Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival

A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS ) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS with clinicopathologic characteristics of, and survival following, breast cancer. Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment. The PRS was associated with more favorable tumor characteristics. In BCAC, increasing PRS was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent. An increased PRS is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS as increasing PRS is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.