BRAF Mutation in Papillary Thyroid Cancer and Its Value in Tailoring Initial Treatment A Systematic Review and Meta-Analysis

and Department of Epidemiology (KAC), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Medicine (Impact Factor: 4.87). 08/2012; 91(5):274-86. DOI: 10.1097/MD.0b013e31826a9c71
Source: PubMed

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.

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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.
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    ABSTRACT: Mutations in the V-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) play an important role in the pathogenesis of papillary thyroid cancer (PTC). In this study, a BRAF V600E mutation was detected in formalin-fixed and paraffin-embedded PTC samples using multiplex allele-specific polymerase chain reaction and denaturing high-performance liquid chromatography. The sensitivity of the assays was validated in two cell lines, K1 and RO82-W-1, which were respectively positive and negative for the mutation. The method enabled detection of very low concentrations (~1%) of the mutation, with positive findings obtained in 119 of the 187 samples (63.6%). The mutation was not detected in 20 cases of benign thyroid diseases. The presence of the mutation was significantly associated with ages >45 years, the tumor-nodes-metastasis stage, region of metastasis, and clinical outcome (P < 0.05). Although no correlation was found between the mutation and lymph node metastasis, the proportions of patients carrying a mutation differed significantly between central and lateral cervical lymph node metastasis (P < 0.05). Multivariate logistic regression analysis also indicated the presence of mutation, tumor size, and cervical lymph node metastasis to be independent predictors for recurrence and distant metastasis. We conclude that a high proportion of PTC cases likely harbors the BRAF V600E mutation. This mutation can be used as an independent factor for predicting the recurrence and distal metastasis of PTC tumors.
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    ABSTRACT: Background We examined the frequency of the BRAFV600E mutation and compare the clinicopathological features based on the BRAFV600E mutation status in multifocal papillary thyroid carcinoma (PTC). Methods A total 85 patients who were diagnosed with multifocal PTC were enrolled. We confirmed the status of the BRAFV600E mutation in each tumor focus by the real-time polymerase chain reaction technique. Results Among the 85 patients, 49 (57.6%), 34 (40.0%) and 2 (2.4%) patients were determined to have all BRAFV600E-positive, mixed BRAFV600E and all BRAFV600E-negative in their tumor foci, respectively. When we compared clinicopathologic features according to the BRAFV600E mutation status of the dominant tumor, the BRAFV600E -positive group (n = 70) showed more extrathyroidal invasion in the dominant tumor (32.9% vs. 6.7%, P = 0.041) and more lymph node metastasis (67.2% vs. 40.0%, P = 0.049) than the BRAFV600E -negative group (n = 15). Considering all tumor foci, the all BRAFV600E mutation group exhibited a younger population (P = 0.039), showed increased extrathyroidal invasion (38.8% vs. 14.7%, P = 0.017) and lymph node metastasis (71.4% vs. 48.4%, P = 0.038), and received more radioactive iodine therapy (79.2% vs. 52.9%, P = 0.012) than the mixed BRAFV600E mutation group. A larger tumor size and heavier preoperative body weight was positively correlated with the relative expression of BRAF V600E mutation calculated by 2-△△Ct method. Conclusions Most of the Korean patients with multifocal PTC had the BRAFV600E mutation in one or more tumor foci, and all BRAFV600E positive multifocal PTC showed more aggressive features.
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