Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment
Authors: Morra Anna , Escala-Garcia Maria , Beesley Jonathan , Keeman Renske , Canisius Sander , Ahearn Thomas U. , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Auer Paul L. , Augustinsson Annelie , Beane Freeman Laura E. , Becher Heiko , Beckmann Matthias W. , Behrens Sabine , Bojesen Stig E. , Bolla Manjeet K. , Brenner Hermann , Brüning Thomas , Buys Saundra S. , Caan Bette , Campa Daniele , Canzian Federico , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Cheng Ting-Yuan David , Clarke Christine L. ,   NBCS Collaborators, Børresen-Dale Anne-Lise , Sahlberg Kristine K. , Ottestad Lars , Kåresen Rolf , Schlichting Ellen , Holmen Marit Muri , Sauer Toril , Haakensen Vilde , Engebråten Olav , Naume Bjørn , Fosså Alexander , Kiserud Cecile E. , Reinertsen Kristin V. , Helland Åslaug , Riis Margit , Geisler Jürgen , Grenaker Alnæs Grethe I. , Colonna Sarah V. , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Dennis Joe , Dörk Thilo , Dossus Laure , Dunning Alison M. , Dwek Miriam , Eccles Diana M. , Ekici Arif B. , Eliassen A. Heather , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Flyger Henrik , Fritschi Lin , Gago-Dominguez Manuela , García-Sáenz José A. , Giles Graham G. , Grip Mervi , Guénel Pascal , Gündert Melanie , Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Hart Steven N. , Hartikainen Jaana M. , Hartmann Arndt , He Wei , Hooning Maartje J. , Hoppe Reiner , Hopper John L. , Howell Anthony , Hunter David J. ,   ABCTB Investigators, Clarke Christine , Marsh Deborah , Scott Rodney , Baxter Robert , Yip Desmond , Carpenter Jane , Davis Alison , Pathmanathan Nirmala , Simpson Peter , Graham J. Dinny , Sachchithananthan Mythily ,   kConFab Investigators, Jager Agnes , Jakubowska Anna , Janni Wolfgang , John Esther M. , Jung Audrey Y. , Kaaks Rudolf , Keupers Machteld , Kitahara Cari M. , Koutros Stella , Kraft Peter , Kristensen Vessela N. , Kurian Allison W. , Lacey James V. , Lambrechts Diether , Le Marchand Loic , Lindblom Annika , Linet Martha , Luben Robert N. , Lubiński Jan , Lush Michael , Mannermaa Arto , Manoochehri Mehdi , Margolin Sara , Martens John W. M. , Martinez Maria Elena , Mavroudis Dimitrios , Michailidou Kyriaki , Milne Roger L. , Mulligan Anna Marie , Muranen Taru A. , Nevanlinna Heli , Newman William G. , Nielsen Sune F. , Nordestgaard Børge G. , Olshan Andrew F. , Olsson Håkan , Orr Nick , Park-Simon Tjoung-Won , Patel Alpa V. , Peissel Bernard , Peterlongo Paolo , Plaseska-Karanfilska Dijana , Prajzendanc Karolina , Prentice Ross , Presneau Nadege , Rack Brigitte , Rennert Gad , Rennert Hedy S. , Rhenius Valerie , Romero Atocha , Roylance Rebecca , Ruebner Matthias , Saloustros Emmanouil , Sawyer Elinor J. , Schmutzler Rita K. , Schneeweiss Andreas , Scott Christopher , Shah Mitul , Smichkoska Snezhana , Southey Melissa C. , Stone Jennifer , Surowy Harald , Swerdlow Anthony J. , Tamimi Rulla M. , Tapper William J. , Teras Lauren R. , Terry Mary Beth , Tollenaar Rob A. E. M. , Tomlinson Ian , Troester Melissa A. , Truong Thérèse , Vachon Celine M. , Wang Qin , Hurson Amber N. , Winqvist Robert , Wolk Alicja , Ziogas Argyrios , Brauch Hiltrud , García-Closas Montserrat , Pharoah Paul D. P. , Easton Douglas F. , Chenevix-Trench Georgia , Schmidt Marjanka K. 
Published: August 2021

Abstract
Background
Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.

Methods
We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).

Results
Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.

Conclusions
We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.