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Effect of Polygenic Risk Score on Estimated Breast Cancer Risk Among Carriers of Pathogenic Variants in Predisposition Genes


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In a study reported in the Journal of Clinical Oncology, Gao et al found that use of a polygenic risk score (PRS) modified the estimated risk of breast cancer among both carriers and noncarriers of established pathogenic variants in breast cancer predisposition genes.

Study Details

The study included 26,798 White women with breast cancer and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium. Participants were assessed for pathogenic variants in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. The PRS, reflecting risk based on the combined effect of multiple single-nucleotide polymorphisms, was developed using 105 common variants with effect estimates derived from breast cancer genome-wide association studies.

Key Findings

Changes in estimated lifetime risk of breast cancer from the 10th to 90th percentiles of PRS among general population noncarriers were 6.7% to 18.2% among women without and 9.1% to 23.9% among women with a first-degree relative with breast cancer.

Changes in lifetime risk from the 10th to 90th percentiles of PRS among carriers were larger for ATM (12.8%–32.3% in women without and 17.0%–42.9% in women with a first-degree relative with breast cancer), CHEK2 (15.2%–37.3% and 20.0%–46.6%), and PALB2 (21.5%–49.2% and 27.9%–59.5%) than for BRCA1 (36.1%–46.9% and 45.4%–57.3%) and BRCA2 (43.8%–55.3% and 53.9%–65.9%). Changes in PRS did not substantially affect estimated risk for carriers of BARD1, BRIP1, CDH1, or NF1.

Carriers with estimated > 20% lifetime risk of breast cancer based on PRS included 99.9% of those without and 99.9% of those with a first-degree relative with breast cancer for BRCA1, 99.9% and 99.9% for BRCA2, 92.9% and 98.0% for PALB2, 52.5% and 78.8% for ATM, and 68.7% and 89.9% for CHEK2. Noncarriers with estimated > 20% lifetime risk of breast cancer based on PRS included 6.1% of those without and 21.2% of those with a first-degree relative with breast cancer.

The investigators concluded, “PRS facilitates personalization of breast cancer risk among carriers of pathogenic variants in predisposition genes. Incorporating PRS into breast cancer risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.”

Peter Kraft, PhD, of the Harvard T.H. Chan School of Public Health, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Institutes of Health and the Breast Cancer Research Foundation. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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