Breast cancer risk stratification in women of screening age: Incremental effects of adding mammographic density, polygenic risk and a gene panel

D Gareth Evans, Elke Van Veen, Elaine Harkness, Adam Brentnall, Susan Astley, Helen Byers, Emma Woodward, Sarah Sampson, Jake Southworth, Sacha Howell, Anthony Maxwell, William Newman, Jack Cuzick, Tony Howell

Research output: Contribution to journalArticlepeer-review

Abstract

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:10,025 of 57,902 women aged 46-73 years in the Predicting-Risk-Of-Cancer-At-Screening-(PROCAS) study provided DNA samples. A case-control study was used to evaluate breast cancer risk-assessment using a polygenic-risk-score (PRS), cancer gene panel-(n=33), mammographic-density (density-residual-DR) and questionnaire risk factors (Tyrer-Cuzick-model-TC8). 525 cases and 1410 controls underwent gene panel testing and PRS (18/143/313-Single-Nucleotide-Polymorphisms-(SNPs)).
Results:-Actionable pathogenic variants-(PGVs) in BRCA1/2 were found in 1.7% cases and 0.55% controls and overall PGVs in 6.1%/1.3% respectively. A combined assessment of TC8-DR-SNP313+gene-panel provided the best risk-stratification with 26.1% controls/9.7% cases identified at <1.4% 10-year risk and 9.01%/23.3% at ≥8% 10-year risk. As actionable PGVs were uncommon, discrimination was identical with/without gene panel-(with/without:AUC=0.67,95%CI=0.64-0.70). Only 7/17 PGVs in cases resulted in actionable risk category change.
Extended case-(n=644) control-(n=1779) series with TC8-DR-SNP143 identified 18.9% controls and only 6.4% of stage 2+ cases at <1.4% 10-year risk, but 20.7% controls/47.9% of stage 2+ cases ≥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.
Original languageEnglish
JournalGenetics in Medicine
Publication statusAccepted/In press - 14 Mar 2022

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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