Study Links Specific Hormone Therapies to Breast Cancer Risk in Younger Women

Study findings suggest a positive association between estrogen plus progestin hormone replacement therapy (EP-HRT) and increased risk of breast cancer in young adult women. The data, published in Lancet Oncology, may provide deeper insight into the potential risks of specific HRT types in premenopausal and postmenopausal women to better guide clinical decision-making.¹

HRT Hormone Therapy sign surrounded by plants and hormone therapy pills | Image Credit: © tilialucida - stock.adobe.com

“Hormone therapy can greatly improve the quality of life for women experiencing severe menopausal symptoms or those who have had surgeries that affect their hormone levels,” Katie O’Brien, PhD, lead author of National Institutes of Health (NIH)’s National Institute of Environmental Health Sciences (NIEHS), said in an official NIH release. “Our study provides greater understanding of the risks associated with different types of hormone therapy, which we hope will help patients and their doctors develop more informed treatment plans.”²

Hormone replacement therapy (HRT) is often used to ease the symptoms of menopause, such as hot flashes, vaginal dryness, and mood swings, that arise as estrogen levels naturally decline with age. It may also be recommended for individuals who have undergone a hysterectomy or oophorectomy. There are 2 main types of HRT: estrogen-only therapy (E-HRT), typically reserved for those who no longer have a uterus, and combined estrogen-progestin therapy (EP-HRT), which is used when the uterus is intact to help reduce the risk of endometrial cancer.^2,3

Studies confirm that estrogen plus progestin is a risk factor for breast cancer in postmenopausal women, but there are few data on the impact of these therapies in young women who may need HRT following gynecological surgery or for perimenopausal symptom relief. In a pooled cohort analysis, an international team of researchers at the NIH investigated the relationship between exogenous hormone therapy and the risk of young-onset breast cancer, drawing on data from 10 to 13 prospective cohort studies conducted across North America, Europe, Asia, and Australia. This large-scale analysis followed women up to age 55, focusing on the impact of hormone therapy (HT; used interchangeably with HRT) on breast cancer incidence in younger populations—a group for whom data has historically been limited.^1,2

A total of 459,476 women between the ages of 16 and 54 years (mean age 42.0 years) were included in the study. Over a median follow-up of 7.8 years, 2% of participants (n = 8455) were diagnosed with breast cancer before age 55. HT use was reported by 15% of participants, with the most common regimens being estrogen plus progestin therapy (6%) and unopposed estrogen (5%).¹

The researchers found no overall association between HT of any type and young-onset breast cancer (HR, 0.96; 95% CI, 0.88-1.04). However, use of estrogen-only therapy was associated with a significantly lower risk (HR, 0.86; 95% CI, 0.75-0.98), corresponding to a 0.5% absolute risk reduction by age 55.¹

In contrast, combined estrogen plus progestin therapy was associated with a modestly elevated risk of young-onset breast cancer (HR, 1.10; 95% CI, 0.98-1.24), particularly with longer duration of use (>2 years; HR, 1.18; 95% CI, 1.01-1.38). The association was strongest among women with intact uteri and ovaries (HR, 1.15; 95% CI, 1.02-1.31).¹

The team also reported results from a subtype-specific analysis, which revealed that estrogen plus progestin therapy was more strongly associated with estrogen receptor–negative (HR, 1.44; 95% CI, 1.11-1.88) and triple-negative breast cancer (HR, 1.50; 95% CI, 1.02-2.20), suggesting potential biological differences in hormone sensitivity.¹

These findings offer new insight into the differential impact of hormone therapy formulations on breast cancer risk in younger women. The results align with existing data on hormone therapy and later-onset breast cancer while highlighting the importance of individualized risk assessment when considering hormone use before age 55.

“These findings underscore the need for personalized medical advice when considering hormone therapy,” said Dale Sandler, PhD, NIEHS scientist and senior author, in an official NIH release. “Women and their health care providers should weigh the benefits of symptom relief against the potential risks associated with hormone therapy, especially EP-HT. For women with an intact uterus and ovaries, the increased risk of breast cancer with EP-HT should prompt careful deliberation.”²

REFERENCES

1. O’Brien K, House M, 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. The Lancet Oncol. June 30, 2025. doi: 10.1016/S1470-2045(25)00211-6

2. Breast cancer risk in younger women may be influenced by hormone therapy. NIH. June 30, 2025. Accessed July 2, 2025. http://nih.gov/news-events/news-releases/breast-cancer-risk-younger-women-may-be-influenced-hormone-therapy

3. Hormone therapy for menopause. American College of Obstetricians and Gynecologists. February 2024. Accessed July 2, 2025. https://www.acog.org/womens-health/faqs/hormone-therapy-for-menopause