Premenopausal levels of circulating insulin-like growth factor I and the risk of postmenopausal breast cancer: A population-based, nested case-control study.

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OBJECTIVE: Increased levels of insulin-like growth factor I (IGF-I) have been implicated in the development of breast cancer, as IGF-I may directly stimulate the proliferation of breast cells and promote growth and survival of transformed cells. Higher circulating levels of IGF-I have been associated with increased risk premenopausal breast cancer but not postmenopausal breast cancer. However, most studies of postmenopausal breast cancer have been based on postmenopausal IGF-I levels. We investigated whether circulating levels of IGF-I prior to menopause are associated with breast cancer diagnosed after menopause in a population-based nested case-control study. METHODS: Cohort participants were enrolled and blood was drawn in 1974 (n = 15,192) and 1989 (n=18,724). Cases were defined as women diagnosed with a primary breast cancer at ages ≥ 55 with no prior history of cancer. Cases diagnosed through May 2001 were identified using population-based cancer registries. One control was individually matched to each case on cohort participation, age, race, menopausal status and date at blood draw. Controls were cancer-free up to the time of cases’ diagnosis. After 27 years of follow-up, we identified 152 postmenopausal cases who were premenopausal at the time of blood draw. Levels of IGF-I and IGF binding protein 3 (IGFBP-3) were measured using ELISA assays, and tertiles were calculated based on the controls. The association between IGF-I and breast cancer was determined using conditional logistic regression, adjusting for IGFBP-3. RESULTS: IGF-I levels decreased with age (p=0.0001). Increased IGF-I levels measured prior to menopause were weakly associated with postmenopausal breast cancer (middle vs. lowest third of IGF-I: OR=1.18, 95% CI= 0.69-2.03; upper third: OR= 1.60, 95% CI= 0.86-2.99, p trend=0.14). A stronger dose-response between premenopausal IGF-I levels and postmenopausal breast cancer was observed among women 25-36 years old at the time of blood draw (middle vs. lowest third of IGF-I: OR= 2.88, 95% CI= 0.54-15.50; upper third: OR= 5.31, 95% CI= 0.85-33.13; p trend= 0.06). CONCLUSION: Increased circulating levels of IGF-I measured prior to menopause were positively associated with postmenopausal breast cancer, especially among younger women. Early-life exposure to IGF-I may be an important predictor of postmenopausal breast cancer.