Combination Hormone Replacement Therapy and Risk of Breast Cancer

Invited commentary by Drs. Paula Silverman and Cheryl Thompson 

A recent study by Jones et al. in The British Journal of Cancer (BJC)(Jones ME. Br J Cancer. 2016 Aug 23) estimated an almost 3 fold (2.74 times) increase risk of breast cancer among post-menopausal women who used combination estrogen and progesterone hormone replacement therapy (HRT).  This risk was 3.27 fold for women who used the combination therapy for 15 years or longer.  As with other studies, the authors found no increased risk of breast cancer among women taking estrogen-only therapy.

Early studies from the Women's Health Initiative and Million Women Study showed a marked increase in breast cancer risk among women using combination therapy.  Since then, estimates, derived mostly from retrospective studies, consistently suggested an association of combination therapy and breast cancer risk, although not nearly as strong, with estimates mostly in the 1.5-2 times range. 

In 2002, the combination therapy arm of the Women's Health Initiative trial was stopped when the investigators concluded that the risks, including increased breast cancer risk, outweighed the benefits.  Since then, there has been a strong shift in prescribing practice, with fewer women being prescribed combination therapy each year.  With this changing practice, we expected the number of post-menopausal breast cancer cases to decline.  Indeed, this has been the case though there has been some controversy about whether the decline was due to less HRT use or fewer women receiving mammograms, another recent trend.

This new report in BJC that attempted to address shortcomings in previous studies by utilizing the Breakthrough Generations Study, which includes more detailed data on both HRT use and timing with menopause, suggests that the change in prescribing practices may have a larger than expected impact on cancer incidence.  Statistical analyses on their data suggest that not having yearly updated data on HRT and menopausal status, typical of most epidemiological studies, may have underestimated the effect by up to 59%. 

Paula Silverman, MD, is a member of the Case Comprehensive Cancer Center, Associate Professor of Medicine at the Case Western Reserve University (CWRU) School of Medicine, and Director of the Breast Cancer Program at UH Seidman Cancer Center; Cheryl Thompson, PhD is a member of the Case Comprehensive Cancer Center and Assistant Professor of Nutrition at the CWRU School of Medicine.