ABSTRACT
PURPOSE: High circulating insulin-like growth factor (IGF) -I and/or low IGF-binding protein (IGFBP) -3 levels are associated with increased breast cancer risk in unaffected premenopausal women. We determined whether IGF-I and IGFBP-3 predict second breast cancer risk, and whether their changes during fenretinide explain observed reductions in second breast cancer in women =50 years of age. EXPERIMENTAL DESIGN: Within a Phase III trial, we measured baseline and 1-year levels of IGF-I, IGFBP-3, and their ratio in 302 subjects on fenretinide and 220 controls who provided plasma samples. The prognostic effect of IGF-I and IGFBP-3, and the surrogate effect of IGF-I during fenretinide were assessed by Cox models after 9.4 years. RESULTS: Among controls, high IGF-I and low IGFBP-3 were associated with elevated second breast cancer risk [top versus bottom tertile, IGF-I, hazard ratio (HR) = 1.94, 95% confidence interval (CI), 0.87-4.31, P = 0.105; and IGFBP-3, HR = 0.40, 95% CI, 0.18-0.93, P = 0.033]. Fenretinide induced reductions of IGF-I, IGFBP-3, and IGF-I:IGFBP-3 of 8% (95% CI, 2-12%; P = 0.004), 3% (95% CI, 1-5%; P = 0.002), and 5% (95% CI, 0-10%; P = 0.050), respectively. Second breast cancer risk was reduced by 39% (HR = 0.61; 95% CI, 0.40-0.94; P = 0.026). The percentage of treatment effect explained by IGF-I and IGF-I:IGFBP-3 reductions were 4.8% (95% CI, 0.8-28.9%) and 3.1% (95% CI, 0.5-20.8%), respectively. CONCLUSIONS: Fenretinide induced a moderate reduction of IGF-I, which marginally explains observed cancer risk reductions in women =50 years of age. In this age group high IGF-I and particularly low IGFBP-3 levels predict second breast cancer risk.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Breast Neoplasms/prevention & control , Breast Neoplasms/secondary , Fenretinide/therapeutic use , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/biosynthesis , Adult , Female , Humans , Middle Aged , Neoplasm Metastasis/prevention & control , Premenopause , Prognosis , Proportional Hazards Models , Risk , Time FactorsABSTRACT
BACKGROUND: Dysplastic oral leukoplakia (DOL) has been the index lesion in prevention trials for upper aerodigestive tract squamous cell carcinoma (SCC). Vitamin A derivatives, including 13-cis retinoic acid (13-CRA), have been used to treat DOL and to reduce the risk of subsequent SCC. Results from a trial of 13-CRA in patients with DOL are presented here. Transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor messenger RNA (mRNA) expression were studied to validate their use as surrogate endpoint biomarkers in prevention trials for SCC. STUDY DESIGN: In a prospective, randomized, double-blind trial of 13-CRA in 28 patients with DOL, TGF-alpha and epidermal growth factor receptor mRNA expression were analyzed in sequential biopsy specimens of DOL and of adjacent normal-appearing mucosa, utilizing a quantitative, competitive, reverse transcriptase polymerase chain reaction and were compared using the Wilcoxon signed-rank test for paired comparisons. RESULTS: In biopsy specimens of DOL, TGF-alpha mRNA expression at baseline, but not baseline expression of epidermal growth factor receptor mRNA, was significantly elevated when compared with its expression in specimens from adjacent normal-appearing mucosa (p = 0.003). In patients randomized to 13-CRA who had > or = 50% clearance of DOL during treatment, significant modulation of TGF-alpha mRNA overexpression was seen after 6 months of treatment (p = 0.016). TGF-alpha mRNA overexpression at baseline predicted a subsequent response to 13-CRA (p 0.066). CONCLUSIONS: The full extent of the association between TGF-alpha overexpression and the development of SCC is unknown. Evidence is presented in this article that TGF-alpha overexpression mediates the relationship between 13-CRA and DOL, but there is no direct evidence that it mediates the relationship between 13-CRA and the prevention of SCC. Determination of the extent to which TGF-alpha overexpression mediates this relationship and complete validation of TGF-alpha's role as a surrogate endpoint biomarker await the results of animal and human trials that utilize reduction in the incidence of SCC as their endpoint.