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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.
Highlights
Cancer arises through accumulation of genomic aberrations
According to the Response Evaluation Criteria in Solid Tumors version 1.1 [15], the imaging measurement of tumor response was qualitatively classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD)
All cases were treatment-na€ve at the time of diagnosis in our center, and FOLFIRINOX therapy was given as initial treatment except one patient
Summary
Numerous evidence has revealed complicated mutational landscape in various types of cancer and genetic heterogeneity among patients [1, 2]. These somatic alterations are almost exclusively present in tumor cells, and thereby serve as specific biomarkers for cancer patients. It has been shown that mutant DNA within tumor cells can be released into blood, and sequencing of circulating nucleic acids in plasma represents a way of liquid biopsy. Besides the ease of blood sample acquirement, the profiling of cell-free DNA (cfDNA) in plasma is more likely to recapitulate the whole genetic spectrum of tumor compared with tissue sequencing [3].
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