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Original Contribution
April 10, 2013

Association Between BRAF V600E Mutation and Mortality in Patients With Papillary Thyroid Cancer

Author Affiliations

Author Affiliations: Laboratory for Cellular and Molecular Thyroid Research (Drs Xing and Alzahrani), Division of Endocrinology and Metabolism (Dr Ladenson), Department of Medicine, Department of Otolaryngology–Head and Neck Surgery (Drs Tufano, Pai, and Sidransky), Endocrine Surgery Section, Department of Surgery (Dr Zeiger), and Department of Pathology (Drs Westra and Clark), Johns Hopkins University School of Medicine, and Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (Ms Carson), Baltimore, Maryland; Endocrinology Unit, Department of Clinical and Experimental Medicine, World Health Organization Collaborating Center for the Study and Treatment of Thyroid Diseases and Other Endocrine and Metabolic Disorders, University of Pisa, Pisa, Italy (Drs Viola and Elisei); Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic (Drs Bendlova and Sykorova); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Yip); Operative Unit of Endocrinology, Department of Internal Medicine–DIMED, University of Padua (Dr Mian), and Veneto Institute of Oncology, Instituto di Ricovero e Cura a Carattere Scientifico (Dr Vianello), Padua, Italy; Department of Medicine, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (Drs Tuttle, Robenshtok, and Fagin); Department of Internal Medicine, University of Perugia, Perugia, Italy (Dr Puxeddu); Department of Clinical Sciences and Community Health, University of Milan, and Endocrine Unit, Fondazione Instituto di Ricovero e Cura a Carattere Scientifico Cà Granda, Milan, Italy (Dr Fugazzola); Departments of Oncological and Reconstructive Surgery and Nuclear Medicine (Dr Czarniecka) and Endocrine Oncology (Dr Jarzab), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland; Endocrine Surgical Unit (Drs O’Neill and Sywak) and Cancer Genetics, Kolling Institute of Medical Research (Dr Clifton-Bligh), University of Sydney, St Leonards, New South Wales, Australia; Department of Cancer Molecular Pathology, School of Medicine and Griffith Health Institute, Gold Coast, Queensland, Australia (Dr Lam); Department of Endocrinology and Nutrition, Hospital La Paz, Health Research Institute (Dr Riesco-Eizaguirre), and Biomedical Research Institute Alberto Sols, Spanish Council of Research and Autonomous University of Madrid (Drs Riesco-Eizaguirre and Santisteban), Madrid, Spain; andDepartment of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan (Dr Nakayama).

JAMA. 2013;309(14):1493-1501. doi:10.1001/jama.2013.3190

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 a median 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 mutation-negative 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.