No rise in breast cancer risk for young BRCA carriers on menopausal hormone therapy

For young women with a pathogenic variant in BRCA1 or BRCA2, initiating hormone replacement therapy following surgical menopause does not appear to significantly increase the risk of breast cancer, with oestrogen-alone therapy even conferring protection, according to a study.

In a prospective matched analysis, breast cancer occurred in 12.9 percent of participants who initiated menopausal hormone therapy (MHT) over a mean follow-up of 6.6 years (MHT group) vs 18.9 percent of those who did not initiate MHT over a mean follow-up of 4.6 years (control group). The 15-year cumulative incidence of breast cancer was 24.5 percent vs 42.9 percent, respectively. [J Natl Cancer Inst 2025;doi:10.1093/jnci/djaf363]

The use of any MHT was associated with a 52-percent reduction in breast cancer risk compared with nonuse (hazard ratio [HR], 0.48, 95 percent confidence interval [CI], 0.36–0.63; p<0.0001). The risk reduction was even greater with oestrogen-alone therapy (HR, 0.37, 95 percent CI, 0.24–0.57; p<0.0001).

No adverse or protective effect on breast cancer risk was observed with the use of the oestrogen–progestogen combination (HR, 0.94, 95 percent CI, 0.54–1.63; p=0.82), progestogen monotherapy (HR, 1.14, 95 percent CI, 0.21–6.22; p=0.88), or tibolone monotherapy (HR, 0.57, 95 percent CI, 0.19–1.69; p=0.31). 

Meanwhile, conjugated equine oestrogen plus bazedoxifene had a potential protective effect, with none of the 43 users developing breast cancer over a mean follow-up of 6.2 years.

Stratified analyses

Analysis stratified by BRCA mutation type yielded similar results. Compared with nonuse, any MHT use was associated with a 50-percent reduction in breast cancer risk among BRCA1 carriers (HR, 0.50, 95 percent CI, 0.37–0.66; p<0.0001) and a 65-percent reduction among BRCA2 carriers (HR, 0.35, 95 percent CI, 0.15–0.82; p=0.02).

Looking at participants who used oestrogen-alone therapy, a significant reduction in breast cancer risk was observed with transdermal oestradiol (HR, 0.46, 95 percent CI, 0.25–0.82; p=0.008). Nonsignificant risk estimates were observed with oral oestradiol (p=0.29), oral conjugated equine oestrogen (p=0.19), and oral synthetic oestrogen (p=0.27) due to smaller sample sizes.

Reassuring data

“These findings provide evidence on the safety of oestrogen-containing MHT for the management of symptoms after oophorectomy,” said first study author Dr Joanne Kotsopoulos from the University of Toronto in Toronto, Ontario, Canada.

“The observed protective effect of oestrogen-alone therapy on breast cancer risk suggests that a hysterectomy might be considered at the time of oophorectomy, so that women can avail themselves of the potential benefit of unopposed oestrogen,” Kotsopoulos added.

Noting the low uptake of MHT in the study cohort (37 percent of potentially eligible), the author hoped that the data would encourage increased use of MHT in women undergoing early surgical menopause. “These young women need not suffer physical, psychological, and emotional disturbances of abrupt menopause due to misinformation regarding the safety of oestrogen therapy.”

Study details

The study involved 676 women (mean age 43.8 years)—including 548 BRCA1 carriers and 128 BRCA2 carriers—each in the MHT and control groups. These participants were matched according to type of gene mutation (BRCA 1 or 2), birth year, baseline age, age at menopause, oophorectomy status, and age at oophorectomy.

Across the two groups, 94.8 percent of women had bilateral oophorectomy (mean age at the time of surgery 44 years), and more than 80 percent were parous. Fewer women in the MHT group than in the control group had undergone preventive mastectomy (18.6 percent vs 28.7 percent; p<0.0001). The mean duration of MHT use was 5.7 years, and 9.2 percent of women in the control group initiated MHT ≥1 year after study inclusion.

Kotsopoulos acknowledged several study limitations, including the small strata and lack of data on tumour receptor status. She called for additional studies to replicate the findings in high-risk women.