Abstract 3333: Ultra-sensitive detection of KRAS mutations in circulating tumor DNA predicts survival in pancreatic adenocarcinoma

Abstract Introduction: The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene is mutated in over 90% of pancreatic adenocarcinoma (PDAC). These mutations are predominantly single-base missense variants, 98% of which are found at codon 12 (G12), codon 13 (G13), or codon 61 (Q61). Numerous studies have demonstrated the clinical utility of these KRAS mutations in PDAC, more recently employing liquid biopsy technology as a preferred method to analyze mutations non-invasively. This study aimed to investigate the prognostic potential of pathogenic KRAS G12, G13, or Q61 mutations harbored by circulating tumor DNA (ctDNA) in resectable PDAC prior to treatment initiation using an ultra-sensitive liquid biopsy panel. Methods: Plasma samples for patients at our institution with resectable disease at diagnosis were collected prior to chemotherapy initiation. This study cohort included 45 patients (median age 73; 42% male and 58% female; 86.7% Non-Hispanic White, 2.2% Non-Hispanic Black, 8.9% Hispanic White, 2.2% American Indian). At diagnosis, 68.8% had resectable disease (Stage IA-IIA), 15.6% had borderline resectable disease (Stage IIB), and 15.6% had locally advanced disease (Stage III). 38 patients received 3-12 cycles of neoadjuvant chemotherapy with modified FOLFIRINOX and/or Gemcitabine/Abraxane, 27 patients received 1-8 cycles of adjuvant chemotherapy, and 29 patients underwent upfront or interval surgery with Whipple procedure or distal pancreatectomy. Baseline ctDNA was analyzed for KRAS G12/G13/Q61 mutations using the PredicineCARE liquid biopsy assay (20, 000x sequencing depth) and the PredicineCARE Ultra assay (>100, 000x sequencing depth), providing full KRAS gene coverage. Results: The PredicineCARE assay identified pathogenic KRAS mutations (G12/G13/Q61) in 11 patients. Of these, 8 had co-occurring G12 and Q61 mutations. Presence of any KRAS mutation determined by CARE assay at baseline was not significantly associated with overall survival (OS) (HR 2.96, 95% CI 0.85-10.29), however, detection of a G12 mutation was significantly predictive of worse OS (HR 4.93, 95% CI 1.39-17.44). Co-occurrence of KRAS G12 and Q61 mutations in baseline ctDNA was also predictive of worse OS (HR 3.89, 95% CI 1.12-13.54). The PredicineCARE Ultra assay identified KRAS mutations in an additional 7 patients who were mutation-negative by the standard CARE assay. Baseline KRAS G12/G13 mutations detected with the Ultra assay were predictive of OS (HR 3.71, 95% CI 1.04-13.28), in addition to demonstrating 100% concordance with CARE assay results for overlapping mutations. Conclusion: Ultra-sensitive liquid biopsy assays such as the PredicineCARE Ultra panel demonstrate robust detection of pertinent KRAS mutations that significantly improves prognostic stratification for PDAC patients, demonstrating the potential of advanced liquid biopsy technology in improving outcomes in PDAC. Citation Format: Madison Cox, Amy Wells, Dominic Vitello, Larissa Masnyk, Chengwei Peng, John Abad, Qiang Zhang, Pan Du, Shidong Jia, Akhil Chawla. Ultra-sensitive detection of KRAS mutations in circulating tumor DNA predicts survival in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3333.