Download This Paper
Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.
Breast Cancer Risk Stratification in Women of Screening Age: Incremental Effects of Adding Mammographic Density, Polygenic Risk and a Gene Panel
24 Pages Posted: 25 Jun 2021
More...Abstract
Background: There is great promise in risk stratification in breast cancer 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: 10,025/57,902 women aged 46-73 years in the Predicting-Risk-Of-Cancer-At-Screening study provided DNA samples. A case-control study within this cohort 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).
Findings: 525 cases and 1410 controls underwent gene panel testing and a PRS (18,143,313 Single-Nucleotide-Polymorphisms-(SNPs)). Actionable pathogenic variants (PGVs) in BRCA1/2 were found in 1.7% of cases and 0.55% of controls and overall PGVs in 6.1% of cancers (PALB2=4, ATM =6, CHEK2 =10) and 1.3% of controls. A combined assessment of TC8-DR-SNP313+gene-panel provided the best risk-stratification with 26.1% controls and only 9.7% cases identified at <1.4% 10-year risk and 9.01% controls and 23.3% cases at ≥8% 10-year risk but TC8-DR-SNP143+gene panel provided the best AUC=0.680 (95%CI=0.652–0.715, however addition of a panel did not significantly improve discrimination. Only 7/17 PGVs in cases resulted in actionable risk category change. An extended case (n=621) control (n=1794) series with TC8-DR-SNP143 identified 18.9% of controls and only 5.6% of stage 2+ cases at <1.4% 10-year risk, but 20.7% of controls and 47.9% of stage 2+ cases at ≥5% 10-year risk.
Interpretations: Addition of a gene panel has marginal additional risk-stratification value to a PRS (143/313 SNPs) in a combined model, but is important for those individual women. Further studies and economic analysis will determine whether adding a panel to a PRS is a cost-effective strategy for risk-stratification.
Funding: National Institute for Health Research RP-PG-0707-10031 and Biomedical Research Centre (IS-BRC-1215-20007). Prevent Breast Cancer (references GA10-033/GA13-006).
Declaration of Interest: None to declare.
Ethical Approval: Approved by the North Manchester Research Ethics Committee (ref.
09/H1008/81).
Keywords: SNPs, Polygenic risk score, BRCA1, BRCA2, PALB2, CHEK2, ATM, breast cancer, mammographic density, pathology, early detection
Suggested Citation: Suggested Citation