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Circulating tumor DNA harboring the BRAF V600E mutation may predict poor outcomes of primary papillary thyroid cancer patients.

BACKGROUND
The significance of circulating tumor DNA (ctDNA) in primary papillary thyroid cancer (PTC) has yet to be well established. This study aimed to clarify whether ctDNA carrying the BRAF V600E mutation in plasma from primary PTC patients before and after surgery can predict outcomes.


METHODS
Twenty-two primary PTC patients without distant metastasis, who underwent surgical resection at the University of Tokyo Hospital, were eligible for this study. Genomic DNA of the primary tumor was extracted from formalin-fixed and paraffin-embedded specimens, and the BRAF V600E mutation was detected by droplet digital PCR (ddPCR). Pre- and post-surgery ctDNAs were extracted from matched plasma samples obtained from 22 patients and analyzed for the BRAF V600E mutation using ddPCR.


RESULTS
The BRAF V600E mutation was detected in 16 of 22 (73%) primary tumors. Five of 16 (31%) cases carrying the BRAF V600E mutation in their tumors showed the identical mutation in pre-surgery plasma. Extra-thyroidal extension of the primary tumor correlated significantly with the BRAF V600E mutation in pre-surgery ctDNA (p=0.025). In the five patients carrying the BRAF V600E mutation in pre-surgery ctDNA, the fractional abundance of the BRAF V600E alleles to the total BRAF alleles in the primary tumor was significantly higher than that in the 11 patients without mutated BRAF in pre-surgery ctDNA (mean, 34% vs. 17%) (P<0.01). Moreover, one patient with the mutated BRAF V600E in the primary tumor showed the identical mutation not in pre-surgery ctDNA but in post-surgery ctDNA. This patient had regional lymph node recurrence six months after surgery.


CONCLUSIONS
Pre-surgery ctDNA with the BRAF V600E mutation was detected in 31% of cases with primary PTCs carrying the identical mutation. Detection of the BRAF V600E mutation in pre-surgery plasma can provide information on the increased fractional abundance of the mutated BRAF V600E alleles and local progression of the primary tumor. Furthermore, the fractional abundance of the mutated BRAF V600E in post-surgery ctDNA might predict PTC recurrence.