Insulin and related factors in breast-cancer mortality

background. High levels of insulin have been associated with increased risk of breast cancer, and poorer survival after a diagnosis of breast cancer. To study possible modifiable factors affecting breast cancer survival, in 1991 data and sera were collected from 603 breast cancer patients and archived. The current study made use of these prospective 10-year cohort data to test the prognostic value of insulin and C-peptide levels and related lifestyle factors in breast cancer survival. Objectives. The primary aim of this study was to test the hypothesis that elevated insulin at diagnosis is directly related to breast cancer mortality, as well as insulin-related factors including body size and shape, dietary intake and physical inactivity. A secondary aim was to describe the effect on mortality of changes made in the hyperinsulinernia-related lifestyle factors of dietary intake and body size during the first 2 years post-diagnosis. Methods. Using a prospective design, outcomes for cohort members were ascertained by linkage to the BC Cancer Registry and Cancer Agency Information System (CAIS). The primary outcome of interest was breast-cancer mortality, but all-cause mortality was also examined. Archived sera were tested for insulin, C-peptide (an index of insulin secretion), fmctosamine (a marker of glycemia over the previous 1 to 3 weeks) and SHBG (sex hormone binding globulin) by personnel blinded to participant outcomes. Lifestyle data, including dietary, physical activity and body size factors were analysed using Cox proportional hazards models to relate the prognostic markers to outcomes, controlling for potential confounders such as age, tumour stage, and menopausal status. Data for the biological variables were analyzed as a nested case-control study due to limited serum volumes, with at least one survivor as a control for each breast cancer death, matched on stage at diagnosis and length of follow-up. Results. Serum insulin levels at diagnosis were directly related to breast-cancer mortality in post-menopausal women, with evidence of a non-linear relationship (OR, 5.2; 95% CI, 1.0- 27.8 for the 2n d quartile; OR, 5.0; 95% CI, 1.0-24.4 for the 3rd quartile; OR, 2.6; 95% CI, 0.4, 14.6 for 4th quartile, compared with the 1st quartile), but no relationship was observed in premenopausal women. No significant association with breast-cancer mortality was observed for C-peptide, fmctosamine or SHBG levels at diagnosis. Increased waist-to-hip ratio (WHR) at diagnosis was directly related to both breast-cancer mortality (RR, 3.2; 95% CI, 1.3-8.1 comparing highest quartile to lowest quartile) and all-cause mortality (RR, 2.6; 95% CI, 1.3-5.1) in post-menopausal women, but not in pre-menopausal women (RR, 1.0; 95% CI, 0.4-2.7), independent of age and body-mass index (BMI). The association was restricted to women with estrogen receptor (ER)-positive tumours. Dietary intake of total fat and saturated fat was direcdy related to breast-cancer mortality in pre-menopausal women (RR, 4.8; 95% CI, 1.3- 18.1, comparing highest to lowest quartile of total fat intake), but not in post-menopausal women. Dietary protein intake was inversely related to breast-cancer mortality (RR, 0.4; 95% CI, 0.2-0.8) for all women. No significant association with breast-cancer mortality was found for BMI, physical activity, dietary intake of carbohydrate, fiber, alcohol, total energy or glycemic load (glycemic index times number of grams) at diagnosis. Analysis of changes made during the first 2 years post-diagnosis showed that only changes in BMI were significantly related to mortality, where a decrease of 5% or more was associated with more risk (RR, 4.1; 95% CI, 1.3-13.0 for pre-menopausal women; RR, 2.5; 95% CI, 1.0-5.8 for post-menopausal women) than an increase of 5% or more (RR, 2.0; 95% CI, 0.8-5.0 for pre-menopausal women; RR, 1.6; 95% CI, 0.8-3.4 for post-menopausal women), compared with no change (plus or minus less than 5%). Conclusions. The results are consistent with the study hypothesis, supporting an association between hyperinsulinemia and breast-cancer mortality, modified by menopausal status and ER tumour subtype.Medicine, Faculty ofPopulation and Public Health (SPPH), School ofGraduat