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Background High level physical activity is associated with lower colorectal cancer mortality, likely through insulin sensitization. IRS1 (insulin receptor substrate 1) is a mediator of insulin and insulin-like growth factor (IGF) signaling pathways, and its down-regulation is associated with insulin resistance. Therefore, we hypothesized that tumor IRS1 expression status might modify cellular sensitivity to insulin and IGF, and the prognostic association of physical activity. Methods We assessed IRS1 expression level in 371 stage I–III rectal and colon cancers in the Nurses’ Health Study and the Health Professionals Follow-up Study by immunohistochemistry. In survival analysis, Cox proportional hazards model was used to assess an interaction between post-diagnosis physical activity (ordinal scale of sex-specific quartiles Q1 to Q4) and IRS1 expression (ordinal scale of negative, low, and high), controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, and KRAS, BRAF and PIK3CA mutation status. Results There was a statistically significant interaction between post-diagnosis physical activity and tumor IRS1 expression in colorectal cancer-specific mortality analysis (Pinteraction=0.005). Multivariable hazard ratio (95% confidence interval) for higher post-diagnosis physical activity (Q3–Q4 vs. Q1–Q2) was 0.15 (0.02–1.38) in IRS1-negative group, 0.45 (0.19–1.03) in IRS1-low group, and 1.32 (0.50–3.53) in IRS1-high group. Conclusions The association of post-diagnosis physical activity with colorectal carcinoma patient survival may differ by tumor IRS1 expression level. If validated, tumor IRS1 expression status may serve as a predictive marker to identify subgroups of patients who might gain greater survival benefit from increased level of exercise.

MMP-7 predicts recurrence in curatively resected CRC patients.