BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors

Abstract

Purpose: Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs).

Methods: BOADICEA incorporates the effects of truncating variants in BRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information.

Results: Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17-<30% (moderate risk according to National Institute for Health and Care Excellence [NICE] guidelines) and 1.1% a lifetime risk of ≥30% (high risk).

Conclusion: This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.

Keywords: BOADICEA; PRS; breast cancer; rare variants; risk prediction.

Fig. 1

Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA)-predicted breast cancer risk for a female with unknown family history (equivalent to the distribution of risk in the population) and untested for rare pathogenic variants on the basis of the different predictors of risk (questionnaire-based risk factors [QRFs], mammographic density [MD], and polygenic risk scores [PRS]). Variability due to residual family history of cancer is not taken into account. (a, c) Ten-year risk from age 40 to age 50 years; (b, d) lifetime risk (from age 20 to 80 years). (a, b) Probability density function against absolute risk for 10-year and lifetime risks respectively; (c, d) absolute risk against cumulative distribution. The backgrounds of the graphs are shaded to indicate the familial breast cancer risk categories based on the National Institute for Health and Care Excellence (NICE) guidelines: (1) near-population risk shaded in pink (<17% for lifetime risk and <3% for 10-year risk), (2) moderate risk shaded in yellow (≥17% and <30% for lifetime risk and ≥3% and <8% for 10-year risk), and (3) high risk, shaded in blue (≥30% for lifetime risk and ≥8% for 10-year risk). Specific values are given in Table 1. The vertical lines in (a, b) and horizontal lines in (c, d) (labeled “No QRFs, MD or PRS”) correspond to the population risk of breast cancer. Predictions based on UK  breast cancer incidence.

Fig. 2

Predicted Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk for a female with a mother affected at age 50 and untested for rare pathogenic variants on the basis of the different predictors of risk (questionnaire-based risk factors (QRFs), mammographic density (MD), and polygenic risk scores [PRS]). (a, c) Ten-year risk from age 40 to age 50 years; (b, d) lifetime risk (age 20 to 80 years). The backgrounds of the graphs are shaded to indicate the familial breast cancer risk categories based on the National Institute for Health and Care Excellence (NICE) guidelines: (1) near-population risk, shaded in pink (<17% for lifetime risk and <3% for 10-year risk); (2) moderate risk, shaded in yellow (≥17% and <30% for lifetime risk and ≥3% and <8% for 10-year risk); and (3) high risk, shaded in blue (≥30% for lifetime risk and ≥8% for 10-year risk). Predictions based on UK breast cancer incidence.

Fig. 3

Predicted Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk for a female intermediate-risk rare pathogenic variant carrier, on the basis of the different predictors of risk (questionnaire-based risk factors [QRFs], mammographic density [MD], and polygenic risk scores [PRS]). (a, c) Lifetime risk (age 20 to 80 years) for a CHEK2 1100delC carrier with unknown family history; (b, d) lifetime risk for a CHEK2 1100delC carrier with her mother affected at age 50. (e, f) Risk for a PALB2 and an ATM rare pathogenic variant carrier respectively, both with unknown family history. The backgrounds of the graphs are shaded to indicate the familial breast cancer risk categories based on the National Institute for Health and Care Excellence (NICE) guidelines: (1) near-population risk shaded in pink (<17%), (2) moderate risk shaded in yellow (≥17% and <30%), and (3) high risk shaded in blue (≥30%). Predictions based on UK breast cancer incidence.