Circulating Levels of Insulin-like Growth Factors, their Binding Proteins, and Breast Cancer Risk

Abstract
Background: Earlier data support the hypothesis that the relation between circulating insulin-like growth factor-I (IGF-I) levels and breast cancer risk differs by menopausal status. The strong association of IGF-I with height in childhood and weak or no association between adult levels and adult height also suggest that IGF levels in young women may better reflect an exposure time period of importance to breast cancer. Few studies have assessed IGF binding protein-1 (IGFBP-1) or free IGF and breast cancer risk. Materials and Methods: We conducted a large case-control study nested within the prospective Nurses' Health Study. Plasma concentrations of IGF-I, free IGF, IGFBP-3, and IGFBP-1 were measured in blood samples collected in 1989 to 1990. Eight hundred women were identified who had a diagnosis of invasive or in situ breast cancer after blood collection, up to 1998, 27% of whom were premenopausal at blood collection. To those 800 women, one to two controls were age-matched for a total of 1,129 controls. We used logistic regression models to estimate the relative risk (RR) of breast cancer associated with IGF levels. Findings: Among postmenopausal women, neither IGF-I, IGFBP-3, IGFBP-1, nor free IGF was associated with breast cancer risk [RRs, top versus bottom quintile: IGF-I, 1.0; 95% confidence interval (95% CI), 0.7-1.4; IGFBP-3, 0.8; 95% CI, 0.6-1.1; IGFBP-1, 0.9; 95% CI, 0.6-1.5; and free IGF, 1.0; 95% CI, 0.6-1.4]. Among premenopausal women, IGFBP-3, IGFBP-1, and free IGF similarly were not associated with breast cancer risk (RRs, top versus bottom quintile: IGFBP-3, 1.2; 95% CI, 0.8-2.3; IGFBP-1, 1.5; 95% CI, 0.8-3.0; and free IGF, 1.1; 95% CI, 0.7-2.1). Higher IGF-I plasma levels, however, were associated with a modestly elevated breast cancer risk (RR, 1.6; 95% CI, 1.0-2.6) among the premenopausal women, with a stronger association among premenopausal women ages ≤50 (RR, 2.5; 95% CI, 1.4-4.3); further adjustment for IGFBP-3 did not greatly change these estimates. Interpretation: Circulating IGF-I levels seem to be modestly associated with breast cancer risk among premenopausal women, but not among postmenopausal women. IGFBP-3, IGFBP-1, and free IGF are not associated with breast cancer risk in either premenopausal or postmenopausal women in this cohort.

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