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 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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Xing and Sidransky reported receiving royalties as coholders of a licensed US patent related to BRAF V600E mutation in thyroid cancer. Dr Elisei reports board membership, consultancy, and/or payment for lectures/speakers bureaus for AstraZeneca, Bayer, Exelixis, Genzyme, and Roche. Dr Fagin reports that he is lead investigator in clinical trials with an AZ MEK inhibitor and receives grant support for preclinical studies with this and other compounds in BRAF mutant thyroid cancer models. Dr Puxeddu reports consultancy for Euro 7000. Dr Jarzab reports consultancy for AstraZeneca, employment by AstraZeneca, Novartis, Pfizer, Bayer, Roche, Eisai, OxiGene, and Exelixis for clinical trials, payment for lecturing and development of educational presentations by Novartis and Ipsen, payment for manuscript preparation by Molecular and Cellular Endocrinology, and payment for travel/meeting expenses by Novartis, Sanofi, and Ipsen. Dr Tufano reports consultancy for Ethicon Endosurgery and Medtronic. Dr Clifton-Bligh reports advisory board membership (money to his institution) for Amgen, Merck Sharp & Dohme, Ipsen, and Genzyme. No other disclosures were reported.

Figures

Figure 1

Kaplan-Meier Survival Curves of PTC-Specific Survival by BRAF V600E Mutation Status Comparison of patient survival, represented by log-rank P values in each panel, was performed between BRAF V600E–negative and BRAF V600E–positive groups for all patients and for patients with conventional papillary thyroid cancer (PTC). Follow-up time is truncated at 12 years.

Figure 2

Kaplan-Meier Survival Curves of the Interaction of BRAF V600E Mutation With Clinicopathological Risk Factors in Affecting Disease-Specific Survival of Patients With Papillary Thyroid Cancer In all panels, follow-up time is truncated at 12 years. In each panel, P values are from the log-rank test adjusted for multiple comparisons comparing each stratum with patients negative for both the BRAF V600E mutation and the indicated clinicopathological factor.

Figure 3

Kaplan-Meier Survival Curves of the Interaction of BRAF V600E Mutation With Age in Affecting Disease-Specific Survival of Patients With Papillary Thyroid Cancer In all panels, follow-up time is truncated at 12 years. In each panel, P values are from the log-rank test adjusted for multiple comparisons comparing each stratum with patients negative for both the BRAF V600E mutation and younger than 45 years (panel A) or younger than 60 years (panel B).