Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models
Menée en Australie à partir de données portant sur une cohorte de 24 469 femmes âgées de 27 à 76 ans, cette étude évalue l'intérêt d'ajouter à deux modèles prédictifs (prenant en compte les antécédents familiaux et des facteurs liés au mode de vie) un système de score basé sur la présence de 313 variants génétiques pour identifier avec plus de précision les patientes pouvant bénéficier d'un dépistage personnalisé du cancer du sein et d'une chimioprévention
The BOADICEA and IBIS breast cancer risk models are used to provide advice on screening intervals and chemoprevention. We evaluated the performance of these models, which both now incorporate polygenic risk scores (PRSs), using a prospective cohort study.We used a case-cohort design, involving women in the Melbourne Collaborative Cohort Study aged 50-75 years when surveyed in 2003-2007, of whom 408 had a first primary breast cancer diagnosed within 10 years (cases) and 2,783 were from the sub-cohort. Ten-year risks were calculated based on lifestyle factors, family history data and a 313-variant PRS. Discrimination was assessed using a C-statistic compared with 0.50 and calibration using the expected/observed number of cases (E/O).When the PRS was added to models with lifestyle factors and family history, the C-statistic (95% confidence interval [CI]) increased from 0.57 (0.54 to 0.60) to 0.62 (0.60 to 0.65) using IBIS, and from 0.56 (0.53 to 0.59) to 0.62 (0.59-0.64) using BOADICEA. IBIS under-predicted risk (E/O=0.62, 95% CI = 0.48 to 0.80) for women in the lowest risk category (<1.7%) and over-predicted risk (E/O=1.40, 95% CI = 1.18 to 1.67) in the highest risk category (≥5%); Hosmer-Lemeshow test for calibration in quantiles of risk, two-sided P<0.001. BOADICEA under-predicted risk (E/O=0.82, 95% CI = 0.67 to 0.99) in the second highest risk category (3.4%-5%); Hosmer-Lemeshow test, two-sided P=0.02.While the inclusion of a 313 genetic variant PRS doubles discriminatory accuracy (relative to reference 0.50), models with and without this PRS have relatively modest discrimination and might require re-calibration before their clinical and wider use is promoted.
JNCI Cancer Spectrum , article en libre accès, 2020