli Lilly, Exact Sciences, Gilead Sciences, MSD, Menari Asia-Pacific, Mersana Therapeutics, Novartis, Roche–Genentech and SAGA Diagnostics. The disclosures from all the authors are outside the submitted work.

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Lobo-Martins, S., Luen, S.J., Piccart, M. et al. Tailoring targeted therapies for younger women with ER-positive early-stage breast cancer. Nat Rev Clin Oncol (2026). https://doi.org/10.1038/s41571-026-01120-7

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