Monitoring Tumor Burden in Response to FOLFIRINOX Chemotherapy Via Profiling Circulating Cell-Free DNA in Pancreatic Cancer

Abstract

We aimed to explore the application of circulating cell-free DNA (cfDNA) profiling in monitoring tumor burden in patients with pancreatic ductal adenocarcinoma (PDAC). Thirty-eight patients with advanced PDAC receiving first-line FOLFIRINOX chemotherapy were prospectively enrolled. Next-generation sequencing for a panel of 560 genes covering a wide range of cancer-related loci was performed to profile cfDNA. In total, 25 patients (65.8%) had at least one common driver gene alterations (KRAS, TP53, SMAD4, CDKN2A) detected within cfDNA. In contrast, no above tumor-related recurrent mutations were found in plasma from 13 healthy individuals. Concordant alterations in plasma cfDNA and tumor tissue DNA was confirmed in two of three patients with available tissues. Further analysis showed that mutant allele fraction (MAF) for altered loci in cfDNA correlated with tumor stage, metastatic burden, and overall survival. Serial blood samples were collected from 17 patients after chemotherapy. We found that allele fraction for specific altered loci declined in chemotherapy-responding subjects. For cases who were resistant to this therapeutic regimen, increased ctDNA MAF was observed at the time of disease progression. Meanwhile, the dynamics of total cfDNA concentration correlated with tumor burden following chemotherapy. Collectively, we provide evidence that pretreatment ctDNA level correlates with tumor burden in PDAC, and serial cfDNA analysis is a robust tool for monitoring cancer response to chemotherapy.

Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer

“…Current evidence for the use of ctDNA for therapeutic tracking in PDAC is limited to several smaller series in patients with metastatic disease (Supplementary Table S1). For instance, in a recent study of patients with metastatic PDAC treated with FOLIRINOX, serial testing found concomitantly reduced ctDNA for 12 patients with partial response or stable disease (48). Another study showed that reduction in KRAS ctDNA was associated with tumor responses observed by CT scan in 10 of 13 patients with metastatic PDAC (49).…”

Genome‐wide profiling of circulating tumor DNA depicts landscape of copy number alterations in pancreatic cancer with liver metastasis

“…As ctDNA is believed to randomly derive from necrotic and apoptotic tumor cells across the whole tissue, it thus presumably provides a more representative genomic picture of tumor than regional tissuebased strategies. Numerous studies have shown that ctDNA profiling was able to identify and track cancerspecific mutations, which is helpful in diagnosis, prediction of prognosis, and treatment response, and guiding personalized therapeutics [11,[13][14][15]. Emerging evidence suggested the ability of genome-wide or exome-wide ctDNA sequencing to capture genetic diversity including aberrations of copy number and chromosome structure in addition to single nucleotide variants [16,17].…”

Impact of circulating tumor DNA in hepatocellular and pancreatic carcinomas

“…However, there is still a lack of consensus in the clinical applicability of current PC subtyping approaches. Recently, plasma cfDNA profiling in 38 patients with advanced PC receiving firstline FOLFIRINOX chemotherapy could demonstrate that 65.8% of patients had at least one common driver gene alteration in KRAS, TP53, SMAD4, or CDKN2A in high concordance with corresponding tumor tissue (Table 2) (Wei et al 2019). Interestingly, the dynamics of total cfDNA concentration correlated positively with tumor burden following chemotherapy and might be a promising tool for early response prediction and therapy surveillance in patients with advanced PC.…”