Genetic prediction of long-term effects of aromatase inhibition on cancer and non-neoplastic disease risk
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Background Anastrozole, 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. Methods We 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). Results Genetically-proxied aromatase inhibition was associated with reduced risk of ER+ breast cancer (OR:0·78, 95%CI:0·67-0·92) and decreased heel bone mineral density (−0·32SD change, 95%CI:-0·36,-0·28). When examining the repurposing potential of anastrozole to other cancers, we found that genetically-proxied aromatase inhibition reduced endometrial cancer risk (OR:0·34, 95%CI:0·26-0·44). In PheWAS, genetically-proxied aromatase inhibition was associated with 6 outcomes ( P FDR <0·05) including reduced risk of endometrial polyps (OR:0·58, 95%CI:0·45-0·74) and postmenopausal bleeding (OR:0·67, 95%CI:0·54-0·83), with stronger effects in women with higher BMI ( P LRT =1·26×10 - 3 and 0·02, respectively). Conclusion Our 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.
Source: medRxiv
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Wellcome Trust, University Hospitals Bristol NHS Foundation Trust, NIHR Bristol Biomedical Research Centre, Cancer Research UK, National Institute for Health and Care Research, University of Bristol, National Institutes of Health, Medical Research Council, National Health and Medical Research Council
Awards: G1087756281, G1131969086, Reproductive and cardio-metabolic health, G1935686924, G2466259667, G2538597952, G2803518814, G2909306038, G3176767667, G323433674, G324601231, G3356050007, G3609641447, G4603568690, G4816721500, G514036959, G5260012927, G5329469444, Statistical Methods for Improving Causal Analyses, G6050707053, Data mining epidemiological relationships: integration of causal analysis with published evidence, Identifying adverse effects of cancer drugs using combined genetic and observational approaches, NIHR Senior Investigator Award, Identifying adverse effects of cancer drugs using combined genetic and observational approaches, Mendelian randomization to hypothesis-free causal inference, G713132879, G7264751730, G7385817896, G8173965379, G8201869620, G8502142660, G8823207686
OpenAlex ID: W7160305354