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Background: Patients with pancreatic cancer often develop progressive weight loss and sarcopenia, described as cancer cachexia syndrome. Despite evidence showing that pancreatic cancer cachexia is associated with a poor prognosis, reduced tolerance to therapy, and diminished quality of life, no predictive biomarkers have been identified to date. Certain mutant KRAS isoforms are associated with significant alterations to tumor metabolism and have been correlated with changes in weight and survival. However, the clinical implications resulting from specific KRAS mutations in pancreatic cancer have yet to be fully explored. Methods: A retrospective analysis was performed to compare weight changes and survival in 150 pancreatic cancer patients with various KRAS alterations identified by next-generation sequencing (Foundation Medicine, Inc., Cambridge, MA). Survival data and weights documented between 6 months prior to diagnosis and the date of death or the last follow-up visit were abstracted from the medical record and evaluated using statistical analyses, including functional principal component analysis for sparse functional data, Ward cluster, logistic regression, analysis of variance, and Cox regression. Using derivative principal component scores, we separated patients into two groups demonstrating either constant or decreasing weight over time. Results: 77% of evaluated patients had a KRAS mutation, and 21% had KRAS wild-type. Of patients with mutant KRAS, 84% had an alteration at G12, 10% at Q61, and 3% at G13. While there was no significant difference in weight changes between KRAS wild-type patients and patients with a Q61 mutation, patients with non-Q61 mutations were 2.5 times more likely (p = 0.05) than wild-type patients to demonstrate weight loss over time. Furthermore, KRAS mutants had worse survival when compared to KRAS wild-type patients. Irrespective of mutational status, patients whose weight did not decrease were 69% less likely to die (p = 0.039). Conclusion: We demonstrated that mutant KRAS isoforms G12 and G13 mutations correlate with weight loss, whereas Q61 KRAS mutations and wild-type KRAS do not. Furthermore, weight loss in all patients increased their risk of death. These findings suggest that KRAS subtypes may have unique genotype-to-phenotype features, particularly with weight loss that could warrant tailored therapeutic strategies in at-risk subgroups. Future studies of larger scope, and ideally prospective in nature, are warranted in patients stratified by KRAS isoform. Citation Format: Haesoo Kim, Camille Ng, Marcio A. Diniz, Michel H. Montoril, Michelle Guan, Victor Brodsky, Eric Vail, Richard Tuli, Edik Blais, Sungjin Kim, Emanuel Petricoin III, Jun Gong, Veronica R. Placencio-Hickok, Andrew E. Hendifar. Association of mutant KRAS isoforms with weight loss in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C27.