BRAF Mutation in Papillary Thyroid Cancer and Its Value in Tailoring Initial Treatment

Abstract

Clinicians have long sought to characterize biological markers of neoplasia as objective indicators of tumor presence, pathogenicity, and prognosis. Armed with data that correlate biomarker activity with disease presence and progression, clinicians can develop treatment strategies that address risks of disease recurrence or persistence and progression. The B-type Raf kinase (BRAF V600E) mutation in exon 15 of the BRAF gene has been noted to be a putative prognostic marker of the most prevalent form of thyroid cancer, papillary thyroid cancer (PTC)--a tumor type with high proclivity for recurrence or persistence. There has been a remarkable interest in determining the association of BRAF mutation with PTC recurrence or persistence. Using many new studies that have been published recently, we performed a meta-analysis to investigate correlations of BRAF mutation status with PTC prognosis, focusing on the recurrence or persistence of the disease after initial treatment. The study was based on published studies included in the PubMed and Embase databases addressing the BRAF mutation and the frequency of recurrence of PTC. We selected studies with data that enabled measurement of the risk ratio for recurrent disease. We also analyzed the factors that are classically known to be associated with recurrence. These factors included lymph node metastasis, extrathyroidal extension, distant metastasis, and American Joint Committee on Cancer (AJCC) stages III/IV. We used 14 articles that included an analysis of these factors as well as PTC recurrence data, with a total of 2470 patients from 9 different countries. The overall prevalence of the BRAF mutation was 45%. The risk ratios in BRAF mutation-positive patients were 1.93 (95% confidence interval [CI], 1.61-2.32; Z = 7.01; p < 0.00001) for PTC recurrence, 1.32 (95% CI, 1.20-1.45; Z = 5.73; p < 0.00001) for lymph node metastasis, 1.71 (95% CI, 1.50-1.94; Z = 8.09; p < 0.00001) for extrathyroidal extension, 0.95 (95% CI, 0.63-1.44; Z = 0.23; p = 0.82) for distant metastasis, and 1.70 (95% CI, 1.45-1.99; Z = 6.46; p < 0.00001) for advanced stage AJCC III/IV. Thus, in this meta-analysis, the BRAF mutation in PTC was significantly associated with PTC recurrence, lymph node metastasis, extrathyroidal extension, and advanced stage AJCC III/IV. Patients with PTC harboring mutated BRAF are likely to demonstrate factors that are associated with an increased risk for recurrence of the disease, offering new prospects for optimizing and tailoring initial treatment strategies to prevent recurrence.

An update on molecular biology of thyroid cancers

“…The BRAF point mutation is the most common mutation in PTC (35-70%) and has recently been reported to be associated with poor prognostic features like extrathyroidal soft tissue infiltration, lymph node metastasis, disease aggressiveness, tumor recurrence, loss of radioiodine avidity and, thus, resistance to annual therapeutic methods [29][30][31][32][33][34]199,200]. Additionally, the BRAF mutation occurs most commonly in aggressive subtypes of PTC [178,201].…”

BRAF V600E mutation in prognostication of papillary thyroid cancer (PTC) recurrence

“…Another meta-analysis by Tufano et al assessed the correlation between BRAF mutation and recurrence or persistent disease (38). It analyzed 14 papers (the number of patients assessed from 9 countries was 2,470 in total).…”

BRAF V600E and TERT Promoter Mutations Cooperatively Identify the Most Aggressive Papillary Thyroid Cancer With Highest Recurrence

“…[8][9][10][11] BRAF V600E is the most common oncogene in PTC, with an average prevalence of 45%, 12 and it promotes PTC tumorigenesis through constitutively activating the mitogen-activated protein kinase pathway and other mechanisms. 13 We recently reported for the first time common mutations in the promoter of the gene for telomerase reverse transcriptase (TERT) in thyroid cancers, 14 particularly the chr5:1,295,228CϾT mutation (C228T), which represents the nucleotide change of Ϫ124 CϾT from the ATG translation start site of the TERT gene.…”