Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk
Authors: Kapoor Pooja Middha , Mavaddat Nasim , Choudhury Parichoy Pal , Wilcox Amber N , Lindström Sara , Behrens Sabine , Michailidou Kyriaki , Dennis Joe , Bolla Manjeet K , Wang Qin , Jung Audrey , Abu-Ful Zomoroda , Ahearn Thomas , Andrulis Irene L , Anton-Culver Hoda , Arndt Volker , Aronson Kristan J , Auer Paul L , Freeman Laura E Beane , Becher Heiko , Beckmann Matthias W , Beeghly-Fadiel Alicia , Benitez Javier , Bernstein Leslie , Bojesen Stig E , Brauch Hiltrud , Brenner Hermann , Brüning Thomas , Cai Qiuyin , Campa Daniele , Canzian Federico , Carracedo Angel , Carter Brian D , Castelao Jose E , Chanock Stephen J , Chatterjee Nilanjan , Chenevix-Trench Georgia , Clarke Christine L , Couch Fergus J , Cox Angela , Cross Simon S , Czene Kamila , Dai James Y , Earp H Shelton , Ekici Arif B , Eliassen A Heather , Eriksson Mikael , Evans D Gareth , Fasching Peter A , Figueroa Jonine , Fritschi Lin , Gabrielson Marike , Gago-Dominguez Manuela , Gao Chi , Gapstur Susan M , Gaudet Mia M , Giles Graham G , González-Neira Anna , Guénel Pascal , Haeberle Lothar , Haiman Christopher A , Håkansson Niclas , Hall Per , Hamann Ute , Hatse Sigrid , Heyworth Jane , Holleczek Bernd , Hoover Robert N , Hopper John L , Howell Anthony , Hunter David J ,   ABCTB Investigators,   kConFab/AOCS Investigators, John Esther M , Jones Michael E , Kaaks Rudolf , Keeman Renske , Kitahara Cari M , Ko Yon-Dschun , Koutros Stella , Kurian Allison W , Lambrechts Diether , Le Marchand Loic , Lee Eunjung , Lejbkowicz Flavio , Linet Martha , Lissowska Jolanta , Llaneza Ana , MacInnis Robert J , Martinez Maria Elena , Maurer Tabea , McLean Catriona , Neuhausen Susan L , Newman William G , Norman Aaron , O’Brien Katie M , Olshan Andrew F , Olson Janet E , Olsson Håkan , Orr Nick , Perou Charles M , Pita Guillermo , Polley Eric C , Prentice Ross L , Rennert Gad , Rennert Hedy S , Ruddy Kathryn J , Sandler Dale P , Saunders Christobel , Schoemaker Minouk J , Schöttker Ben , Schumacher Fredrick , Scott Christopher , Scott Rodney J , Shu Xiao-Ou , Smeets Ann , Southey Melissa C , Spinelli John J , Stone Jennifer , Swerdlow Anthony J , Tamimi Rulla M , Taylor Jack A , Troester Melissa A , Vachon Celine M , van Veen Elke M , Wang Xiaoliang , Weinberg Clarice R , Weltens Caroline , Willett Walter , Winham Stacey J , Wolk Alicja , Yang Xiaohong R , Zheng Wei , Ziogas Argyrios , Dunning Alison M , Pharoah Paul D P , Schmidt Marjanka K , Kraft Peter , Easton Douglas F , Milne Roger L , García-Closas Montserrat , Chang-Claude Jenny 
Published: April 2020

Abstract
We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.