Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women.

Authors

Ho PJ, Loo CKY, Lim RJY, Goh MH, Abubakar M, Ahearn TU, Andrulis IL, Antonenkova NN, Aronson KJ, Augustinsson A, Behrens S, Bodelon C, Bogdanova NV, Bolla MK, Brantley KD, Brenner H, Byers H, Camp NJ, Castelao JE, Cessna MH, ...show more Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi JY, Colonna SV, Czene K, Daly MB, Derouane F, Dörk T, Eliassen AH, Engel C, Eriksson M, Evans DG, Fletcher O, Fritschi L, Gago-Dominguez M, Genkinger JM, Geurts-Giele WRR, Glendon G, Hall P, Hamann U, Ho CYS, Ho WK, Hooning MJ, Hoppe R, Howell A, Humphreys K, Ito H, Iwasaki M, Jakubowska A, Jernström H, John EM, Johnson N, Kang D, Kim SW, Kitahara CM, Ko YD, Kraft P, Kwong A, Lambrechts D, Larsson S, Li S, Lindblom A, Linet M, Lissowska J, Lophatananon A, MacInnis RJ, Mannermaa A, Manoukian S, Margolin S, Matsuo K, Michailidou K, Milne RL, Mohd Taib NA, Muir KR, Murphy RA, Newman WG, O'Brien KM, Obi N, Olopade OI, Panayiotidis MI, Park SK, Park-Simon TW, Patel AV, Peterlongo P, Plaseska-Karanfilska D, Pylkäs K, Rashid MU, Rennert G, Rodriguez J, Saloustros E, Sandler DP, Sawyer EJ, Scott CG, Shahi S, Shu XO, Shulman K, Simard J, Southey MC, Stone J, Taylor JA, Teo SH, Teras LR, Terry MB, Torres D, Vachon CM, Houdt MV, Verhoeven J, Weinberg CR, Wolk A, Yamaji T, Yip CH, Zheng W, Hartman M, Li J, On Behalf Of The Abctb Investigators, kConFab Investigators, MyBrCa Investigators, Sgbcc Investigators

Affiliations

• Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA.
• Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
• N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040 Minsk, Belarus.
• Department of Public Health Sciences, Sinclair Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
• Oncology, Department of Clinical Sciences in Lund, Lund University, 221 85 Lund, Sweden.
• Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
• Department of Population Science, American Cancer Society, Atlanta, GA 30303, USA.
• Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
• Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Abstract

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.