Physical activity and risk of breast and endometrial cancers: a Mendelian randomization study

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSThe causality of the association between physical activity and risk of breast and endometrial cancers is uncertain because available evidence is based exclusively on observational studies, which are potentially susceptible to confounding and reverse causation. ObjectiveTo investigate whether increased physical activity is causally associated with decreased risk of breast and endometrial cancers, using a two-sample Mendelian randomization study design. Design, Setting, and ParticipantsGenome-wide association studies of physical activity, breast cancer, and endometrial cancer, published up to April 31, 2019, were identified using PubMed and the GWAS catalog. Twelve single nucleotide polymorphisms (SNP) known at P < 5 x 10-8 to be associated with accelerometer-assessed or self-reported physical activity served as instrumental variables. Genetic summary data from four large consortia provided SNP-outcome associations [Breast Cancer Association Consortium; Discovery, Biology and Risk of Inherited Variants in Breast Cancer Consortium; Endometrial Cancer Association Consortium]. Main Outcomes and MeasuresThe primary outcomes were risk of breast cancer and risk of endometrial cancer. Secondary outcomes were estrogen receptor positive (ER+) and ER-breast cancers. Odds ratios (ORs) and 95% confidence intervals (CIs) per mean acceleration in milli-gravities of accelerometer-assessed physical activity and per one standard deviation (1-SD) increase in metabolic-equivalent (MET)-minutes/week of self-reported moderate-to-vigorous physical activity were computed using the inverse variance weighted method. A series of sensitivity analyses addressed the potential impact of heterogeneity, pleiotropy, and outliers. ResultsSummary data were available for 122,977 breast cancers and 12,270 endometrial cancers. Genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of breast and endometrial cancers. The associations (ORs [95% CI] per 1-SD increase in mean acceleration) were 0.88 (0.85-0.91) for breast cancer and 0.90 (0.83-0.97) for endometrial cancer. In addition, genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of ER+ breast cancer. We found no evidence for an association between genetic predisposition to self-reported physical activity and risk of total breast cancer, breast cancer subtypes, or endometrial cancer. Conclusion and RelevanceThis first Mendelian randomization study shows that objectively-assessed physical activity plays a causal role in protecting against breast and endometrial cancers.