Hormone Therapy Use Differentially Associated With Breast Cancer Subtypes

There are clear differences in the associations between current estrogen-progestin therapy use and luminal-like breast cancer subtypes, as well as other subtypes, a study published in JAMA Network Open found.¹

The use of hormone therapy is not new and has frequently been used to treat menopausal symptoms for women in every stage of menopause and women who’ve had their ovaries, uterus, or both removed. Estrogen-progestin therapy (EPT) is considered a safer alternative to estrogen-only hormone therapy (ET) because it reduces the risk of endometrial cancer.² However, it may increase the risk of breast cancer.

Menopausal hormone therapy is associated with a higher risk of developing certain breast cancer subtypes. | Image Credit: vectorfusionart - stock.adobe.com

The new study sought to determine associations between current EPT use and luminal-like breast cancer subtypes and other subtypes.¹ The study used data from 42,269 individuals with breast cancer, 28.2% (11,901) of whom were premenopausal, 71.8% (30,368) postmenopausal, and 55.2% (23,353) of whom had a known intrinsic-like subtype of breast cancer.

The intrinsic-like subtypes of breast cancers measured were luminal A–like, luminal B–like, luminal B-ERBB2 (formerly HER2 or HER2/neu)–like, ERBB2 enriched–like, or triple negative. The findings suggested that women currently using EPT and maintaining a healthy weight were more likely to be diagnosed with luminal A–like (OR, 2.51 [95% CI, 2.26-2.80]), luminal B–like (OR, 1.47 [95% CI, 1.17-1.86]), or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes.

Adjusting for BMI in individuals with obesity did not materially change the observed associations for luminal A-like (OR, 1.40 [95% CI, 1.02-1.92]) or luminal B-ERBB2-like (OR, 1.68 [95% CI, 1.01-2.78]) tumors. However, among women with overweight, EPT use showed a positive association with luminal A–like (OR, 2.18 [95% CI, 1.83-2.61]) and luminal B–ERBB2–like (OR, 1.83 [95% CI, 1.32-2.55]) tumors.

“The association between current EPT use and luminal A–like and luminal B–ERBB2-like tumors was consistent across BMI groups, albeit attenuated with greater adiposity,” the author wrote. “However, the association between current EPT use and luminal B–like tumors was limited to women with healthy weight.”

On the other hand, the study also showed a positive association with current ET use and luminal A-like breast cancer in women with a healthy weight (OR, 1.16 [95% CI, 1.01-1.32]), as well as a lower occurrence of ERBB2-enriched–like (OR, 0.58 [95% CI, 0.38-0.89]) and triple-negative (OR, 0.73 [95% CI, 0.54-0.97]) tumors. There was an inverse association between current ET usage and higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]).

For example, women with current ET usage and overweight were less likely to be diagnosed with luminal A–like (OR, 0.75 [95% CI, 0.62-0.91]), luminal B–like (OR, 0.49 [95% CI, 0.33-0.72]), or triple-negative (OR, 0.59 [95% CI, 0.41-0.86]) tumors. Women with obesity and current ET users were also less likely to be diagnosed with luminal A–like (OR, 0.65 [95% CI, 0.50-0.85]), luminal B–like (OR, 0.44 [95% CI, 0.25-0.76]), luminal B–ERBB2-like (OR, 0.41 [95% CI, 0.23-0.74]), or triple-negative (OR, 0.66 [95% CI, 0.43-1.00]) tumors.

Oral contraceptive usage was also associated with an increased risk of breast cancer—however, unlike MHT, its association did not differ with body mass index.² In premenopausal women, current OC users were more likely to be diagnosed with luminal A–like (OR, 1.27 [95% CI, 1.05-1.54]) or luminal B–like (OR, 1.46 [95% CI, 1.07-1.98]) with no association for other subtypes.

When compared with women who have never used OC, women who used OC in the last 5 years were more likely to be diagnosed with luminal ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75; 95% CI, 1.33-2.29; P < .04 for heterogeneity) tumors. There was no modification for BMI influencing associations between OC use and breast cancer risk.

The study was limited in demographic range; study participants and data were predominately women of European ancestry (approximately 84%). Additionally, 20% of the tumor subtypes were categorized based on immunohistochemistry of estrogen and progestin receptors, which the author claims may be inaccurate because of the varying thresholds for positivity and interpretation of criteria.

“These results provide further evidence of etiologic heterogeneity in breast carcinogenesis. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted,” the authors wrote.

References

Le Cornet C, Jung AY, Behrens S, et al. Exogenous hormones, tumor intrinsic subtypes, and breast cancer. JAMA Netw Open. 2025;8(7):e2519236. doi:10.1001/jamanetworkopen.2025.19236

Menopausal hormone therapy and cancer risk. American Cancer Society. February 13, 2015. Accessed July 9, 2025. https://www.cancer.org/cancer/risk-prevention/medical-treatments/menopausal-hormone-replacement-therapy-and-cancer-risk.html