Response of the insulin-like growth factor (IGF) system to IGF-IR inhibition and androgen deprivation in a neoadjuvant prostate cancer trial: effects of obesity and androgen deprivation

Abstract

Context: Prostate cancer patients at increased risk for relapse after prostatectomy were treated in a neoadjuvant study with androgen deprivation therapy (ADT) in combination with cixutumumab, an inhibitory fully human monoclonal antibody against IGF receptor 1 (IGF-IR).

Objective: A clinical trial with prospective collection of serum and tissue was designed to test the potential clinical efficacy of neoadjuvant IGF-IR blockade combined with ADT in these patients. The effect of body mass index (BMI) on response of IGF-IR/insulin components to IGF-IR blockade was also examined.

Design: Eligibility for the trial required the presence of high-risk prostate adenocarcinoma. Treatment consisted of bicalutamide, goserelin, and cixutumumab for 13 weeks before prostatectomy. Here we report on an analysis of serum samples from 29 enrolled patients. Changes in IGF and glucose homeostasis pathways were compared to control samples from patients in a concurrent clinical trial of neoadjuvant ADT alone.

Results: Significant increases were seen in GH (P = .001), IGF-I (P < .0001), IGF-II (P = .003), IGF binding protein (IGFBP)-3 (P < .0001), C-peptide (P = .0038), and insulin (P = .05) compared to patients treated with ADT alone. IGFBP-1 levels were significantly lower in the cixutumumab plus ADT cohort (P = .001). No significant changes in blood glucose were evident. Patients with BMIs in the normal range had significantly higher GH (P < .05) and IGFBP-1 (P < 0.5) levels compared to overweight and obese patients.

Conclusions: Patients with IGF-IR blockade in combination with ADT demonstrated significant changes in IGF and glucose homeostasis pathway factors compared to patients receiving ADT alone. In the patients receiving combination therapy, patients with normal BMI had serum levels of glucose homeostasis components similar to individuals in the ADT-alone cohort, whereas patients with overweight and obese BMIs had serum levels that differed from the ADT cohort.

Trial registration: ClinicalTrials.gov NCT00298155 NCT00769795.

Figures

Figure 1.

A, Effects of IGF-IR blockade and hormone therapy on IGF pathway homeostasis. Serum levels of GH, IGF-I, IGF-II, and IGFBP-3 were measured by ELISA. *P < .05, **P < .01, ***P < .001, ****P < .0001, NeoADT cohort compared to NeoADT plus A12 (cixutumumab) cohort. B, Effects of IGF-IR blockade and hormone therapy on glucose homeostasis and insulin activity. Serum levels of blood glucose, insulin, C-peptide, and IGFBP-1 were determined by ELISA. *P < 0.05, **P < 0.01, NeoADT cohort compared to NeoADT plus A12 cohort.

Figure 2.

BMI affects serum components of the IGF and glucose homeostasis pathways. Patients were divided based on established BMI categories of normal weight (18.0–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (>30 kg/m2). *P < .01, significant differences among all 3 groups using one-way ANOVA. #, Trending toward significance (P = .06). No changes in blood glucose, insulin, or C-peptide were seen in the normal-weight group. In contrast, overweight and obese patients trended toward increased levels of blood glucose (overweight, P = .08; obese, P = .07), insulin (overweight, P = .09; obese, P = .11), and C-peptide (overweight, P = .07; obese, P = .07) during treatment.