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

Mingzhao Xing, MD, PhD; Ali S. Alzahrani, MD; Kathryn A. Carson, ScM; David Viola, MD; Rossella Elisei, MD; Bela Bendlova, PhD; Linwah Yip, MD; Caterina Mian, MD; Federica Vianello, MD; R. Michael Tuttle, MD; Eyal Robenshtok, MD; James A. Fagin, MD; Efisio Puxeddu, MD, PhD; Laura Fugazzola, MD; Agnieszka Czarniecka, MD; Barbara Jarzab, MD, PhD; Christine J. O’Neill, MBBS(Hons), MS; Mark S. Sywak, MD; Alfred K. Lam, MD, PhD; Garcilaso Riesco-Eizaguirre, MD, PhD; Pilar Santisteban, PhD; Hirotaka Nakayama, MD; Ralph P. Tufano, MD; Sara I. Pai, M.D, PhD; Martha A. Zeiger, MD; William H. Westra, MD; Douglas P. Clark, MD; Roderick Clifton-Bligh, PhD; David Sidransky, MD; Paul W. Ladenson, MD; Vlasta Sykorova, PhD

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

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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 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.