Akiko Hanyuda1, Sun A Kim2, Alejandro Martinez-Fernandez2, Zhi Rong Qian2, Mai Yamauchi2, Reiko Nishihara1,2,3,4, Teppei Morikawa2,5, Xiaoyun Liao2, Kentaro Inamura2,6, Kosuke Mima2, Yin Cao1,7,8, Xuehong Zhang2,9, Kana Wu1, Andrew T Chan2,7,8,9, Edward L Giovannucci1,4, Jeffrey A Meyerhardt2, Charles S Fuchs2,9, Ramesh A Shivdasani2, Shuji Ogino10,11,12. 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.
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 tumorIRS1 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 tumorIRS1 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 carcinomapatient survival may differ by tumorIRS1 expression level. If validated, tumorIRS1 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.
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