Abstract PR004: Inflammation links KRAS-driven tumor biology to adverse host phenotypes in pancreatic cancer
Dina L. Tataran, Leonor P.S Schubert, Adam S. Bryce, Stephan Dreyer, Judith Dixon, Fraser Duthie, David K. Chang, Fieke E.M FroelingAbstract
Introduction:
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers globally. Most patients present with advanced disease and unfit for treatment. Many patients exhibit profound tumor-associated systemic effects contributing to rapid functional decline, including cancer-associated cachexia and elevated systemic inflammatory response. We hypothesize that KRAS-driven pro-tumorigenic and inflammatory signaling drives aberrant systemic inflammation, contributing to cachexia. Here we investigate the relationship between systemic inflammation, body composition changes defining adverse host phenotypes, and tumor-intrinsic molecular events underpinning these features.
Methods:
A clinically well-annotated retrospective metastatic PDAC patient cohort (n=306) was characterized using routinely collected blood biomarkers, and CT imaging. Systemic inflammation was assessed using C-reactive protein, modified Glasgow Prognostic Score, and neutrophil-lymphocyte ratio. CT-derived body composition changes were used to quantify cachexia via L3-based tissue segmentation. Body composition phenotypes were defined and validated in an independent retrospective borderline resectable PDAC patient cohort (n=219). Genomic, transcriptomic and spatial molecular profiling was available for a subset of patients and used to explore molecular correlates of adverse host events. We acknowledge the use of AI for coding assistance.
Results:
Based on combined scores of skeletal muscle and subcutaneous adipose loss, we defined novel prognostic and predictive body composition phenotypes in metastatic and borderline resectable PDAC. Adverse body composition changes associated with elevated systemic inflammation. Transcriptomic analysis demonstrated that high systemic inflammation strongly associated with the squamous/basal-like molecular subtype and its defining gene programs, including inflammatory and TGF-b signaling. Squamous/basal-like tumors were enriched for KRAS G12D mutations, which associated with increased inflammatory and pro-tumorigenic signaling, and higher levels of systemic inflammation compared with other KRAS G12 variants. In addition, we observed an association between adverse body composition, worsening adipose quality and KRAS G12D mutations. Furthermore, KRAS G12D-mutant tumors showed higher GDF-15 expression, and associated with poor clinical outcome.
Conclusion:
We identified novel body composition phenotypes as features of the host response to KRAS-driven tumor progression, with KRAS G12D variants driving systemic inflammation, aggressive tumor biology, and an adverse host phenotype with cancer-associated cachexia. Altogether these findings highlight the use of body composition as a clinically relevant biomarker in informing treatment strategies, and support the notion that cachexia is a result, or symptom of elevated inflammation in response to KRAS-driven tumor progression, highlighting the need for therapeutic strategies which combat tumor progression and mitigate host events to improve outcomes for patients with PDAC.
Citation Format:
Dina L. Tataran, Leonor P.S Schubert, Adam S. Bryce, Stephan Dreyer, Judith Dixon, Fraser Duthie, David K. Chang, Fieke E.M Froeling. Inflammation links KRAS-driven tumor biology to adverse host phenotypes in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr PR004.