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This version published online on September 20, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0987
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Submitted on May 5, 2005
Accepted on September 6, 2005

BRAF Mutation Predicts a Poorer Clinical Prognosis for Papillary Thyroid Cancer

Mingzhao Xing*, William H. Westra, Ralph P. Tufano, Yoram Cohen, Eli Rosenbaum, Kerry J. Rhoden, Kathryn A. Carson, Vasily Vasko, Alexandr Larin, Giovanni Tallini, Sara Tolaney, Elizabeth H. Holt, Pei Hui, Christopher B. Umbricht, Shehzad Basaria, Marge Ewertz, Anthony. P. Tufaro, Joseph A. Califano, Matthew D. Ringel, Martha A. Zeiger, David Sidransky, and Paul W. Ladenson

Division of Endocrinology and Metabolism (M.X., S.T., M.E., P.W.L.), Department of Medicine, Department of Pathology (W.H.W.), Department of Otolaryngology-Head and Neck Surgery (R.P.T., Y.C., E.R., J.A.C., D.S.), the Johns Hopkins University School of Medicine, Baltimore, Maryland 21287. J.B. Pierce Laboratory (K.J.R.), Yale University School of Medicine, New Haven, CT 06510. Department of Pathology (G.T.), University of Bologna School of Medicine, Bologna, Italy. Department of Epidemiology (K.A.C.), the Johns Hopkins University Bloomberg School of Public Health. Washington Hospital Center and Medstar Research Institute (V.V), Washington, D.C. 20010. Hospital for Endocrine Surgery (A.L.), Kiev, Ukraine. Department of Pathology (G.T., P.H.), and Section of Endocrinology-Department of Internal Medicine (E.H.H.), Yale University School of Medicine, New Haven, CT 06510. Department of Surgery (C.B.U., A.P.T., M.A.Z.), Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Endocrinology and Metabolism (S.B.), the Johns Hopkins Bayview Medical Center, Baltimore, Maryland 21224. Divisions of Endocrinology and Oncology (M.D.R.), the Ohio State University and Arthur G. James Cancer Center, Columbus, Ohio 43210

* To whom correspondence should be addressed. E-mail: mxing1{at}jhmi.edu.

Context Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this caner.

Objective To investigate the prognostic value of BRAF mutation in patients with PTC.

Design, Setting, and SubjectsIn a multi-center study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed.

Main Outcome Measure Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence.

Results We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25% vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3-29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (OR = 4.0; 95% CI, 1.1-14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I /II disease, 22% vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease.

Conclusions In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Threfore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.
Key words: BRAF mutation • thyroid cancer • prognosis • molecular marker




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