title: Survival Benefit of Exercise Differs by Tumor IRS1 Expression Status in Colorectal Cancer.
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.
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hanyuda
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martinez-Fernandez
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.|Department of Pathology, University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.|Division of Pathology, Cancer Institute, JFCR, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.|Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.|Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.|Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. shuji_ogino@dfci.harvard.edu.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. shuji_ogino@dfci.harvard.edu.|Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA. shuji_ogino@dfci.harvard.edu.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000628:therapy; D019175:DNA Methylation; D005081:Exercise Therapy / Q000401:mortality*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins