Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study
Authors: Dixon-Suen Suzanne C , Lewis Sarah J , Martin Richard M , English Dallas R , Boyle Terry , Giles Graham G , Michailidou Kyriaki , Bolla Manjeet K , Wang Qin , Dennis Joe , Lush Michael , Investigators ABCTB , Ahearn Thomas U , Ambrosone Christine B , Andrulis Irene L , Anton-Culver Hoda , Arndt Volker , Aronson Kristan J , Augustinsson Annelie , Auvinen Päivi , Beane Freeman Laura E , Becher Heiko , Beckmann Matthias W , Behrens Sabine , Bermisheva Marina , Blomqvist Carl , Bogdanova Natalia V , Bojesen Stig E , Bonanni Bernardo , Brenner Hermann , Brüning Thomas , Buys Saundra S , Camp Nicola J , Campa Daniele , Canzian Federico , Castelao Jose E , Cessna Melissa H , Chang-Claude Jenny , Chanock Stephen J , Clarke Christine L , Conroy Don M , Couch Fergus J , Cox Angela , Cross Simon S , Czene Kamila , Daly Mary B , Devilee Peter , Dörk Thilo , Dwek Miriam , Eccles Diana M , Eliassen A. Heather , Engel Christoph , Eriksson Mikael , Evans D. Gareth , Fasching Peter A , Fletcher Olivia , Flyger Henrik , Fritschi Lin , Gabrielson Marike , Gago-Dominguez Manuela , García-Closas Montserrat , García-Sáenz José A , Goldberg Mark S , Guénel Pascal , Gündert Melanie , Hahnen Eric , Haiman Christopher A , Häberle Lothar , Håkansson Niclas , Hall Per , Hamann Ute , Hart Steven N , Harvie Michelle , Hillemanns Peter , Hollestelle Antoinette , Hooning Maartje J , Hoppe Reiner , Hopper John , Howell Anthony , Hunter David J , Jakubowska Anna , Janni Wolfgang , John Esther M , Jung Audrey , Kaaks Rudolf , Keeman Renske , Kitahara Cari M , Koutros Stella , Kraft Peter , Kristensen Vessela N , Kubelka-Sabit Katerina , Kurian Allison W , Lacey James V , Lambrechts Diether , Le Marchand Loic , Lindblom Annika , Loibl Sibylle , Lubiński Jan , Mannermaa Arto , Manoochehri Mehdi , Margolin Sara , Martinez Maria Elena , Mavroudis Dimitrios , Menon Usha , Mulligan Anna Marie , Murphy Rachel A , Collaborators NBCS , Nevanlinna Heli , Nevelsteen Ines , Newman William G , Offit Kenneth , Olshan Andrew F , Olsson Håkan , Orr Nick , Patel Alpa , Peto Julian , Plaseska-Karanfilska Dijana , Presneau Nadege , Rack Brigitte , Radice Paolo , Rees-Punia Erika , Rennert Gad , Rennert Hedy S , Romero Atocha , Saloustros Emmanouil , Sandler Dale P , Schmidt Marjanka K , Schmutzler Rita K , Schwentner Lukas , Scott Christopher , Shah Mitul , Shu Xiao-Ou , Simard Jacques , Southey Melissa C , Stone Jennifer , Surowy Harald , Swerdlow Anthony J , Tamimi Rulla M , Tapper William J , Taylor Jack A , Terry Mary Beth , Tollenaar Rob A E M , Troester Melissa A , Truong Thérèse , Untch Michael , Vachon Celine M , Joseph Vijai , Wappenschmidt Barbara , Weinberg Clarice R , Wolk Alicja , Yannoukakos Drakoulis , Zheng Wei , Ziogas Argyrios , Dunning Alison M , Pharoah Paul D P , Easton Douglas F , Milne Roger L , Lynch Brigid M 
Published: September 2022

Objectives
Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.

Methods

We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (n
snps
=5) or sedentary time (n
snps
=6), or accelerometer-measured (n
snps
=1) or self-reported (n
snps
=5) vigorous physical activity.

Results
Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).

Conclusion
Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.