Breast cancer risk stratification in women of screening age: Incremental effects of adding mammographic density, polygenic risk, and a gene panel
Authors
Evans, D Gareth Rvan Veen, E. M.
Harkness, E. F.
Brentnall, A. R.
Astley, Susan
Byers, Helen
Woodward, Emma R
Sampson, S.
Southworth, J.
Howell, Sacha J
Maxwell, Anthony J
Newman, W. G.
Cuzick, J.
Howell, Anthony
Affiliation
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomIssue Date
2022
Metadata
Show full item recordAbstract
Purpose: There is great promise in breast cancer risk stratification to target screening and prevention. It is unclear whether adding gene panels to other risk tools improves breast cancer risk stratification and adds discriminatory benefit on a population basis. Methods: In total, 10,025 of 57,902 women aged 46 to 73 years in the Predicting Risk of Cancer at Screening study provided DNA samples. A case-control study was used to evaluate breast cancer risk assessment using polygenic risk scores (PRSs), cancer gene panel (n = 33), mammographic density (density residual [DR]), and risk factors collected using a self-completed 2-page questionnaire (Tyrer-Cuzick [TC] model version 8). In total, 525 cases and 1410 controls underwent gene panel testing and PRS calculation (18, 143, and/or 313 single-nucleotide polymorphisms [SNPs]). Results: Actionable pathogenic variants (PGVs) in BRCA1/2 were found in 1.7% of cases and 0.55% of controls, and overall PGVs were found in 6.1% of cases and 1.3% of controls. A combined assessment of TC8-DR-SNP313 and gene panel provided the best risk stratification with 26.1% of controls and 9.7% of cases identified at <1.4% 10-year risk and 9.01% of controls and 23.3% of cases at ≥8% 10-year risk. Because actionable PGVs were uncommon, discrimination was identical with/without gene panel (with/without: area under the curve = 0.67, 95% CI = 0.64-0.70). Only 7 of 17 PGVs in cases resulted in actionable risk category change. Extended case (n = 644)-control (n = 1779) series with TC8-DR-SNP143 identified 18.9% of controls and only 6.4% of stage 2+ cases at <1.4% 10-year risk and 20.7% of controls and 47.9% of stage 2+ cases at ≥5% 10-year risk. Conclusion: Further studies and economic analysis will determine whether adding panels to PRS is a cost-effective strategy for risk stratification.Citation
Evans DGR, van Veen EM, Harkness EF, Brentnall AR, Astley SM, Byers H, et al. Breast cancer risk stratification in women of screening age: Incremental effects of adding mammographic density, polygenic risk, and a gene panel. Genetics in Medicine. Elsevier BV; 2022.Journal
Genetics in MedicineDOI
10.1016/j.gim.2022.03.009PubMed ID
35426792Additional Links
https://dx.doi.org/10.1016/j.gim.2022.03.009Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1016/j.gim.2022.03.009