What is the effect of postmenopausal hormone replacement therapy (HRT) on breast cancer risk?

Updated: Dec 16, 2019
  • Author: Jessica Katz, MD, PhD, FACP; Chief Editor: Marie Catherine Lee, MD, FACS  more...
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Consistent epidemiologic data support an increased risk of breast cancer incidence and mortality with the use of postmenopausal HRT. Risk is increased 1.35 times for 5 or more years of HRT use, normalizing 5 years after discontinuing. [24] Risk is directly associated with length of exposure, with the greatest risk observed for the development of hormonally responsive lobular, mixed ductal-lobular, and tubular cancers. [25]

Studies, including the Women’s Health Initiative (WHI) trial, have shown that the incidence of breast cancer was greater in women taking combination estrogen plus progestin formulations than in those taking estrogen-only formulations, and the cancers in women taking combination HRT were more commonly advanced or node positive. This risk seems to achieve demonstrable significance at 3 or more years of exposure. Combination HRT also appears to be associated with increased mortality. [26]

Published results of the WHI of estrogen-only and combination-HRT for the prevention of chronic disease indicate that the adverse outcomes associated with long-term use outweigh the potential disease prevention benefits, particularly for women older than 65 years.

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 risk [27] :

  • 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 contrast, long-term data from two WHI trials in more than 10,000 women showed lasting decreases in breast cancer incidence and death in those receiving estrogen-only HRT with conjugated equine estrogen. At over 16 years of cumulative follow-up, breast cancer diagnosis was 23% lower in women with prior hysterectomy randomized to estrogen-only HRT compared with those assigned to placebo (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). As in other studies, menopausal HRT with estrogen plus progestin was associated with persistent increases in breast cancer incidence and death. [28]

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