Harry B. Burke- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
There has been a great deal of interest in the relationship between hormone replacement therapy (HRT) and image-detected breast cancer and it has been suggested that HRT causes breast cancer (1). In this paper, I summarize the key information regarding the relationship between HRT and breast cancer and I present an alternative view of HRT’s role in breast cancer. I suggest that HRT enhances the image of estrogen-receptor (ER) positive breast cancer which makes it easier to detect by mammographic screening, resulting in more early detected breast cancers because of lead time bias.
First, HRT does not cause breast cancer in all women. Most women taking HRT are not diagnosed with breast cancer. In the Million Woman Study (2), the women on HRT had 19 additional image-detected breast cancer cases per 1000 women over 10 years. Furthermore, after stopping HRT, the rate of image-detected breast cancer decreases and returns to baseline after approximately five years (3).
Second, women taking HRT have more abnormal mammograms because of their increased breast density due to the HRT (4) and they receive an increased evaluation of the presence of incident breast cancer (5) – resulting in the earlier detection of disease. HRT users are younger and have a lower stage of disease than the non-HRT users. Sener et al. (6) found the median age at diagnosis was 61.0 years for HRT users and 68.0 years for HRT nonusers (P <.001). They also found that HRT users more often had tumors that were <1 cm (P = .007), node negative (P = .033) and grade I (P = .016). Furthermore, compared to non-users, HRT users had a decreased risk of death (hazard ratio = .438, 95% confidence limit = .263 to.729, P = .002). It is not clear how many of these early detected tumors were the result of lead time bias.
Third, HRT is associated with an increased incidence of ER positive tumors (7–11). Without treatment, women with ER positive tumors have a better survival than those with ER negative tumors (12–14). Furthermore, endocrine therapy improves survival in ER positive tumors, including in those women who received HRT (15–18).
In summary, HRT use is associated with a younger age at diagnosis, an earlier stage at detection, and a high likelihood of responding to endocrine therapy – all of which contribute to better outcomes. It may be that HRT enhances our ability to image-detect early breast cancer rather than being a cause of breast cancer and it improves clinical outcomes. An implication of this view is that perimenopausal women may wish to start HRT, not only for its menopausal benefits, but also because of its benefit in the early detection of breast cancer.
Author contributions
HB: Formal analysis, Software, Data curation, Writing – original draft, Visualization, Supervision, Methodology, Validation, Investigation, Resources, Funding acquisition, Conceptualization, Writing – review & editing, Project administration.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Preventive Services Task Force US, Mangione CM, Barry MJ, Nicholson WK, Cabana M, Caughey AB, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: US preventive services task force recommendation statement. JAMA. (2022) 328:1740–6. doi: 10.1001/jama.2022.18625
2. Beral V. Breast cancer and hormone-replacement therapy in the million women study. Lancet (London England). (2003) 362:419–27. doi: 10.1016/s0140-6736(03)14065-2
3. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. (1997) 350(9089):1484. doi: 10.1016/S0140-6736(97)08233-0
4. Chlebowski RT and Anderson GL. Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Institute. (2012) 104:517–27. doi: 10.1093/jnci/djs014
5. Beckmann KR, Farshid G, Roder DM, Hiller JE, and Lynch JW. Impact of hormone replacement therapy use on mammographic screening outcomes. Cancer Causes Control: CCC. (2013) 24:1417–26. doi: 10.1007/s10552-013-0221-1
6. Sener SF, Winchester DJ, Winchester DP, Du H, Barrera E, Bilimoria M, et al. The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival. Am J Surg. (2009) 197:403–7. doi: 10.1016/j.amjsurg.2008.11.014
7. Kim S, Ko Y, Lee HJ, and Lim JE. Menopausal hormone therapy and the risk of breast cancer by histological type and race: A meta-analysis of randomized controlled trials and cohort studies. Breast Cancer Res Treat. (2018) 170:667–75. doi: 10.1007/s10549-018-4782-2
8. Vinogradova Y, Coupland C, and Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ (Clin Res Ed). (2020) 371:m3873. doi: 10.1136/bmj.m3873
9. Godina C, Ottander E, Tryggvadottir H, Borgquist S, Isaksson K, and Jernström H. Prognostic impact of menopausal hormone therapy in breast cancer differs according to tumor characteristics and treatment. Front Oncol. (2020) 10:80. doi: 10.3389/fonc.2020.00080
10. Chen WY, Hankinson SE, Schnitt SJ, Rosner BA, Holmes MD, and Colditz GA. Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma. Cancer. (2004) 101(7):1490–500. doi: 10.1002/cncr.20499
11. Brewster AM, Do KA, Thompson PA, Hahn KM, Sahin AA, Cao Y, et al. Relationship between epidemiologic risk factors and breast cancer recurrence. J Clin Oncol Off J Am Soc Clin Oncol. (2007) 25(28):4438–44. doi: 10.1200/JCO.2007.10.6815
12. Dunnwald LK, Rossing MA, and Li CI. Hormone receptor status, tumor characteristics, and prognosis: A prospective cohort of breast cancer patients. Breast Cancer Res: BCR. (2007) 9:R6. doi: 10.1186/bcr1639
13. Bentzon N, Düring M, Rasmussen BB, Mouridsen H, and Kroman N. Prognostic effect of estrogen receptor status across age in primary breast cancer. Int J Cancer. (2008) 122:1089–94. doi: 10.1002/ijc.22892
14. Sopik V, Sun P, and Narod SA. The prognostic effect of estrogen receptor status differs for younger versus older breast cancer patients. Breast Cancer Res Treat. (2017) 165:391–402. doi: 10.1007/s10549-017-4333-2
15. Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. New Engl J Med. (2017) 377(19):1836–46. doi: 10.1056/NEJMoa1701830
16. Burstein HJ. Systemic therapy for estrogen receptor–positive, HER2-negative breast cancer. New Engl J Med. (2020) 383:2557–70. doi: 10.1056/NEJMra1307118
17. Paakkola NM, Karakatsanis A, Mauri D, Foukakis T, and Valachis A. The prognostic and predictive impact of low estrogen receptor expression in early breast cancer: A systematic review and meta-analysis. ESMO Open. (2021) 6:100289. doi: 10.1016/j.esmoop.2021.100289
Keywords: breast cancer, mammography, hormone replacement therapy, endocrine therapy, early detection, cancer screening
Citation: Burke HB (2025) Association of hormone replacement therapy and image-detected breast cancer. Front. Oncol. 15:1647152. doi: 10.3389/fonc.2025.1647152
Received: 14 June 2025; Accepted: 19 September 2025;
Published: 01 October 2025.
Edited by:
Shivani Rai Paliwal, Guru Ghasidas Vishwavidyalaya, IndiaReviewed by:
Hangcheng Xu, Chinese Academy of Medical Sciences and Peking Union Medical College, ChinaCopyright © 2025 Burke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Harry B. Burke, aGFycnkuYnVya2VAZ21haWwuY29t