Abstract A108: Circulating GDF-15 reflects KRAS variant and co-mutation biology in advanced pancreatic ductal adenocarcinoma
Abrahm Levi, Sargis Hovhannisyan, Maria Cechini, Jun Gong, Andrew E. Hendifar, Arsen OsipovAbstract
Background:
Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine that is frequently elevated in pancreatic ductal adenocarcinoma (PDAC) and has been implicated in cancer cachexia, systemic inflammation, and poor clinical outcomes. Preclinical studies suggest that oncogenic KRAS signaling can regulate GDF-15 expression through downstream MAPK and stress-response pathways, raising the possibility that distinct KRAS alleles may influence circulating GDF-15 levels. Given the high prevalence of cancer cachexia in PDAC, we evaluated associations between serum GDF-15 levels, and KRAS variants and TP53 gene mutations in patients with PDAC.
Methods:
Tumor mutation status and GDF-15 concentrations were retrospectively analyzed across 48 PDAC patients enrolled on an institutional biobank (Pro00054363). GDF-15 levels were measured using an MSD R-Plex Human GDF-15 assay. Welch’s t-tests were used to assess differences in GDF-15 levels between mutation groups.
Results:
In the advanced PDAC cohort, mean GDF-15 concentrations were 1,940 pg/mL for KRAS G12R (n=6), 3,414 pg/mL for KRAS G12D (n=26), and 3,506 pg/mL for KRAS G12V (n=13). Low GDF-15 concentrations (<800 pg/mL), defined in a previous analysis done by our group using a mean of 598 +/- 304 pg/mL for non-cancer patients, was observed in 2 of 6 patients (33.3%) with KRAS G12R tumors compared with 2 of 42 patients (4.8%) in the All-other KRAS comparator cohort. Low GDF-15 was associated with significant increased odds of KRAS G12R status (OR 21.0, 95% CI 1.54-285.70; logistic-regression p=0.022; Fisher’s exact p=0.036). TP53 co-mutation (n=33) was associated with significantly higher mean GDF-15 concentrations compared with TP53 wild-type tumors (n=15) (3,709 pg/mL vs. 1,956 pg/mL, p<0.05).
Conclusion:
Patients with advanced PDAC harboring KRAS G12R mutations demonstrated lower circulating GDF-15 concentrations than those with KRAS G12D or G12V mutations. A subset of KRAS G12R tumors exhibited GDF-15 levels within the range observed in non-cancer patients, suggesting a distinct systemic biologic phenotype. These findings support further investigations of circulating GDF-15 as a noninvasive biomarker of PDAC biology. These findings suggest G12R tumors may induce less systemic stress/cachexia; however, this needs to be evaluated in a larger cohort.
Citation Format:
Abrahm Levi, Sargis Hovhannisyan, Maria Cechini, Jun Gong, Andrew E. Hendifar, Arsen Osipov. Circulating GDF-15 reflects KRAS variant and co-mutation biology in advanced pancreatic ductal adenocarcinoma [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 A108.