Clinical Impact of Polygenic Risk Score for Breast Cancer Risk Prediction in 382 Individuals with Hereditary Breast and Ovarian Cancer Syndrome

SIMPLE SUMMARY: Breast cancer (BC) is the major cause of cancer-related deaths in women worldwide. In addition to genetic diagnostics for variants in high-risk genes, there is a need for better risk stratification to target high-risk individuals. The polygenic risk score (PRS) has emerged as a valuable addition to help sorting women into different risk categories for BC development. This study aimed to evaluate the impact of adding a PRS, based on 313 genetic variants, to standard genetic testing for 382 German women with BC or a family history of the disease. By incorporating the PRS into risk prediction models, meaningful changes in 10-year risks were observed in 13.6% of individuals. Additionally, the inclusion of the PRS led to clinically significant changes in prevention recommendations for 12.0% of cases, supporting the use of the PRS for BC risk assessment in genetic counselling. ABSTRACT: Single nucleotide polymorphisms are currently not considered in breast cancer (BC) risk predictions used in daily practice of genetic counselling and clinical management of familial BC in Germany. This study aimed to assess the clinical value of incorporating a 313-variant-based polygenic risk score (PRS) into BC risk calculations in a cohort of German women with suspected hereditary breast and ovarian cancer syndrome (HBOC). Data from 382 individuals seeking counselling for HBOC were analysed. Risk calculations were performed using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm with and without the inclusion of the PRS. Changes in risk predictions and their impact on clinical management were evaluated. The PRS led to changes in risk stratification based on 10-year risk calculations in 13.6% of individuals. Furthermore, the inclusion of the PRS in BC risk predictions resulted in clinically significant changes in 12.0% of cases, impacting the prevention recommendations established by the German Consortium for Hereditary Breast and Ovarian Cancer. These findings support the implementation of the PRS in genetic counselling for personalized BC risk assessment.