Implementing the Risk Stratification and Clinical Management of Breast Cancer Families Using Polygenic Risk Score Evaluation: A Pilot Study.

Background: The identification of women at high risk of breast cancer (BC) is crucial for personalized screening strategies. Pathogenic and likely pathogenic variants (PVs/LPVs) in susceptibility risk genes explain part of the individual risk. Moreover, a polygenic background, summarized as a polygenic risk score (PRS), contributes to the risk of BC and may modify the individual risk in carrier and non-carrier members of BC families.

Methods: We performed a retrospective pilot study evaluating PRS in women from a subset of high- (BRCA1 and BRCA2) and moderate-risk (PALB2 and ATM) BC families. We included PVs/LPVs carriers and non-carriers and evaluated a PRS based on 577,113 BC-associated variants. Using BOADICEA, we calculated the adjusted lifetime BC risk.

Results: Our data showed that in BRCA1/BRCA2 carriers, PVs have a major role in stratifying the lifetime risk, while PRS improves risk estimation in non-carriers of these families. A different scenario may be observed in PALB2 and ATM families where PRS combined with PV/LPV carrier status gives a more informative lifetime risk.

Conclusions: This study showed that in BC families, the PRS might help to quantify the weight of the genetic familial background, improving the individual risk stratification and contributing to personalized clinical management for carrier and non-carrier women.