Abstract
The circulating free tumor DNA (ctDNA) represents an alternative, minimally invasive source of tumor DNA for molecular profiling. Targeted sequencing with next generation sequencing (NGS) can assess hundred mutations starting from a low DNA input. We performed NGS analysis of ctDNA from 44 patients with metastatic non-small-cell lung carcinoma (NSCLC) and 35 patients with metastatic colorectal carcinoma (CRC). NGS detected EGFR mutations in 17/22 plasma samples from EGFR-mutant NSCLC patients (sensitivity 77.3%). The concordance rate between tissue and plasma in NSCLC was much lower for other mutations such as KRAS that, based on the allelic frequency and the fraction of neoplastic cells, were likely to be sub-clonal. NGS also identified EGFR mutations in plasma samples from two patients with EGFR wild type tumor tissue. Both mutations were confirmed by droplet digital PCR (ddPCR) in both plasma and tissue samples. In CRC, the sensitivity of the NGS plasma analysis for RAS mutations was 100% (6/6) in patients that had not resection of the primary tumor before blood drawing, and 46.2% (6/13) in patients with primary tumor resected before enrollment. Our study showed that NGS is a suitable method for plasma testing. However, its clinical sensitivity is significantly affected by the presence of the primary tumor and by the heterogeneity of driver mutations.
Highlights
The identification of driver mutations in a large fraction of patients with solid tumors and the availability of drugs that are able to block the activation of specific signaling pathways is boosting the development of a novel therapeutic approach defined as genomic-driven oncology [1]
non-small-cell lung carcinoma (NSCLC) patients were previously screened for EGFR mutations whereas CRC patients were tested for KRAS and NRAS mutations by using standard diagnostic methods
We have previously demonstrated that targeted sequencing is able to identify with high sensitivity and specificity somatic mutations in tumor-derived DNA, even when starting from the limited amount of nucleic acids that can be obtained from cytology samples [16]
Summary
The identification of driver mutations in a large fraction of patients with solid tumors and the availability of drugs that are able to block the activation of specific signaling pathways is boosting the development of a novel therapeutic approach defined as genomic-driven oncology [1]. This definition might be considered a synonymous of personalized medicine or precision medicine, in which treatment of the single cancer patient is driven by a specific genetic alteration of the tumor, i.e. a specific biomarker. Molecular monitoring of the disease over the time is necessary in order to identify mechanisms of resistance and to adapt the therapy to the new molecular landscape
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