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

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

Author information

1
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
3
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
4
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
5
Department of Pathology, University of Tokyo Hospital, Tokyo, Japan.
6
Division of Pathology, Cancer Institute, JFCR, Tokyo, Japan.
7
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
8
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
9
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. shuji_ogino@dfci.harvard.edu.
11
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. shuji_ogino@dfci.harvard.edu.
12
Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA. shuji_ogino@dfci.harvard.edu.

Abstract

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.

PMID:
26577117
PMCID:
PMC4747829
[Available on 2017-03-01]
DOI:
10.1245/s10434-015-4967-4
[Indexed for MEDLINE]
Free PMC Article

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