Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival
Authors: Lopes Cardozo Josephine M.N. , Andrulis Irene L. , Bojesen Stig E. , Dörk Thilo , Eccles Diana M. , Fasching Peter A. , Hooning Maartje J. , Keeman Renske , Nevanlinna Heli , Rutgers Emiel J.T. , Easton Douglas F. , Hall Per , Pharoah Paul D.P. , van 't Veer Laura J. , Schmidt Marjanka K. ,   on behalf of the Breast Cancer Association Consortium and MINDACT Collaborators, Ahearn Thomas U. , Anton-Culver Hoda , Arndt Volker , Auer Paul L. , Augustinsson Annelie , Beane Freeman Laura E. , Becher Heiko , Beckmann Matthias W. , Behrens Sabine , Benitez Javier , Bermisheva Marina , Blomqvist Carl , Bolla Manjeet K. , Bonanni Bernardo , Boyle Terry , Brenner Hermann , Brucker Sara Y. , Brüning Thomas , Burwinkel Barbara , Buys Saundra S. , Camp Nicola J. , Canzian Federico , Cardoso Fatima , Castelao Jose E. , Cessna Melissa H. , Chan Tsun L. , Chang-Claude Jenny , Chenevix-Trench Georgia , Choi Ji-Yeob , Colonna Sarah V. , Copson Ellen , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Dennis Joe , Devilee Peter , Drukker Caroline A. , Dunning Alison M. , Dwek Miriam , Eliassen A. Heather , Engel Christoph , Evans D. Gareth , Figueroa Jonine D. , Fletcher Olivia , Flyger Henrik , Gago-Dominguez Manuela , García-Closas Montserrat , García-Sáenz José A. , Genkinger Jeanine , Giles Graham G. , González-Neira Anna , Guénel Pascal , Gündert Melanie , Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hamann Ute , Hartman Mikael , Heemskerk-Gerritsen Bernadette A.M. , Hein Alexander , Ho Weang-Kee , Hoppe Reiner , Hopper John L. , Houlston Richard S. , Howell Anthony , Hunter David J. , Ito Hidemi , Jakubowska Anna , Jernström Helena , John Esther M. , Johnson Nichola , Jones Michael E. , Joseph Vijai , Kaaks Rudolf , Kang Daehee , Kim Sung-Won , Kitahara Cari M. , Koppert Linetta B. , Kosma Veli-Matti , Kraft Peter , Kristensen Vessela N. , Kubelka-Sabit Katerina , Koutros Stella , Kurian Allison W. , Kwong Ava , Lacey James V. , Lambrechts Diether , Le Marchand Loic , Li Jingmei , Lubiński Jan , Lush Michael , Mannermaa Arto , Manoochehri Mehdi , Margolin Sara , Matsuo Keitaro , Mavroudis Dimitrios , Michailidou Kyriaki , Milne Roger L. , Mohd Taib Nur Aishah , Mulligan Anna Marie , Neven Patrick , Newman William G. , Obi Nadia , Offit Kenneth , Olshan Andrew F. , Park Sue K. , Park-Simon Tjoung-Won , Patel Alpa V. , Plaseska-Karanfilska Dijana , Poncet Coralie , Prentice Ross L. , Presneau Nadege , Prevos Renate , Pylkäs Katri , Radice Paolo , Rennert Gad , Rennert Hedy S. , Romero Atocha , Saloustros Emmanouil , Sawyer Elinor J. , Schmutzler Rita K. , Schwentner Lukas , Scott Christopher , Shah Mitul , Shen Chen-Yang , Shu Xiao-Ou , Sim Xueling , Southey Melissa C. , Stone Jennifer , Stram Daniel O. , Tamimi Rulla M. , Teo Soo Hwang , Teras Lauren R. , Terry Mary Beth , Tomczyk Katarzyna , Tomlinson Ian , Troester Melissa A. , Truong Thérèse , Vachon Celine M. , van Ongeval Chantal , Wang Qin , Wappenschmidt Barbara , Wendt Camilla , Winqvist Robert , Wolk Alicja , Wu Anna H. , Yadav Siddhartha , Yip Cheng Har , Zheng Wei , Ziogas Argyrios 
Published: January 2023

PURPOSE A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer. METHODS Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer–specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment. RESULTS The PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor–positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent. CONCLUSION An increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.