Abstract
The detection of rare mutational targets in plasma (liquid biopsy) has emerged as a promising tool for the assessment of patients with cancer. We determined the presence of cell-free DNA containing the BRAFV600E mutations (cfBRAFV600E) in plasma samples from 57 patients with papillary thyroid cancer (PTC) with somatic BRAFV600E mutation-positive primary tumors using microfluidic digital PCR, and co-amplification at lower denaturation temperature (COLD) PCR. Mutant cfBRAFV600E alleles were detected in 24/57 (42.1%) of the examined patients. The presence of cfBRAFV600E was significantly associated with tumor size (p = 0.03), multifocal patterns of growth (p = 0.03), the presence of extrathyroidal gross extension (p = 0.02) and the presence of pulmonary micrometastases (p = 0.04). In patients with low-, intermediate- and high-risk PTCs, cfBRAFV600E was detected in 4/19 (21.0%), 8/22 (36.3%) and 12/16 (75.0%) of cases, respectively. Patients with detectable cfBRAFV600E were characterized by a 4.68 times higher likelihood of non-excellent response to therapy, as compared to patients without detectable cfBRAFV600E (OR (odds ratios), 4.68; 95% CI (confidence intervals)) 1.26–17.32; p = 0.02). In summary, the combination of digital polymerase chain reaction (dPCR) with COLD-PCR enables the detection of BRAFV600E in the liquid biopsy from patients with PTCs and could prove useful for the identification of patients with PTC at an increased risk for a structurally or biochemically incomplete or indeterminate response to treatment.
Highlights
Advances in the understanding of genetic and biologic characteristics of thyroid cancer, coupled with the development of new molecular targeted therapeutics, have led to improved diagnosis and treatment [1]
We examined the utility of liquid biopsy in patients with BRAFV600E-mutant papillary thyroid cancer (PTC)
We focused on the detection of cfBRAFV600E, since this is the most frequent genomic alteration found in PTC and a well established druggable target with already approved pharmacological inhibitors of the BRAF/mitogen-activated protein kinase (MAPK) signaling pathway
Summary
Advances in the understanding of genetic and biologic characteristics of thyroid cancer, coupled with the development of new molecular targeted therapeutics, have led to improved diagnosis and treatment [1]. The analysis of genomic variants revealed a high frequency of activating somatic alterations of genes encoding effectors in the mitogen-activated protein kinase (MAPK) signaling pathway, including the point mutations of BRAF and the RAS genes, as well as fusions involving the RET and NTRK1 tyrosine kinases. BRAF mutations have been the most frequently detected genomic alterations in papillary thyroid cancer (PTC), being primarily mutations encoding V600E substitution [2,3,4]. The presence of BRAFV600E mutation in PTC patients has been associated with increased tumor progression, aggressive clinicopathological features and poorer prognosis, when coupled with a telomerase reverse transcriptase (TERT) promoter mutation. Adverse clinical-pathological features associated with the BRAFV600E mutation include the presence of lymph node metastases, extrathyroidal invasion, distant metastases and advanced cancer stages [3,7]. A linear relationship has been observed between patient age and mortality risk in PTC patients with BRAFV600E mutation [3,9,10]
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