Genetic prediction of long-term effects of aromatase inhibition on cancer and non-neoplastic disease risk

BackgroundAnastrozole, an aromatase inhibitor, is approved for breast cancer prevention in high-risk women. The long-term effects of aromatase inhibition, including its repurposing potential to other cancers, possible adverse effects, and treatment effect heterogeneity across patient subgroups, remain unclear. MethodsWe used the rs727479 variant in CYP19A1 to mimic the effect of long-term pharmacological aromatase inhibition. To evaluate repurposing opportunities, genetic association data on five cancers (211,386 cases, 684,665 controls) were obtained from genome-wide association study consortia. Potential adverse effects were evaluated in a phenome-wide association study (PheWAS) of 449 health-related traits in 162,360 postmenopausal women in the UK Biobank. Effects were investigated across clinically relevant subgroups in the UK Biobank including those defined by body mass index (BMI). ResultsGenetically-proxied aromatase inhibition was associated with reduced risk of ER+ breast cancer (OR:0{middle dot}78, 95%CI:0{middle dot}67-0{middle dot}92) and decreased heel bone mineral density (-0{middle dot}32SD change, 95%CI:-0{middle dot}36,-0{middle dot}28). When examining the repurposing potential of anastrozole to other cancers, we found that genetically-proxied aromatase inhibition reduced endometrial cancer risk (OR:0{middle dot}34, 95%CI:0{middle dot}26-0{middle dot}44). In PheWAS, genetically-proxied aromatase inhibition was associated with 6 outcomes (PFDR<0{middle dot}05) including reduced risk of endometrial polyps (OR:0{middle dot}58, 95%CI:0{middle dot}45-0{middle dot}74) and postmenopausal bleeding (OR:0{middle dot}67, 95%CI:0{middle dot}54-0{middle dot}83), with stronger effects in women with higher BMI (PLRT=1{middle dot}26x10-3 and 0{middle dot}02, respectively). ConclusionOur genetic analyses recapitulate known effects of aromatase inhibition on breast cancer risk and highlight potential repurposing for endometrial cancer prevention. Limited evidence of adverse effects beyond bone mineral density was observed, and subgroup analyses suggested that women with higher BMI may experience greater protection against endometrial conditions.