Abstract A009: Mutant KRAS in Circulating Tumor DNA Assessed by Digit Droplet PCR as a Biomarker in Pancreatic Cancer in Patients Treated with Neoadjuvant Chemotherapy
Authors: Vitello Dominic , Shah Dhavan , Wells Amy , Masnyk Larissa , Cox Madison , Janczewski Lauren , Abad John , Dawravoo Kevin , D'Souza Arlene , Suh Grace , Bayer Robert , Cristofanilli Massimo , Bentrem David , Liu Yingzhe , Zhang Hui , Santana-Santos Lucas , Jennings Lawrence , Zhang Qiang , Chawla Akhil 
Published: September 2024

Abstract
Introduction: The detectability and prognostic significance of circulating tumor DNA (ctDNA) in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy (NAC) is unclear. The objective of this study was to investigate the rate of detection and prognostic value of KRAS mutant ctDNA in PDAC patients after treatment with NAC as assessed by digital droplet polymerase chain reaction (ddPCR). Methods: Patients with newly diagnosed, localized, PDAC were enrolled in a prospective cohort study. Peripheral blood samples were collected at diagnosis, after NAC, and after resection. DNA was extracted from patient plasma samples using the QIAamp Circulating Nucleic Acid Kit #55114 (Qiagen N.V., Venlo Netherlands). Each sample was probed (catalog number 10049550) for KRAS codon 12 exon 2 glycine substitutions for aspartic acid (G12D), valine (G12V), and arginine (G12R). Kaplan-Meier, log-rank, and Cox regression survival analyses were performed. Results: 84 patients were included in the analysis. Patients were most commonly male (53.6%) and had tumors that were radiographically resectable (57.1%). After diagnosis, 79.8% of patients received NAC and 57.1% of patients received curative-intent surgical resection. Samples were collected for analysis from 59 (70.2%), 56 (83.6%), and 45 (93.8%) patients at diagnosis, after NAC, and after resection, respectively. Mutant KRAS ctDNA was detected in 49.3% of patients at diagnosis, 69.6% of patients after NAC, and 54.1% of patients after resection, respectively. The median OS of the cohort was 25.1 months (12.0-not reached [NR]). Detection (hazard ratio [HR] 36.8, 95% confidence interval [CI] 2.9-461.4), copy number (HR 4.0 95% CI 1.6-10.2), and percentage mutation (HR 2.9 95% CI 1.2-6.8) of KRAS G12V ctDNA after resection were all independently associated with shorter OS. Mutant KRAS ctDNA detection was not associated with and OS at other study timepoints. There were 15 (17.9%) patients that cleared mutational ctDNA over the course of treatment. Clearance of ctDNA during NAC was associated with improved overall survival (OS) (18.4 mo. vs NR). Conclusions: In patients with PDAC treated with NAC, KRAS mutations are detectable in ctDNA by ddPCR in the majority of patients over the course of treatment. Detection, copy number, and percentage mutation of KRAS G12V after NAC and resection were each independently associated with shorter OS. Clearance of ctDNA is associated with improved OS. The results demonstrate that KRAS mutant ctDNA predicts prognosis after NAC and resection.
Citation Format: Dominic Vitello, Dhavan Shah, Amy Wells, Larissa Masnyk, Madison Cox, Lauren Janczewski, John Abad, Kevin Dawravoo, Arlene D'Souza, Grace Suh, Robert Bayer, Massimo Cristofanilli, David Bentrem, Yingzhe Liu, Hui Zhang, Lucas Santana-Santos, Lawrence Jennings, Qiang Zhang, Akhil Chawla. Mutant KRAS in Circulating Tumor DNA Assessed by Digit Droplet PCR as a Biomarker in Pancreatic Cancer in Patients Treated with Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A009.