Abstract 1309: Association between insulin resistance and breast cancer risk: A Mendelian randomization analysis of data from 228,000 women of European descent

Abstract

Abstract Background: Epidemiologic studies suggest that insulin resistance may be associated with breast cancer risk. We conducted Mendelian randomization (MR) analyses to reduce the biases associated with previous studies and provide evidence for causal inference. Materials and Methods: We used genetic variants identified in genome-wide association studies for circulating fasting insulin (15 variants), early insulin secretion (16 variants), fasting proinsulin (8 variants), fasting glucose (35 variants), and 2-hour glucose (8 variants) as instruments in MR analyses. To reduce possible pleiotropic effects, variants associated with obesity were removed from the instruments. We first evaluated the association of these instruments with type 2 diabetes risk in 110,452 subjects to assess instrument validity. We then investigated the association of these instruments with breast cancer risk using data obtained from 122,977 cases and 105,974 controls of European descent included in the Breast Cancer Association Consortium (BCAC). Odds ratios (OR) were calculated to measure the associations of instrumental variables with risk of overall breast cancer and its subtypes defined by estrogen-receptor [ER] status. Results: All instrumental variables constructed for this study were strongly associated with type 2 diabetes risk with ORs of 3.01 (p=7.86x10-5), 0.22 (p=3.54x10-14), 1.90 (p=8.28x10-4), 6.11 (p=3.59x10-19), and 1.91 (p=6.8x10-16) for per unit increase of fasting insulin, early insulin secretion, fasting proinsulin, fasting glucose, and 2-hour glucose levels, respectively. Statistically significant associations with overall breast cancer risk were found for fasting insulin (OR=1.36 for per unit increase, 95% CI=1.09-1.70, p=0.011) and fasting proinsulin (OR=1.21, 95% CI=1.06- 1.38, p=0.011). These associations were observed only for ER-positive breast cancer. No statistically significant association at p<0.05 was found for early insulin secretion, fasting glucose, or 2-hour glucose levels. Conclusions: Our study provides strong support that certain insulin resistance traits may be causally associated with risk of breast cancer, particularly ER-positive breast cancer. Citation Format: Xiang Shu, Lang Wu, Nikhil K. Khankari, Kyriaki Michailidou, Manjeet K. Bolla, Jean Wang, Joe Dennis, Xiao-ou Shu, Jacques Simard, Douglas F. Easton, Wei Zheng. Association between insulin resistance and breast cancer risk: A Mendelian randomization analysis of data from 228,000 women of European descent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1309. doi:10.1158/1538-7445.AM2017-1309