Pathway Mutations are Associated with Clinical Outcomes in Localized Pancreatic Cancer Treated with Neoadjuvant Chemoradiation Followed by Surgery

Abstract

The purpose of this study was to determine if mutations in biological pathways are associated with clinical outcomes in patients with localized pancreatic cancer who undergo neoadjuvant chemoradiation followed by surgical resection. Patients treated with neoadjuvant chemoradiation followed by oncologic resection from 2015-2019 who also underwent next generation sequencing (NGS) of the primary tumor were included in this retrospective analysis. NGS was done using either Foundation One (n = 20), in-house Solid Tumor Panel (n = 121), or Tempus XT (n = 1). Genes were included in pathway analysis if at least one patient harbored a mutation in the gene. Pathways were defined from the Molecular Signatures Database Hallmark, KEGG, and Reactome gene sets. A pathway was deemed mutated if at least one gene within the pathway was mutated. Univariable Cox regression was performed to determine the association between pathway mutation status and overall survival (OS) as well as progression-free survival (PFS). In total, 142 patients met criteria for study inclusion. For pathway analysis, 329 genes met inclusion criteria. Patients were typically treated with neoadjuvant chemotherapy (either 5-fluorouracil-based or gemcitabine-based) followed by radiation. Patients received SBRT (n = 104, most commonly 33 Gy in 5 fractions) or conventionally fractionated radiation (n = 38, most commonly 50.4 Gy in 28 fractions). For clinical variables, worse OS was significantly associated with T stage (p = 0.036), N stage (p = 0.044), and lymphovascular invasion (LVI, p = 0.011); worse PFS was significantly associated with T stage (p = 0.0008), N stage (p = 0.022), LVI (p = 0.026), and conventional RT (p = 0.007). Mutations in major pathways were associated with worse OS, notably hedgehog signaling (p = 0.001), chromatin modifying enzymes (p = 0.002), WNT/beta-catenin signaling (p = 0.005), mismatch repair (0.006), E2F targets (p = 0.008), FLT signaling (p = 0.012), VEGF signaling (0.025), innate immune system (p = 0.026), and NOTCH signaling (p = 0.029). Pathway mutations associated with worse PFS included mismatch repair (p = 0.007) and hedgehog signaling (p = 0.013). For pancreatic cancer patients that undergo neoadjuvant chemoradiation followed by oncologic resection of the primary tumor, mutations in key biological pathways are associated with OS and PFS. Characterizing the importance of common pathway mutations may become increasingly valuable to help categorize less commonly mutated genes assayed by NGS.