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Relationships between Plasma Insulin-like Growth Factor-I and Insulin-like Growth Factor Binding Protein-3 and Second Breast Cancer Risk in a Prevention Trial of Fenretinide

Divisions of Chemoprevention [A. D., H. J.], Breast Surgery [U. V.], and Laboratory Medicine [H. J.], European Institute of Oncology, Milan 20141, Italy; Units of Medical Statistics and Biometry [L. M., R. M.], Chemoprevention [E. C., F. F.], Scientific Director’s Office [T. C.], and Preventive Medicine [M. G. D. M., G. D. P.], Istituto Nazionale Tumori, 20133 Milan, Italy; Division of Breast Surgery, Fondazione Maugeri, 27100 Pavia, Italy [A. C.]; and Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland 20852 [M. P., W. F. M.]

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.

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