Development and validation of a residual risk score to predict breast cancer risk in unaffected women negative for mutations on a multi-gene hereditary cancer panel.

Abstract

1579 Background: Women who are unaffected with cancer but have a significant family history of breast cancer (BC) are frequently referred for hereditary cancer testing with multi-gene panels; however, < 10% test positive for clinically actionable mutations. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms) that individually confer modest BC risk, but together may explain the genetic susceptibility for BC in many women without monogenic mutations. Here, we describe the development and validation of a polygenic residual risk score in a large, consecutive cohort of women who tested negative for mutations in known BC susceptibility genes. Methods: This IRB-approved study includes women of European ancestry tested with a multi-gene hereditary cancer panel who were negative for mutations in 11 genes associated with BC ( BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Clinical information was collected from provider-completed test request forms. The dataset was divided into a training (July – November 2016) and validation cohort (November 2016 – April 2017). Multivariable logistic regression models were used to evaluate 94 common variants and develop candidate residual risk scores as predictors of personal BC history (invasive ductal carcinoma, IDC) in the training cohort. Independent variables included age, personal/family cancer history, and ancestry. An optimal subset of the 94 common variants and a residual risk score will be selected through cross-validation followed by independent validation. Results: The training cohort includes 11,838 women (median age 47 years), 18% of whom reported a personal history of IDC and 36% of whom reported BC in a first-degree relative. Results from validation of the residual risk score in an independent cohort of approximately 12,000 women will be completed at the time of presentation. Conclusions: The validation and clinical implementation of a residual risk score for women at risk for hereditary BC may offer significant potential for the management of high-risk, unaffected women who test negative for monogenic BC mutations.