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Hormone Replacement Therapy, Synthetic Progestogens, and Breast Cancer Risk

Background: Hormone Replacement Therapy (HRT) has been associated with an increased risk of breast cancer. The study objective is to evaluate whether the increased risk is dependent on the formulation used. 
 
Methods: We carried out a population-based case-control study using data from the United Kingdom Clinical Practice Research Datalink on women age ≥50 years. Incident cases of breast cancer were age-matched (1:10) with controls of comparable follow-up time with no history of breast cancer. Exposures were classified as ever or never for the following HRT formulations: bioidentical estrogens, animal-derived estrogens, micronized progesterone, and synthetic progestin. Logistic regression analyses were performed to estimate the adjusted effect of HRT formulation on breast cancer. 
 
Findings: Between 1995-2014, 43,183 breast cancer cases were identified and matched to 431,830 controls. In adjusted analyses, compared with women who never used HRT, its use was associated with an increased risk of breast cancer (OR 1·12, 95% CI 1·09-1·15). Compared with never users, estrogens were not associated with breast cancer: bioidentical estrogens (OR 1·04,1·00-1·09), animal-derived estrogens (OR 1·01, 0·96-1·06), both (OR 0·96, 0·89-1·03). Progestogens appeared differentially associated with breast cancer: micronized progesterone (OR 0·99, 0·55-1·79), synthetic progestin (OR 1·28, 1·22-1·35), both (OR 1·32, 0·30-5·77). 
 
Interpretation: While HRT use appears to be associated with an overall increased risk of breast cancer, it appears uniquely in women prescribed formulations containing synthetic progestin. Hence, synthetic progestins should not be given as part of HRT regimens and counseling regarding the risk of breast cancer should consider the effect of formulation used. 
 
Funding Information: Supported by a grant from the Canadian Cancer Society, 703041. 
 
Declaration of Interests: Haim Abenhaim has no conflicts of interest to declare. Samy Suissa has been a Scientific Advisory Committee Member for Atara Bio, Boehringer-Ingelheim, Briston-Myers-Squibb, Merck, MorphoSys, and Seqirus. He has also been a speaker for AstraZeneca and Novartis. All work was unrelated to this study. Laurent Azoulay received consulting fees from Janssen and Pfizer for work unrelated to this study. Andrea Spence has no conflicts of interest to declare. Nicholas Czuzoj-Shulman has no conflicts of interest to declare. Togas Tulandi has no conflicts of interest to declare. 
 
Ethics Approval Statement: The Independent Scientific Advisory Committee of the Clinical Practice Research Datalink and the Research Ethics Board of the Jewish General Hospital, Montreal, 
Quebec, Canada approved the study.