Obi, Nadia

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Abstract Background Most breast biopsies are diagnosed as benign breast disease, with 1.5- to 4-fold increased breast cancer risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in breast cancer risk assessment of these patients. We assessed whether a 313–single nucleotide variation (formerly single-nucleotide polymorphism) polygenic risk score stratifies risk of benign breast disease patients. Methods We pooled data from 5 Breast Cancer Association Consortium case-control studies (mean age = 59.9 years), including 6706 participants with breast cancer and 8488 participants without breast cancer. Using logistic regression, we estimated breast cancer risk associations by self-reported benign breast disease history and strata of polygenic risk score, with median polygenic risk score category among women without benign breast disease as the referent. We assessed interactions and mediation of benign breast disease and polygenic risk score with breast cancer risk. Results Benign breast disease history was associated with increased breast cancer risk (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.37 to 1.60; P &lt; .001). Polygenic risk score increased breast cancer risk, irrespective of benign breast disease history (Pinteraction = .48), with minimal evidence of mediation of either factor by the other. Women with benign breast disease and polygenic risk score in the highest tertile had more than twofold increased odds of breast cancer (OR = 2.73, 95% CI = 2.41 to 3.09), and those with benign breast disease and polygenic risk score in the lowest tertile experienced reduced breast cancer risk (OR = 0.79, 95% CI = 0.70 to 0.91) compared with the referent group. Women with benign breast disease and polygenic risk score in the highest decile had a 3.7-fold increase (95% CI = 3.00 to 4.61) compared with those with median polygenic risk score without benign breast disease. Conclusion Breast cancer risks are elevated among women with benign breast disease and increase progressively with polygenic risk score, suggesting that optimal combinations of these factors may improve risk stratification.