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Estrogen-Progestin Therapy Elevates Risk for Breast Cancer — Should This Influence Clinical Practice?

16 September 2019

Andrew M. Kaunitz, MD and JoAnn E. Manson, MD, DrPH
NEJM Journal Watch

No; benefits will outweigh risks for many menopausal patients who, through discussion of research findings and shared decision making, can make informed choices about HT use.

Hormone therapy (HT) is the most effective treatment for bothersome menopausal vasomotor symptoms. However, after initial publication of findings from the Women's Health Initiative (WHI) randomized clinical trial in 2002, which found that estrogen-progestin therapy (EPT) increased risk for cardiovascular events and breast cancer among women aged 50 to 79 at enrollment (NEJM Journal Watch Womens Health Nov 2013 and JAMA 2013 Oct 2; 310:1353), use of HT plummeted in the U.S. and globally. Subsequently, the estrogen-alone trial in women with hysterectomy showed that conjugated estrogens (for a median of 7 years) did not increase breast cancer risk. Both regimens raised risk for stroke and venous thromboembolism but lowered risk for fractures and diabetes. Thus, HT has a complex risk-benefit pattern, with studies suggesting more-favorable profiles in younger than older women.

Although observational studies over the past several decades have linked HT to increased breast cancer risk, the specific associations with HT formulation, route of delivery, and duration have been poorly studied. In a recent meta-analysis (Lancet Aug 29 2019 [e-pub]), investigators used individual participant data from 58 observational studies reported between 1992 and 2018 to quantify the strength of the relation and the roles of these factors in the HT−breast cancer connection.

All systemic HT formulations (including those using oral conjugated equine estrogens or estradiol or transdermal estradiol) were associated with excess risk for breast cancer. Use of EPT was associated with a greater risk for breast cancer than was estrogen-only therapy (ET). Type of progestogen did not appear to affect these associations. Vaginal estrogen was not associated with increased risk. Assuming the reported associations are causal, the authors estimated the absolute risk for breast cancer up to age 70. For never-users of HT and women who initiated EPT at age 50 and continued for 5 years, risks were 6.3% and 8.3%, respectively; the two percentage-point difference indicates one additional breast cancer case per 50 treated women. At 10 years of HT use, risks were approximately twice that at 5 years.

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