Polygenic Breast Cancer Risk for Women Veterans in the Million Veteran Program

Abstract

Accurate breast cancer (BC) risk assessment allows personalized screening and prevention. Prospective validation of prediction models is required before clinical application. Here, we evaluate clinical- and genetic-based BC prediction models in a prospective cohort of women from the Million Veteran Program.

Materials and methods: Clinical BC risk prediction models were validated in combination with a genetic polygenic risk score of 313 (PRS313) single-nucleotide polymorphisms in genetic females without prior BC diagnosis (n = 35,130, mean age 49 years) with 30% non-Hispanic African ancestry (AA). Clinical risk models tested were Breast and Prostate Cancer Cohort Consortium, literature review, and Breast Cancer Risk Assessment Tool, and implemented with or without PRS313. Prediction accuracy and association with incident breast cancer was evaluated with area under the receiver operating characteristic curve (AUC), hazard ratios, and proportion with high absolute lifetime risk.

Results: Three hundred thirty-eight participants developed incident breast cancers with a median follow-up of 3.9 years (2.5 cases/1,000 person-years), with 196 incident cases in women of European ancestry and 112 incident cases in AA women. Individualized Coherent Absolute Risk Estimator-literature review in combination with PRS313 had an AUC of 0.708 (95% CI, 0.659 to 0.758) in women with European or non-African ancestries and 0.625 (0.539 to 0.711) in AA women. Breast Cancer Risk Assessment Tool with PRS313 had an AUC of 0.695 (0.62 to 0.729) in European or non-AA and 0.675 (0.626 to 0.723) in AA women. Incorporation of PRS313 with clinical models improved prediction in European but not in AA women. Models estimated up to 9% of European and 18% of AA women with absolute lifetime risk > 20%.

Conclusion: Clinical and genetic BC risk models predict incident BC in a large prospective multiracial cohort; however, more work is needed to improve genetic risk estimation in AA women.

FIG 1.

Cohort and model exclusions. Number of MVP women included in model validation, with exclusions specified for each model, and number of incident BC events. BC, breast cancer; BCRA, Breast Cancer Risk Assessment; BPC3, Breast and Prostate Cancer Cohort Consortium analysis; Lit, literature review; MVP, Million Veteran Program; PRS, polygenic risk score.

FIG 2.

Kaplan-Meier curves by quartile of 5-year absolute risk for (A and B) BCRAT plus PRS313 and (C and D) iCARE-Lit plus PRS313 models. Quartiles calculated within each HARE cohort. Panels A and C, EUR/HIS/ASN/Missing; Panels B and D, AFR. P values from log-rank test. AFR, African American of non-Hispanic African HARE ancestry; ASN, Asian; BCRA, Breast Cancer Risk Assessment; BCRAT, Breast Cancer Risk Assessment Tool; EUR, non-Hispanic women of European HARE ancestry; HARE, harmonized ancestry and race/ethnicity; HIS, Hispanic; iCARE-Lit, Individualized Coherent Absolute Risk Estimator-literature review; PRS, polygenic risk score.

FIG 3.

Distribution of 5-year absolute risk estimates for each model, stratified by HARE cohort (AFR, African American women with HARE non-Hispanic African ancestry; EUR/HIS/ASN/Missing, all other HARE ancestry groups) and BC incidence (BC, with incident breast cancer diagnosis; no BC, no diagnosis of breast cancer in follow-up). ASN, Asian; BCRA, Breast Cancer Risk Assessment; BPC3, Breast and Prostate Cancer Cohort Consortium analysis; EUR, non-Hispanic women of European HARE ancestry; HARE, harmonized ancestry and race/ethnicity; HIS, Hispanic; iCARE-Lit, Individualized Coherent Absolute Risk Estimator-literature review; PRS, polygenic risk score.