Clinical and molecular correlates of circulating tumor fraction in patients with metastatic pancreatic ductal adenocarcinoma.

Abstract

Pre-existing and emerging molecular-targeted therapies have been identified for the treatment of pancreatic ductal adenocarcinoma (PDAC) and exemplify the need for incorporating tumor sequencing into routine clinical practice. Tumor profiling through circulating tumor DNA (ctDNA) represents an important opportunity in PDAC due to the aggressive nature of the disease. Circulating tumor fraction (CTF) levels are highly variable within and between cancer types and influence the accuracy of plasma-based tumor profiling, and the variability and factors related to CTF levels in PDAC are not well understood. ctDNA sequencing (PredicineATLAS) and clinical metadata from a cohort of 166 patients with metastatic PDAC (mPDAC) was generated as part of the PA.7 trial (NCT02879318). Patients were stratified into high CTF (>30% CTF; 35/166, 21.08%) and low CTF (131/166, 78.92%) groups for comparative analysis. Matched RNA-sequencing data was available for 20 patients. High CTF was associated with lower overall survival (OS; HR=1.87, 95% CI=1.27-2.75; p=0.0014) as well as clinical presentation that was indicative of higher disease burden, with CTF highest in patients that had liver metastases and distant metastases including bulky lymph nodes versus patients with no liver metastases (p<0.001). Exploratory gene expression analysis revealed positive association between CTF and up-regulation of cell cycle-related pathways, which included CDK4 (p=0.0093) and MT2A (p=0.012), as well as glycolytic (p=0.0028) and basal-like (p=0.029) subtyping genes. These data demonstrate the heterogeneity of CTF and its associated factors in mPDAC, which converge towards an aggressive phenotype from both clinical and molecular standpoints.