Body mass index and somatic variants in biliary tract cancers.

Abstract

e14636 Background: Obesity is postulated to exacerbate the oncogenic effects of select oncogenes. The metabolic and inflammatory changes associated with obesity contribute to oncogenesis, however a direct association between obesity and somatic mutagenesis is unknown, Herein, we investigate the relationship between body mass index (BMI) and somatic alterations in patients with biliary tract cancer (BTC). Methods: A retrospective cohort study of patients (pts) with BTC at Memorial Sloan Kettering was conducted from January 2022 to December 2023. Pts were divided based on BMI into: obese (BMI ≥30 kg/m 2 ) and non-obese (BMI <30 kg/m 2 ) (J Clin Oncol 43, 2025). Results of somatic next-generation sequencing (NGS) using the MSK-IMPACTv7 platform were abstracted from medical records and compared between groups using Fisher’s exact test for categorical and Wilcoxon rank sum test for continuous variables. Overall survival (OS) from diagnosis was estimated using Kaplan Meier method and compared between groups using log-rank test. Cox proportional hazards model was used to correlate tumor mutation burden (TMB) and genetic alterations occurring in at least 10% of patients with OS. Results: A total of N=78 pts with BTC (71 pts with intrahepatic cholangiocarcinoma (CCA), 5 pts with extrahepatic CCA, and 2 pts with gallbladder cancer) and who had NGS results were evaluated. Table 1 summarizes NGS results according to BMI. There was no statistically significant difference in the occurrence of particular somatic mutations when comparing tumors in obese and non-obese pts. However, tumors in obese pts had a higher frequency of CDKN2A mutations than tumors in non-obese patients (26% vs 16%, p=0.4). Univariate OS noted that pts with higher tumor mutation burden (HR: 1.17, 95% CI: 1.00-1.38, p-value 0.054) and pts with tumors harboring CDKN2A mutations (HR: 2.29, 95% CI: 0.95-5.51, p-value 0.064) may be associated with higher mortality, although the results were not significant. Conclusions: There is no significant association between BMI and somatic mutations in BTC in this limited study. However, obese pts may have a higher frequency of CDKN2A mutations compared to non-obese pts, suggesting a potential link between obesity and somatic mutagenesis. This association requires further investigation in larger studies while acknowledging that the modulatory effects of obesity on carcinogenesis are complex. Somatic alterations according to BMI. Somatic alteration Overalln = 78 BMI ≥30 kg/m 2 n = 27 BMI <30 kg/m 2 n = 51 p-value TMB 2.50 (1.60, 4.10) 3.30 (2.50, 4.90) 2.50 (1.60, 4.10) 0.3 ARID1A 24 (31%) 8 (30%) 16 (31%) >0.9 TP53 17 (22%) 6 (22%) 11 (22%) >0.9 KRAS 16 (21%) 6 (22%) 10 (20%) 0.8 CDKN2A 15 (19%) 7 (26%) 8 (16%) 0.4 IDH1 12 (15%) 5 (19%) 7 (14%) 0.7 BAP1 11 (14%) 5 (19%) 6 (12%) 0.5 ERBB2 8 (10%) 2 (7.4%) 6 (12%) 0.7 SMAD4 8 (10%) 5 (19%) 3 (5.9%) 0.12