Hormone therapy in younger women: reassessing risk narratives in the era of precision menopausal care

The relationship between hormone therapy (HT) and breast cancer risk has been shaped for decades by data derived predominantly from postmenopausal populations. Clinical paradigms, patient counselling, and public perception have consequently been anchored in trials such as the Women’s Health Initiative (1) and observational cohorts like the Million Women Study (2), which profoundly influenced prescription practices worldwide. These two studies (1,2) while influential are subject to ongoing debate and challenges in medical literature. Yet an important demographic has remained underrepresented in this narrative: women initiating HT before the age of 55 years, including those in early perimenopause or those requiring treatment following gynaecological surgery. This pooled analysis marks a pivotal advance by addressing this long-standing gap in evidence (3).

This large, multinational pooled analysis of prospective cohorts offers an unprecedented opportunity to evaluate this knowledge gap. With nearly half a million women and over 8,000 incident cases of young-onset breast cancer, the study not only confirms the heterogeneity of HT effects but also emphasizes the need to disentangle the impact of unopposed oestrogen from that of combined oestrogen-progestin regimens in younger women. In this study, ever use of any HT was not associated with incident young-onset breast cancer in the overall meta-analysis. Most striking, however, was the inverse association observed between unopposed oestrogen and breast cancer diagnosed before age 55 years, contrasted with the increased risk linked to combined therapy, particularly among long-term users and those with intact uteri and ovaries (3).

These findings challenge monolithic interpretations of HT as uniformly carcinogenic. Instead, they reinforce a nuanced, type-specific and context-dependent model of risk. For clinicians, this represents a crucial inflection point: the data suggest that oestrogen-alone therapy, often used by women post-hysterectomy or oophorectomy, may confer a modest protective effect against early-onset breast cancer. Conversely, oestrogen plus progestin therapy, especially with durations exceeding two years or when used by women without prior gynaecological surgery, emerges as a possible risk amplifier (3).

Estrogen exerts proliferative effects on mammary epithelium, yet paradoxically, its unopposed administration appears to reduce malignancy risk (4). This counterintuitive phenomenon has been previously reported in the postmenopausal setting and is possibly explained by complex endocrine feedback loops or induction of apoptosis in susceptible breast cells. Interestingly, however, progestins, when combined with estrogen, may potentiate carcinogenesis through synergistic stimulation of mammary gland proliferation and modulation of inflammatory pathways. These data suggest the importance of distinguishing these pathways in younger women, who may experience different hormonal milieus and cumulative exposure risk profiles.

Additionally, the association between Estrogen-plus-progestin therapy and adverse outcomes was most pronounced in specific subtypes of breast cancer, including estrogen receptor-negative and triple-negative phenotypes. These subtypes, historically linked with aggressive behavior and poorer prognosis, further complicate the therapeutic landscape If confirmed in additional studies, such differential susceptibility by race or other variables underscores the potential role of HT in shaping not only breast cancer incidence but also its biological aggressiveness.

From a methodological perspective, the strength of this pooled analysis lies in its comprehensive harmonization of cohort data, inclusion of diverse populations across continents, and robust use of multi-variable Cox regression stratified by cohort. Furthermore, histological subtyping of tumors enabled more granularity in the interpretation of outcomes.

Nevertheless, the study has limitations. As in all observational research, residual confounding remains a concern. Additionally, the lack of data on specific formulations, dosing regimens, routes of administration (oral versus transdermal), and adherence to hormonal treatments limit generalization of the conclusions. Furthermore, the absence of genetic data on cancer predisposition or detailed reproductive history (e.g., age at first full-term pregnancy) precludes complete risk stratification. Although multiple imputation methods were employed to address missing data, the imputation of receptor status in some cohorts introduces further uncertainty These findings highlight the necessity for individualized risk assessments and tailored HT recommendations, particularly for younger women navigating treatment options.

In the present landscape of individualized medicine, these findings are highly relevant. In light of these data, women initiating HT for menopausal symptoms or post-surgical sequelae before age 55 years represent an unique risk group for breast cancer development. This study offers clinicians a data-driven basis to tailor these decisions: favouring unopposed oestrogen when clinically indicated and exercising caution with combined therapy, specially those with intact reproductive organs or genetic predisposition. Furthermore, the lowest duration of two years of combined therapy should be emphasized to mitigate potential risks.

For clinical guidelines, the study invites reflection and possible revision. It may be time to move beyond age alone as the primary threshold in HT risk assessment. Therefore, we should be attentive to type of therapy, duration, initiation age, surgical history, and subtype-specific risk. Stratification based on these clinical data empowers shared decision-making processes between physician and patient.

Prospective trials incorporating biomarkers and molecular subtyping could clarify causal pathways and inform safer therapeutic formulations. Additionally, studying the interaction between HT and other risk factors such as obesity, metabolic syndrome, or inflammatory markers may further refine risk prediction models.

In conclusion, this landmark pooled cohort analysis introduces evidence provides a deeper understanding of HT use in women under 55 years. While unopposed estrogen emerges as potentially protective in this group, estrogen plus progestin combination therapy warrants careful consideration, particularly in high-risk contexts, such as in women with family history of Breast Cancer. Even though, studies involving pooling of different cohorts of patients may be limit some of the conclusions, these findings suggest a more individualized, evidence-based approach to menopausal management in younger women.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-166/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-166/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002;288:321-33. [Crossref] [PubMed]
2. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-27. [Crossref] [PubMed]
3. O'Brien KM, House MG, Goldberg M, et al. Hormone therapy use and young-onset breast cancer: a pooled analysis of prospective cohorts included in the Premenopausal Breast Cancer Collaborative Group. Lancet Oncol 2025;26:911-23. [Crossref] [PubMed]
4. Shah NR, Wong T. Current breast cancer risks of hormone replacement therapy in postmenopausal women. Expert Opin Pharmacother 2006;7:2455-63. [Crossref] [PubMed]