Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer Journal Article


Authors: Xing, M. M.; Alzahrani, A. S.; Carson, K. A.; Viola, D.; Elisei, R.; Bendlova, B.; Yip, L.; Mian, C.; Vianello, F.; Tuttle, R. M.; Robenshtok, E.; Fagin, J. A.; Puxeddu, E.; Fugazzola, L.; Czarniecka, A.; Jarzab, B.; O'Neill, C. J.; Sywak, M. S.; Lam, A. K.; Riesco-Eizaguirre, G.; Santisteban, P.; Nakayama, H.; Tufano, R. P.; Pai, S. I.; Zeiger, M. A.; Westra, W. H.; Clark, D. P.; Clifton-Bligh, R.; Sidransky, D.; Ladenson, P. W.; Sykorova, V.
Article Title: Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer
Abstract: Importance: BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. Objective: To investigate the relationship between BRAF V600E mutation and PTC-related mortality. Design, Setting, and Participants: Retrospective study of 1849 patients (1411 women and 438 men) with amedian age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. Main Outcomes and Measures: Patient deaths specifically caused by PTC. Results: Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) ( P < .001) in BRAF V600E-positive vs mutationnegative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). Conclusions and Relevance: In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC. ©2013 American Medical Association. All rights reserved.
Journal Title: JAMA - Journal of the American Medical Association
Volume: 309
Issue: 14
ISSN: 0098-7484
Publisher: American Medical Association  
Date Published: 2013-04-10
Start Page: 1493
End Page: 1501
Language: English
PROVIDER: scopus
PUBMED: 23571588
DOI: 10.1001/jama.2013.3190
PMCID: PMC3791140
DOI/URL:
Notes: --- - Cited By (since 1996):2 - "Export Date: 1 May 2013" - "CODEN: JAMAA" - ":doi 10.1001/jama.2013.3190" - "Source: Scopus"
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. James A Fagin
    181 Fagin
  2. Robert M Tuttle
    483 Tuttle