Abstract Background: Obesity is associated with breast cancer (BC) in postmenopausal women, but its relationship with intrinsic subtype is unclear. We examined associations of body mass index (BMI) with intrinsic subtype and expression of selected genes among women with invasive BC. Methods: A case-cohort of 1,676 BC patients was sampled from two prospective Kaiser Permanente Northern California cohorts: LACE (AJCC stage I (≥1 cm), II, IIIA diagnosed 1997-2000) and Pathways (invasive stage ≥0.5 cm diagnosed 2006-2008). The PAM50 quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) assay was used to: a) classify tumors into intrinsic subtype (Luminal A, Luminal B, Basal-like, HER2-E, Normal-like) and b) assess gene expression levels for ESR1, PGR, ERBB2, and a composite of 10 proliferation genes. BMI was from self-reported weight and height within one year prior to BC diagnosis and categorized as: normal (<25 kg/m2), overweight (25-29 kg/m2), obese (30-34 kg/m2), and highly obese (≥35 kg/m2). Using multinomial logistic regression, we evaluated associations of BMI with non-Luminal A intrinsic subtypes. Linear regression models were used to evaluate associations with gene expression. Models were stratified by menopausal status and adjusted for age at diagnosis, race/ethnicity, and stage. Results: The cohort was comprised of 52% Luminal A, 21% Luminal B, 10% Basal-like, 14% HER2-E, and 3% Normal-like subtypes. Basal-like was more prevalent in the highly obese (19%), compared with the other BMI groups (8%-10%), whereas Luminal A was less common in the highly obese (36%), compared with the other groups (49%-57%). Greater expression of proliferation genes was seen with increasing BMI (p<0.01). In the postmenopausal group, compared to normal weight women, those who were highly obese had an increased odds of Basal-like vs. Luminal A tumors (OR=4.14; 95% CI: 2.08, 8.23) and Luminal B vs. Luminal A tumors (OR=3.17; 95% CI: 1.54, 6.54). However, these elevated odds were largely non-significant and attenuated among obese and overweight women. In the postmenopausal group, highly obese women had tumors with higher expression of proliferation genes compared with normal weight women (β=0.48; 95% CI: 0.16, 0.79), yet obese (β=0.14; 95% CI: -0.09, 0.37) and overweight (β=0.11; 95% CI: -0.10, 0.33) women did not. In contrast, being highly obese was associated with lower ESR1 expression (β=-0.51; 95% CI: -1.09, 0.06) compared with normal weight, whereas obese (β=0.28; 95% CI: -0.16, 0.71) and overweight (β=0.04; 95% CI: -0.32, 0.39) were not. These reported associations, except for ESR1 expression, were not evident in premenopausal women. Discussion: Among postmenopausal women with breast cancer, those who were highly obese, but not mildly obese, had increased odds of Basal-like and Luminal B subtypes and had tumors with greater expression of proliferation genes. Tumor subtypes may vary by level of obesity. Citation Format: Marilyn L. Kwan, Candyce H. Kroenke, Carol Sweeney, Philip S. Bernard, Erin Weltzien, Adrienne Castillo, Rachel E. Factor, Kaylynn Shakespear, Inga J. Stijleman, Charles P. Quesenberry, Laurel A. Habel, Lawrence H. Kushi, Bette J. Caan. Association of high obesity with PAM50 breast cancer intrinsic subtypes and gene expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3263. doi:10.1158/1538-7445.AM2014-3263