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

and Department of Epidemiology (KAC), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Medicine (Impact Factor: 5.72). 08/2012; 91(5):274-86. DOI: 10.1097/MD.0b013e31826a9c71
Source: PubMed


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.

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    • "The aggressive nature of TCVPTC may be related to a higher prevalence of BRAF mutations.26 BRAF mutations in PTC have been correlated with aggressive tumor behavior, including extrathyroidal extension, tumor recurrence, advanced tumor stage at presentation and lymph node metastasis,27 even in microcarcinomas.28 The BRAF oncogene is a strong activator of the mitogen-activated protein kinase signaling pathway, which leads to uncontrolled cell proliferation and transformation into malignancy.29 BRAF mutation also plays a role in extracellular matrix remodeling and is associated with an increase in matrix metalloproteinases, a desmoplastic stromal reaction, and invasiveness.30 "
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    ABSTRACT: Background The tall cell variant of papillary thyroid carcinoma (TCVPTC) is more aggressive than classic papillary thyroid carcinoma (PTC), but the percentage of tall cells needed to diagnose TCVPTC remains controversial. In addition, little is known about the clinicopathologic features of classic PTC with tall cell features (TCF). Methods We retrospectively selected and reviewed the clinicopathologic features and presence of the BRAF mutation in 203 cases of classic PTC, 149 cases of classic PTC with TCF, and 95 cases of TCVPTCs, which were defined as PTCs having <10%, 10-50%, and ≥50% tall cells, respectively. Results TCVPTCs and classic PTCs with TCF did not vary significantly in clinicopathologic characteristics such as pathologic (p) T stage, extrathyroidal extension, pN stage, lateral lymph node metastasis, or BRAF mutations; however, these features differed significantly in TCVPTCs and classic PTCs with TCF in comparison to classic PTCs. Similar results were obtained in a subanalysis of patients with microcarcinomas (≤1.0 cm in size). Conclusions Classic PTCs with TCF showed a similar BRAF mutation rate and clinicopathologic features to TCVPTCs, but more aggressive characteristics than classic PTCs.
    Full-text · Article · Jun 2014 · The Korean Journal of Pathology
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    • "The majority of studies have demonstrated that the BRAF V600E mutation is common in PTC and that the frequency varies from 18 to 87%. Although certain studies have indicated that geographical and histological subtype classification factors may account for these differences, the reliability of the detection method must also be taken into consideration (7,15). In the present study, multiplex allele-specific PCR combined with DHPLC was used to detect the mutation. "
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    ABSTRACT: The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) and to determine the correlation between this mutation and indicators of poor prognosis and outcome in patients with PTC. The BRAF V600E mutation status was analyzed in 187 tumor samples using the multiplex allele-specific PCR method. Univariate and multivariate analyses were performed to investigate the association of the BRAF V600E mutation with clinical features and patient outcome. The sensitivity of the multiplex allele-specific PCR combined with denaturing high-performance liquid chromatography reached ~1%. The BRAF V600E mutation was observed in 63.6% (119/187) of tumor tissues, predominantly in PTC specimens, and no BRAF mutation was identified in other benign-type thyroid diseases. The univariate analysis indicated that the BRAF V600E mutation was associated with age, tumor stage and prognosis (P<0.05). In addition, the frequency of the BRAF V600E mutation was significantly different in the central (75.3%) and lateral neck (49.3%) lymph nodes of patients with lymph node metastasis. Multivariate logistic regression analysis showed that the BRAF V600E mutation (HR, 2.471; 95% CI, 1.149-5.312) and lymph node metastasis (HR, 3.003; 95% CI, 1.027-8.771) are independent factors that predict tumor prognosis. Thus, the BRAF V600E mutation is an independent risk factor that may be used to predict thyroid cancer persistence/recurrence.
    Full-text · Article · Feb 2014 · Oncology letters
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    ABSTRACT: The impact of metastasized cervical lymph nodes (CLN) identified on central neck dissection (CND) on the recurrence/persistence of papillary thyroid cancer (PTC) and the extent of CND needed to reduce recurrence/persistence have not been firmly established. To assess the impact of CLN metastasis and BRAF mutation on the recurrence/persistence of PTC and the potential of BRAF mutation in assisting CND. Analyses of 379 consecutive patients with PTC who underwent thyroidectomy with (n=243) or without CND (n=136) at a tertiary-care academic hospital during the period 2001-2010 for their clinicopathological outcomes and BRAF mutation status. Increasingly aggressive tumor characteristics were found as the extent of CND was advanced following conventional risk criteria from non-CND to limited CND to formal CND. Disease recurrence/persistence rate also sharply rose from 4.7% to 15.7% and 40.5% in these CND settings, respectively (P<0.0001). CLN metastasis rate rose from 18.0% to 77.3% from limited CND to formal CND (P<0.0001). An increasing rate of BRAF mutation was also found from less to more extensive CND. A strong association of CLN metastasis and BRAF mutation with disease recurrence/persistence was revealed on Kaplan Meier analysis and BRAF mutation strongly predicted CLN metastasis. CLN metastases found on CND are closely associated with disease recurrence/persistence of PTC, which are both strongly predicted by BRAF mutation. Current selection of PTC patients for CND is appropriate, but higher extent of the procedure, as guided by preoperative BRAF mutation testing, may be needed to reduce recurrence/persistence of PTC.
    Full-text · Article · Nov 2012 · Endocrine Related Cancer
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