The influence of overweight and insulin resistance on localised and advanced breast cancer risk: A prospective study

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The exact mechanisms responsible for the complexity of the effect of overweight and obesity on breast cancer risk remain unknown. Excess weight has a number of metabolic consequences including development of insulin resistance and hyperinsulinemia, impaired glucose metabolism, hypertension and altered concentrations of circulating adipocytokines. So far, relatively few prospective epidemiologic studies have examined how these different metabolic components may be related to breast cancer risk and tumor progression, and the results have been largely inconclusive. We conducted a case-control study nested in a prospective cohort recruited during 1985-2005 in Northern Sweden, to investigate the associations of breast cancer risk with body mass index (BMI), leptin, adiponectin, C-peptide, glycated hemoglobin (HbA1c) and hypertension. We also examined whether these associations may be modified by tumor progression status (localized vs. advanced) and estrogen and progesterone receptor status. During follow-up, 561 women developed invasive breast cancer and 561 controls were selected after matching on age, subcohort and time between blood sampling and blood analysis. Conditional logistic regression was used to calculate odds ratios (OR) as estimates of relative risk and 95% confidence intervals (CI). Further adjustment was made for BMI and HRT use, whilst number of births and age at first delivery were also examined as potential confounders. Cases had a median age of 52.5 years at recruitment, and during follow-up the median time to diagnosis was 4.4 years. There was significant heterogeneity of the breast cancer association with BMI, leptin, C-peptide, HbA1c and diastolic blood pressure, according to whether the breast tumor was localized or advanced at diagnosis (Pheterogeneity all <0.05 in crude models). For advanced disease, the multivariate-adjusted ORs when comparing the highest versus the lowest tertile was for BMI = 1.26 (95% CI 0.83-1.90), leptin = 1.61 (95% CI 1.07-2.44), C-peptide = 1.38 (95% CI 0.94-2.01), HbA1c = 0.91 (95% CI 0.58-1.42) and diastolic blood pressure = 1.82 (95% CI 0.92-3.62). For localized disease, the multivariate-adjusted ORs when comparing the highest versus the lowest tertile was for BMI = 0.47 (95% CI 0.29-0.77), leptin = 0.70 (95% CI 0.44-1.12), C-peptide = 0.83 (95% CI 0.54-1.29), HbA1c = 0.46 (95% CI 0.27-0.76) and diastolic blood pressure = 0.61 (95% CI 0.30-1.24). Adiponectin was not statistically significantly related to risk. There was no evidence for effect modification by tumor receptor status. This prospective study supports a role for BMI, leptin, insulin and blood pressure in breast tumor progression.