Originally published as JCO Early Release 10.1200/JCO.2008.17.9945 on December 8 2008

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Insulin, the Insulin-Like Growth Factor Axis, and Mortality in Patients With Nonmetastatic Colorectal Cancer

Brian M. Wolpin, Jeffrey A. Meyerhardt, Andrew T. Chan, Kimmie Ng, Jennifer A. Chan, Kana Wu, Michael N. Pollak, Edward L. Giovannucci, Charles S. Fuchs

From the Department of Medical Oncology, Dana-Farber Cancer Institute; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; Gastrointestinal Unit, Massachusetts General Hospital; Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA; and the Department of Medicine and Oncology, Jewish General Hospital and McGill University, Montreal, Quebec, Canada

Corresponding author: Brian Wolpin, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: bwolpin{at}partners.org

Purpose Obesity, sedentary lifestyle, and Western dietary pattern have been linked to increased risk of cancer recurrence and mortality among patients with surgically resected colorectal cancer. Excess energy balance leads to increased circulating insulin and depressed levels of circulating insulin-like growth factor binding protein (IGFBP) -1, which promote cancer cell growth in preclinical models.

Patients and Methods Among 373 patients diagnosed with nonmetastatic colorectal cancer between 1991 and 2004, we performed a prospective observational study nested within two large US cohorts to evaluate the association between mortality and prediagnosis circulating C-peptide (a marker of insulin secretion), IGFBP-1, insulin-like growth factor-I (IGF-I), and IGFBP-3.

Results Compared with patients in the bottom quartile, patients in the top quartile of plasma C-peptide had an age-adjusted hazard ratio (HR) for death of 1.87 (95% CI, 1.04 to 3.36; P = .03 for trend), whereas those in the top quartile of circulating IGFBP-1 had a significant reduction in mortality (HR = 0.48; 95% CI, 0.28 to 0.84; P = .02 for trend). Little change in these estimates was noted after adjusting for other covariates known or suspected to influence survival. No associations were noted between mortality and IGF-I or IGFBP-3, which are two components of the IGF axis not closely correlated with lifestyle factors.

Conclusion Among patients with surgically resected colorectal cancer, higher levels of prediagnosis plasma C-peptide and lower levels of prediagnosis plasma IGFBP-1 were associated with increased mortality. Circulating insulin and IGFBP-1 are potential mediators of the association between lifestyle factors and mortality after colorectal cancer resection.

published online ahead of print at www.jco.org on December 8, 2008.

Supported by Grants No. CA118553, CA87969, CA108341, CA127003-01, and CA09001 from the National Cancer Institute, National Institutes of Health, Bethesda, MD.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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