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After menopause, estradiol is primarily synthesized in peripheral tissues by the enzyme aromatase, encoded by  CYP19A1 .  CYP19A1  variation associates with circulating estradiol in postmenopausal women and this variation is best represented by the intronic variant rs727479. This variation appears to have pleiotropic effects as it also associates with endometrial cancer risk. Indeed, estradiol plays an important role in the development of breast and endometrial cancer. Aromatase inhibitor (AI) drugs are used in the treatment of both diseases, however, response rates for AIs are low and there is currently no way to identify breast or endometrial cancer patients who are more likely to receive a clinical benefit. Multiple studies have proposed that genetic variation in  CYP19A1  will have effects on AI efficacy: eight candidate variant studies of sample size greater than 50 describe associations between  CYP19A1  variation and the outcome of patients treated with AIs. Nominally significant associations with patient outcome were reported for several variants, including rs727479. However, only an association between rs4646 and time to progression was replicated in an independent study. Moreover, rs4646 is also the only variant that has an association with patient outcome that passes a multiple testing threshold and this variant is in linkage disequilibrium with rs727479, supporting the hypothesis that associations with patient outcome may be driven through the effects on circulating estradiol. Despite this preliminary evidence, well phenotyped and comprehensively genotyped patient sets need to be studied before conclusions can be drawn about the effects of  CYP19A1  variation on AI efficacy.

frontiers in pharmacology

The Association of CYP19A1 Variation with Circulating Estradiol and Aromatase Inhibitor Outcome: Can CYP19A1 Variants Be Used to Predict Treatment Efficacy?