IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405

Abstract

Background: Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.

Methods: Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.

Results: Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; P _nonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; P _trend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; P _trend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; P _trend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (P _nonlinearity = .03).

Conclusions: Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

Figure 1.

Derivation of the study cohort. ^aThe number of blood samples analyzed was based on a priori power calculations estimating that a sample of approximately 1000 patients would provide a power of 0.96 for testing the null hypothesis of independence of 2-year overall survival over quintiles of insulin-like growth factor-1 at a statistical significance level of .05. CALGB = Cancer and Leukemia Group B, now Alliance for Clinical Trials in Oncology.

Figure 2.

Restricted cubic splines depicting hazard ratios for (A) all-cause mortality (OS) as a function of plasma IGFBP-3 concentration and (B) disease progression or mortality (PFS) as function of plasma adiponectin concentration (n = 1086). Hazard ratios treat the median concentrations of adiponectin and IGFBP-3 as reference values. Dashed lines indicate 95% confidence intervals. Models were adjusted for age (continuous variable), sex (female, male), performance status (ECOG 0 vs 1 or 2), planned chemotherapy (FOLFIRI, mFOLFOX6), prior adjuvant chemotherapy (yes, no), assigned treatment arm (bevacizumab, cetuximab, bevacizumab + cetuximab), KRAS status (wild-type, mutant, indeterminate, missing), tumor sidedness (right or transverse colon vs left colon or rectum), plasma albumin (continuous variable), diabetes (yes, no), and body mass index (<20.9, 21-24.9, 25-29.9, 30-34.9, ≥35 kg/m²). The adjusted model for IGFBP-3 is further adjusted for IGF-1 (continuous and nonlinear term). CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; FOLFIRI = leucovorin, fluorouracil, and irinotecan; HR = hazard ratio; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor-binding protein-3; mFOLFOX6 = leucovorin, fluorouracil, and oxaliplatin; OS = overall survival; PFS = progression-free survival.

Figure 3.

Multivariate hazard ratios with 95% confidence intervals for (A) all-cause mortality (overall survival) and (B) disease progression or mortality (progression-free survival) in patients with advanced or metastatic colorectal cancer, stratified across various patient, disease, and treatment characteristics. The forest plot represents the hazard ratios of the comparison of the highest quintile of a given marker (eg, IGFBP-3) to the lowest quintile. Adjusting with Cox proportional hazards regression for age (continuous variable), sex (female, male), performance status (ECOG 0 vs 1 or 2), planned chemotherapy (FOLFIRI, mFOLFOX6), prior adjuvant chemotherapy (yes, no), assigned treatment arm (bevacizumab, cetuximab, bevacizumab + cetuximab), KRAS status (wild-type, mutant, indeterminate/missing), tumor sidedness (right or transverse colon vs left colon or rectum), plasma albumin (continuous variable), diabetes (yes, no), and body mass index (<20.9, 21-24.9, 25-29.9, 30-34.9, ≥35 kg/m²). The adjusted model for IGFBP-3 is further adjusted for IGF-1 (continuous and nonlinear term). BMI = body mass index; ECOG = Eastern Cooperative Oncology Group; FOLFIRI = leucovorin, fluorouracil, and irinotecan; IGF-1 = insulin-like growth factor-1; IGFBP-3 = insulin-like growth factor-binding protein-3; IGFBP-7 = insulin-like growth factor-binding protein-7; MET h/w = metabolic equivalent task-hours per week; mFOLFOX6 = leucovorin, fluorouracil, and oxaliplatin.

Figure 4.

Multivariate hazard ratios with 95% confidence intervals for (A) all-cause mortality (overall survival) and (B) disease progression or mortality (progression-free survival) in patients with advanced or metastatic colorectal cancer, stratified across various molecular tumor markers. The forest plot represents the hazard ratios of the comparison of the highest quintile of a given marker (eg, IGFBP-3) to the lowest quintile. Adjusting with Cox proportional hazards regression for age (continuous variable), sex (female, male), performance status (ECOG 0 vs 1 or 2), planned chemotherapy (FOLFIRI, mFOLFOX6), prior adjuvant chemotherapy (yes, no), assigned treatment arm (bevacizumab, cetuximab, bevacizumab + cetuximab), KRAS status (wild-type, mutant, indeterminate/missing), tumor sidedness (right or transverse colon vs left colon or rectum), plasma albumin (continuous variable), diabetes (yes, no), and body mass index (<20.9, 21-24.9, 25-29.9, 30-34.9, ≥35 kg/m²). The adjusted model for IGFBP-3 is further adjusted for IGF-1 (continuous and nonlinear term). ECOG = Eastern Cooperative Oncology Group; FOLFIRI = leucovorin, fluorouracil, and irinotecan; IGF-1 = insulin-like growth factor-1; IGFBP-3 = insulin-like growth factor-binding protein-3; IGFBP-7 = insulin-like growth factor-binding protein-7; mFOLFOX6 = leucovorin, fluorouracil, and oxaliplatin; MSI = microsatellite instability; MSS = microsatellite stable.