Survival Benefit of Exercise Differs by Tumor IRS1 Expression Status in Colorectal Cancer

Ann Surg Oncol. 2016 Mar;23(3):908-17. doi: 10.1245/s10434-015-4967-4. Epub 2015 Nov 17.


Background: High-level physical activity is associated with lower colorectal cancer (CRC) mortality, likely through insulin sensitization. Insulin receptor substrate 1 (IRS1) 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, long interspersed nucleotide element-1 (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 CRC-specific mortality analysis (P interaction = 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 the IRS1-negative group, 0.45 (0.19-1.03) in the IRS1-low group, and 1.32 (0.50-3.53) in the 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 an increased level of exercise.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / mortality*
  • Colorectal Neoplasms / therapy
  • DNA Methylation
  • Exercise Therapy / mortality*
  • Female
  • Follow-Up Studies
  • Humans
  • Immunoenzyme Techniques
  • Insulin Receptor Substrate Proteins / metabolism*
  • Long Interspersed Nucleotide Elements
  • Male
  • Microsatellite Instability
  • Mutation / genetics
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Prospective Studies
  • Survival Rate
  • Tissue Array Analysis


  • Biomarkers, Tumor
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins