Physical inactivity in ovarian carcinogenesis

Background: Recreational physical activity is not currently recognized as a protective or prognostic factor associated with epithelial ovarian cancer (EOC) risk or survival. To address current gaps in the scientific literature, we undertook a comprehensive research project to further investigate a potential role for recreational physical inactivity in epithelial ovarian carcinogenesis. Methods: First, we conducted a pooled analysis utilizing individual-level data from 11 studies (N=9024 cases and N=13643 controls) within the Ovarian Cancer Association Consortium (OCAC) to examine the association between recreational physical inactivity with EOC risk. Next, we pooled individual-level data from 12 OCAC studies to investigate the association between chronic, pre-diagnostic recreational physical inactivity with mortality and disease progression among 6,806 patients diagnosed with invasive EOC. Lastly, in the context that adiponectin and leptin have been touted as potential mediators of the association between physical activity and cancer endpoints, we conducted a case-control pilot study (N=153) at Roswell Park Cancer Institute (RPCI) to examine a potential role of dysregulated adiponectin and leptin concentrations in ovarian carcinogenesis. Results: We observed a significant positive association between self-reported recreational physical inactivity and risk of epithelial ovarian cancer (OR=1.39, 95% CI: 1.18--1.63) and the association remained significant and was similar in magnitude in subgroup analyses for all EOC histotypes. We also observed a significant positive association between self-reported physical inactivity with risk of all-cause mortality and disease progression: HR=1.22 (95% CI: 1.12--1.33) and HR=1.20 (95% CI: 1.08--1.33), respectively. Significant associations between inactivity and EOC outcomes were observed for EOC overall and among patients with high-grade serous and clear cell tumors. In both pooled analyses, the observed associations between inactivity and EOC endpoints were robust to confounding and were consistently observed in sensitivity analyses designed to reduce bias. Furthermore, we observed no statistical evidence of effect modification in subgroup analyses by BMI classification or tumor characteristics. Lastly, in the case-control pilot study conducted at RPCI, EOC patients had significantly lower mean levels of leptin (p=0.01) and significantly higher A:L ratios (p=0.01). In mediation analyses, we observed a significant association between inactivity and EOC risk (OR=2.74, 95% CI: 1.15--6.52, p=0.023), but there was no convincing statistical evidence suggesting that adiponectin and leptin mediated the observed association. Conclusions: In this series of studies investigating the role of physical inactivity and adipokines in epithelial ovarian carcinogenesis, we observed consistent evidence of a positive association between recreational physical inactivity with EOC risk, mortality and disease progression. Importantly, these associations appear to exert an effect via biological pathways that are, at least in part, independent of obesity and adiponectin and leptin.