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

• Published in: Molecular cancer therapeutics Vol. 18; no. 1; pp. 196 - 203
• Main Authors: Wei, Tao, Zhang, Qi, Li, Xiang, Su, Wei, Li, Guogang, Ma, Tao, Gao, Shunliang, Lou, Jianying, Que, Risheng, Zheng, Lei, Bai, Xueli, Liang, Tingbo
• Format: Journal Article
• Language: English
• Published: United States 01.01.2019
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Case-Control Studies; Circulating Tumor DNA - genetics; Female; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; High-Throughput Nucleotide Sequencing - methods; Humans; Irinotecan - pharmacology; Irinotecan - therapeutic use; Leucovorin - pharmacology; Leucovorin - therapeutic use; Male; Middle Aged; Mutation; Oxaliplatin - pharmacology; Oxaliplatin - therapeutic use; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Prospective Studies; Sequence Analysis, DNA; Treatment Outcome; Tumor Burden - drug effects
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-1298

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.