A landmark study published in The Lancet Oncology by scientists at the National Institutes of Health (NIH), Washington, D.C., has revealed that two commonly used hormone therapies have opposing effects on breast cancer risk in women under the age of 55 years. Hormonal or endocrine therapy works by modulating the body’s hormone activity and is often employed to slow the growth of hormone-sensitive cancers such as breast and prostate cancer. The large-scale international study tracked over 459,000 women aged 16 to 54 for a median period of 7.8 years and found that while overall hormone therapy use was not associated with a higher risk of early-onset breast cancer, the specific type of therapy used significantly influenced risk outcomes.
Women who used unopposed estrogen hormone therapy (E-HT) demonstrated a 14% lower risk of developing breast cancer, with a hazard ratio (HR) of 0.86 and an estimated absolute risk reduction of 0.5% compared to non-users. This protective effect was consistently observed across all breast cancer subtypes. Conversely, women using estrogen plus progestin therapy (EP-HT) had a 10% higher overall risk (HR 1.10), with the risk further increasing to HR 1.18 among those who used it for more than two years. The increased risk was particularly evident in women with an intact uterus and ovaries (HR 1.15). Notably, EP-HT was more strongly associated with aggressive subtypes such as estrogen receptor-negative (HR 1.44) and triple-negative breast cancers (HR 1.50), both of which are more difficult to treat and carry poorer prognoses.
These findings are consistent with prior data from older populations, but this is the first large-scale study to clarify hormone therapy risks in younger women. Supporting these results, a pooled analysis by Levy involving more than ten prospective cohorts of premenopausal women showed no overall increased risk (HR 0.96; 95% CI 0.88–1.04), yet again highlighting the relative safety of estrogen-only therapy and the increased risk posed by combined estrogen-progestogen treatments, particularly in long-term users or those without prior gynecologic surgery.
These findings highlight the need for personalized hormone therapy regimens, where clinicians assess individual risk factors, including family history, gynecologic history, and duration of therapy. Additionally, these findings may prompt updates in clinical guidelines and patient counseling, ensuring women are fully informed of the differential risks associated with hormone therapy types. For patients with symptoms warranting hormone therapy, alternative options, shorter durations, or non-hormonal treatments may be considered, particularly when EP-HT is involved.
Overall, this study reinforces the need for shared decision-making and risk-benefit assessment in younger women intended to receive hormone therapy, and provides valuable evidence to refine both prescribing practices and public health messaging.
Reference
- O’Brien KM, House MG, Goldberg M, Jones ME, Weinberg CR, Gonzalez AB de, et al. Hormone therapy use and young-onset breast cancer: a pooled analysis of prospective cohorts included in the Premenopausal Breast Cancer Collaborative Group. The Lancet Oncology. 2025 Jul 1;26(7):911–23.
- Hayashi S, Kimura M. Mechanisms of hormonal therapy resistance in breast cancer. Int J Clin Oncol. 2015 Apr;20(2):262-7. doi: 10.1007/s10147-015-0788-5. Epub 2015 Feb 5. PMID: 25652907.
- Lévy C. Hormonal therapy for young-onset breast cancer: current understanding and lessons. The Lancet Oncology. 2025 Jul 1;26(7):824–5.