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.
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 language | English |
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Journal | Genetics in Medicine |
Publication status | Accepted/In press - 14 Mar 2022 |
Research Beacons, Institutes and Platforms
- Manchester Cancer Research Centre