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Plasma Insulin-like Growth Factors, Insulin-like Binding Protein-3, and Outcome in Metastatic Colorectal Cancer: Results from Intergroup Trial N9741

Authors' Affiliations: ¹ Department of Medical Oncology, Dana-Farber Cancer Institute and ² Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; ³ Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ⁴ Department of Health Sciences Research, North Central Cancer Treatment Group and ⁵ Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota; ⁶ Research Institute of Jewish General Hospital and McGill University, Montreal, Quebec, Canada

Requests for reprints: Charles S. Fuchs, Dana-Farber Cancer Institute, Boston, MA 02115. Phone: 617-632-5840; Fax: 617-632-5370; E-mail: cfuchs{at}partners.org.

Purpose: Insulin-like growth factor (IGF)-I and IGF-II stimulate neoplastic cell growth and inhibit apoptosis, whereas IGF-binding protein-3 (IGFBP-3) inhibits the bioavailability of IGF-I and has independent proapoptotic activity. We examined the influence of baseline plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide on outcome among patients receiving first-line chemotherapy for metastatic colorectal cancer.

Experimental Design: The plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide as well as data on prognostic factors and body size were measured at baseline among 527 patients participating in a randomized trial of first-line chemotherapy for metastatic colorectal cancer.

Results: Higher baseline plasma IGFBP-3 levels were associated with a significantly greater chemotherapy response rate (P = 0.03) after adjusting for other prognostic factors, whereas neither IGF-I nor IGF-II levels significantly predicted tumor response. Higher levels of IGF-I, IGF-II, and IGFBP-3 were all univariately associated with improved overall survival (P = 0.0001 for all). In a model that mutually adjusted for IGF-I and IGFBP-3, as well as other prognostic factors, increasing baseline-circulating IGFBP-3 was associated with a significantly longer time to tumor progression (P = 0.03), whereas circulating IGF-I was not associated with disease progression (P = 0.95). Levels of C-peptide were not associated with any measure of patient outcome.

Conclusion: Among colorectal cancer patients receiving first-line chemotherapy, increasing levels of IGFBP-3, an endogenous antagonist to IGF-I, are associated with an improved objective treatment response and a prolonged time to cancer progression. The IGF pathway may represent an important target for future treatment strategies.