Abstract P1-09-04: Association between a breast cancer polygenic risk score and contralateral breast cancer risk
Authors: I Kramer, MJ Hooning, N Mavaddat, S Canisius, R Keeman, AJ van den Broek, E Steyerberg, M Hauptmann, PD Pharoah, DF Easton, P Hall, MK Schmidt
Journal: Cancer Research (2019)

Abstract Background Breast cancer patients are at significant risk of a second contralateral, breast cancer (CBC). Identification of women at high or low CBC risk could improve patient management decisions. Previous research has shown that breast cancer-associated single nucleotide polymorphisms (SNPs) summarized in a polygenic risk score (PRS) predict the risk of a first breast cancer with an odds ratio (OR) per 1 SD of 1.55 (95% confidence interval (95%CI)=1.52-1.58) (77-SNP PRS). The aim of this study was to evaluate the association between a recently developed PRS and CBC risk. Methods We identified 19 studies from the Breast Cancer Association Consortium (BCAC) with follow-up information on participating patients and at least 10 patients diagnosed with CBC. This included 38,228 females of European ancestry diagnosed with first invasive breast cancer since 1990. Genotyping was done using the iCOGS array or OncoArray, with genotypes for SNPs not on the arrays estimated by imputation. We used a 313-SNP PRS, optimized for prediction of overall (first) breast cancer in the BCAC dataset. Metachronous CBC risk by PRS was quantified using univariable and multivariable Cox regression analyses stratified by country and adjusted for multiple patient, tumor, and treatment characteristics. We assessed PRS interaction with age, family history, adjuvant systemic therapy, and ER-status. Results Median time to develop a CBC (N=1,046) after a first breast cancer was 5.8 years (range 0.3-21.9). Higher PRS was associated with increased CBC risk: hazard ratio (HR) per 1 SD=1.31 (95%CI=1.23-1.39). Patients in the highest and lowest 5% of the PRS had 1.95 fold and 0.67 fold risks of CBC, respectively, compared with patients in the middle quintile. Adjustments for age, year of diagnosis, family history, tumor size, nodal status, ER-status, or treatment (chemotherapy, endocrine therapy, radiotherapy) did not substantially alter these results. We found an interaction with age at first breast cancer diagnosis (Pinteraction=.002); the PRS was associated with an increased CBC risk for patients aged ≥40 years (HR=1.37, 95%CI=1.28-1.47), but not for patients &amp;lt;40 years (HR=1.06, 95%CI=0.93-1.21). Conclusion The PRS is predictive for the development of CBC in patients ≥40 years at first breast cancer diagnosis. For this group, the PRS could be incorporated in CBC risk prediction models to help define high and low risk patients, and hence optimize screening and treatment strategies. Citation Format: Kramer I, Hooning MJ, Breast Cancer Association Consortium (BCAC), Mavaddat N, Canisius S, Keeman R, van den Broek AJ, Steyerberg E, Hauptmann M, Pharoah PD, Easton DF, Hall P, Schmidt MK. Association between a breast cancer polygenic risk score and contralateral breast cancer risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-04.