What is the role of hormone replacement therapy (HRT) in the etiology of breast cancer?

Updated: Feb 04, 2021
  • Author: Pavani Chalasani, MD, MPH; Chief Editor: John V Kiluk, MD, FACS  more...
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Data obtained from case-control and prospective cohort settings support an increased risk of breast cancer incidence and mortality with the use of postmenopausal HRT. [29] Increased risk of breast cancer has been positively associated with length of exposure, with the greatest risk being observed for hormonally responsive lobular, mixed ductal-lobular, and tubular cancers. [29] Risk is greater among women taking combination HRT than among those taking estrogen-only formulations. [30, 31]

A meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer of 58 international studies that included 143,887 postmenopausal women with invasive breast cancer and 424,972 without breast cancer concluded the following about menopausal HRT and breast cancer [32] :

  • Estrogen plus daily progestin, used for 5 years starting at age 50 years, would increase 20-year breast cancer risks at ages 50–69 years from 6.3% to 8.3%, an absolute increase of 2.0 per 100 women (one in every 50 users).
  • Estrogen plus intermittent progestin, used for 5 years, would increase the 20-year risk from 6.3% to 7.7%, an absolute increase of 1.4 per 100 women (one in 70 users).
  • Estrogen-only menopausal HRT would increase the 20-year risk from 6.3% to 6.8%, an absolute increase of 0.5 per 100 women (one in 200 users), especially in lean women, with little excess risk in obese women.
  • For 10 years of use, the 20-year increases in incidence would be about twice as great as for 5 years of use.

In the Women’s Health Initiative (WHI) trial, the incidence of invasive breast cancer was 26% higher in women randomly assigned to combination HRT than in those assigned to placebo. In contrast, the use of conjugated equine estrogen alone in women who had undergone hysterectomy was associated with a 23% (but not significant) decrease in breast cancer risk in comparison with placebo at initial reporting. On extended follow-up (median, 11.8 years), estrogen-only therapy for 5-9 years in women with hysterectomy was associated with a significant 23% reduction in the annual incidence of invasive breast cancer (0.27%; placebo, 0.35%). [33] Fewer women died of breast cancer in the estrogen-only arm.

A 23% reduction in breast cancer diagnosis in women assigned to estrogen-only HRT persisted over 16 years of cumulative follow-up in two WHI trials in more than 10,000 women (hazard ratio [HR] 0.77, 95% CI 0.62-0.92); most of the reduction was due to fewer diagnoses of estrogen receptor–positive/progesterone receptor–negative disease. In addition, breast cancer deaths were 44% lower with estrogen-only HRT (HR 0.56, 95% CI 0.34-0.92). [34]  

To aid the medical community in the application of HRT, a number of agencies and groups have published recommendations for HRT use in the treatment of menopause and associated bone loss. At present, HRT is not recommended for prevention of cardiovascular disease or dementia or, more generally, for long-term use to prevent disease.

Recommendations differ slightly by agency and by country. For more information see Menopausal Hormone Replacement Therapy

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