Combined associations of a polygenic risk score and classical risk factors with breast cancer risk.

Combining polygenic risk score (PRS) with classical risk factors could improve accuracy of breast cancer prediction models. We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors in women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, for breast cancer risk overall and by ER status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Global and tail-based goodness of fit tests also did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer from classical risk factors was greater for women with higher genetic risk (PRS313 and family history). The average absolute risk difference for women in the lowest and highest deciles of genetic risk due to all classical and the subset of modifiable risk factors is 17.5% and 16.5%, respectively. These findings have implications for development of comprehensive models for risk-stratified prevention of breast cancer.