Combined hormone replacement therapy (HRT), which includes both estrogen and progestin, has been linked to increased breast cancer risk. Strong evidence that combined HRT use could increase the risk of breast cancer was first published in 2002, when participants in the Women’s Health Initiative trial who were taking combined HRT were found to have higher rates of breast cancer than those who did not. A consequent decline in use of HRT was followed by a decline in breast cancer rates in the U.S. and other countries. While combined HRT use is associated with heightened risk of all subtypes, it is most strongly associated with risk of estrogen receptor positive (ER+) and lobular breast cancer. While, generally speaking, regular exercise is associated with reduced risk of breast cancer, one 2012 study reported that the lower risk of breast cancer associated with the highest level of physical activity was observed only in women not using HRT. Now a new study presented at the 2015 American Society for Clinical Oncology (ASCO) Annual Meeting in June has confirmed that ever use of HRT appears to extinguish the preventative effects of physical activity.

Factors influencing the impact of combined HRT on breast cancer risk

Certain women are more susceptible to the harmful effects of HRT than others. Combined HRT increases breast cancer risk more for women who

  • are in perimenopause or early menopause, rather than being older
  • were experiencing severe menopausal symptoms such as frequent hot flashes before using HRT (indicative of low levels of circulating estrogen)
  • experience breast tenderness during combined HRT use
  • consume alcohol
  • have dense breasts.
Short-term HRT use is safer than long-term use, but even short-term use can increase risk. Breast cancer mortality also is increased with use of HRT before diagnosis.

Estrogen-only HRT is safer than combined HRT, but not for high-risk women

Reviews of data from the Women’s Health Initiative HRT trials (which included both combined HRT and estrogen-only HRT) suggest that estrogen-only HRT can reduce breast cancer risk. Endogenous estrogen (produced within the body) appears to promote breast cancer development—reducing estrogen levels by removing the ovaries or using aromatase inhibitors is protective against breast cancer in high-risk women. However, exogenous estrogen (consumed in the form of phytoestrogens or drugs) may prevent breast cancer development in some cases. Note that combined HRT is typically prescribed for women who have not had a hysterectomy since estrogen-only HRT increases the risk of endometrial cancer cancer (the addition of progestin minimizes this risk).

While estrogen-only HRT appears safer than combined HRT in many women with hysterectomies, this does not hold for high-risk women who might already have small, undetected tumors. The problem is that for women with existing ER+ micro-tumors (some of which might otherwise never develop into life-threatening disease), estrogen-only HRT could stimulate tumor growth. Nor are bioidentical hormones necessarily safe to the extent that they relieve symptoms by increasing estrogen levels. Any form of HRT appears to be unsafe for breast cancer survivors.

Latest research finds HRT use counteracts benefits of exercise

The study referenced at the beginning of this news story was designed to investigate the influence of HRT use on the association between physical activity and breast cancer risk. To conduct the study, the authors performed a meta-analysis of combined data from 38 previous prospective studies published between 1987 and 2014. Six of the studies investigated the influence of physical activity according to HRT use. The 38 studies comprised 4,183,888 women in total, including 116,304 breast cancer cases. Breast cancer risk associated with the highest level of physical activity was compared to that of the lowest level of physical activity.

Compared to the lowest level of physical activity, the highest level was associated with a 12% lower risk of breast cancer overall; the risk was 11% lower for ER+/PR+ disease and 20% lower for ER-/PR- disease. The reduction in risk conferred by physical activity was not influenced by whether the physical activity was work-related or not, geographic location, BMI, or menopausal status. The higher the level of physical activity, the greater the breast cancer risk reduction—there was no apparent threshold at which increasing activity failed to produce greater risk reduction.

In the studies that included HRT use, physically active women who never used HRT had a 22% lower risk of breast cancer than inactive women, whereas physically active HRT users had only a 3% lower risk. Women who never used HRT and who made a sustained change from being physically inactive to engaging in four to seven hours per week of mostly vigorous physical activity experienced a 31% reduction in breast cancer risk. The authors conclude that high levels of physical activity can lead to meaningful reductions in breast cancer risk. However ever use of HRT appears to extinguish the preventative effect of physical activity.

Please see our articles on exercise and hormone replacement therapy for more information.