Genomic and transcriptomic predictors of early vs late recurrence after curative intent surgery in patients with pancreatic cancer.

Abstract

754 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third deadliest malignancy with most patients (pts) presenting with advanced disease. In those with localized disease at diagnosis who undergo curative intent surgery followed by adjuvant chemotherapy, the relapse rate remains high (70%). While there are known clinicopathological risk factors to predict relapse, little is known about genomic and transcriptomic features differentiating recurrent PDAC. Methods: We identified PDAC pts who had curative surgery at Princess Margaret Cancer Centre in Toronto, Canada between August 2008-2022 who had whole genome (WGS) and transcriptomic (RNA-Seq) data available. Patients were classified by timing of relapse after surgery: early (≤6 months), intermediate (6–12 months), late (>1 year), or no recurrence. Clinicopathologic and survival data were collected via chart review, and groups were analyzed using Fisher’s exact/Wilcoxon rank sum tests. Kaplan-Meier survival analyses were conducted. Results: Of 715 surgical resections, 170 had clinical and WGS/RNA-Seq data available. Ninety-three pts (55%) were female and 126 (74%) had at least N1 disease. Timing of relapse was classified as early (n=37, 22%), intermediate (n=46; 27%), late (n=61; 36%), and no recurrence (n=26; 15%) at time of data cut-off. There were no statistically significant differences in sex, Moffitt subtype, HRD/MMR status, or driver mutations such as KRAS , CDKN2A , and SMAD4 . Clinicopathological analysis revealed that vascular involvement (p=0.0231), nodal (N) status (p=0.0384), non-adenocarcinoma histology (p=0.0393) and G3 tumors (p<0.001) were significant predictors of early recurrence. Hepatic metastasis accounted for most early recurrences (51%), whereas late recurrences were often locoregional (36%) or pulmonary (20%). Genomic analysis revealed a higher incidence of ARID1A mutations in early vs. late recurrence (20% vs. 3.5%, p=0.0179), with 71% demonstrating monoallelic loss, while low ploidy (p=0.0371), PTEN mutation (p=0.0166) and TP53 wild-type status (p=0.0237) were significantly associated with no recurrence. Higher structural variant counts were also observed in the early recurrence group (p=0.0163). Differential expression analysis demonstrated significant enrichment in gene sets associated with MYC activation, glycolysis and hypoxia response (FDR q-value < 0.001) in early recurrence pts, while the late-recurrence pts showed enrichment in pancreatic beta cell-related gene sets (FDR q-value < 0.01). Conclusions: While clinicopathologic factors have been confirmed as prognostic for recurrence, we identified a higher incidence of ARID1A mutations in the early recurrence group and significant enrichment in gene sets associated with MYC/hypoxia. Multi-omics analysis could further improve recurrence prediction, guiding future therapeutic strategies.