Abstract CS1-1: Polygenic risk scores for breast cancer: Ready or not?

Abstract

Abstract There are increasing attempts to try to stratify cancer risks to enable more targeted early detection and prevention strategies and in particular to balance the risks and benefits of population screening for breast cancer. An increasing number of common genetic variants called Single Nucleotide Polymorphisms (SNPs) have been identified which alter breast cancer risk. Although individually their effect sizes are small they can be used multiplicatively to provide a polygenic risk score (PRS) that accurately predicts risk in both the familial and population setting. Although the first 18 SNPs produce a highly calibrated PRS that is ready for use there are now PRSs of 143 or even 313 SNPs that increase risk stratification although with some loss of calibration. Using data from 9362 women in the Predicting the Risk Of Cancer At Screening (PROCAS) study (500 prospective cancers) and 2000 women in the FH-Risk familial cohort (500 prospective cancers) we have validated the PRS alongside mammographic density (density residual-DR) and standard risk factors to assess future risk of different types of breast cancer. The combined score accurately predicts breast cancers rates with 18-21% of women being predicted in the moderate or high risk categories (≥5% 10 year risk) that developed 41.5-45% of the stage 2+ cancers. In contrast SNP143 is able to identify alongside density and standard risk factors 21% of the general population at <1.4% 10-year risk aged 46-73 years who develop only 9% of the breast cancers. These are also more likely to be potentially 'overdiagnosed' grade 1 and DCIS. The SNP143 is also predictive for oestrogen receptor negative cancers using a 20 SNP PRS. Conclusions: A combined approach using Tyrer-Cuzick, mammographic density and a PRS provides accurate risk stratification not only overall but also for worse prognosis cancers. This provides support for reducing screening intervals in the high and increasing them in the low risk groups. It is high time these highly informative tests were used in risk stratification Citation Format: Evans D. Polygenic risk scores for breast cancer: Ready or not? [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 CS1-1.