AssociationBetween BRAFV600EMutationand MortalityinPatientsWithPapillaryThyroidCancer

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) inBRAFV600E–positive vs mutationnegative 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, 19.1835.94) 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, 0.623.47]). 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 theBRAFV600E 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.

[1]  Rebeccah L. Brown,et al.  Thyroid Cancer: Burden of Illness and Management of Disease , 2011, Journal of Cancer.

[2]  P. Gattuso,et al.  Genomic DNA Extraction and PCR Amplification of Exon 15 of the BRAF Gene and Exons 1 and 2 of the NRAS Gene , 2003 .

[3]  V. Trovisco,et al.  BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC , 2003, Oncogene.

[4]  M. Ladanyi,et al.  Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. , 2009, Cancer research.

[5]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[6]  M. Xing,et al.  BRAF mutation in thyroid cancer. , 2005, Endocrine-related cancer.

[7]  M. A. García-Cabezas,et al.  The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. , 2006, Endocrine-related cancer.

[8]  M. Xing,et al.  BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. , 2007, Endocrine reviews.

[9]  C. Nucera,et al.  BRAF(V600E) and microenvironment in thyroid cancer: a functional link to drive cancer progression. , 2011, Cancer research.

[10]  M. Nikiforova,et al.  Optimizing surgical treatment of papillary thyroid carcinoma associated with BRAF mutation. , 2009, Surgery.

[11]  A. Pinchera,et al.  BRAFV599E Mutation Is the Leading Genetic Event in Adult Sporadic Papillary Thyroid Carcinomas , 2004 .

[12]  H. Namba,et al.  Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. , 2003, The Journal of clinical endocrinology and metabolism.

[13]  M. Xing,et al.  Molecular pathogenesis and mechanisms of thyroid cancer , 2013, Nature Reviews Cancer.

[14]  Stephanie L. Lee,et al.  Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. , 2009, Thyroid : official journal of the American Thyroid Association.

[15]  P. Hou,et al.  The BRAFV600E causes widespread alterations in gene methylation in the genome of melanoma cells , 2012, Cell cycle.

[16]  P. Ladenson,et al.  BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. , 2005, The Journal of clinical endocrinology and metabolism.

[17]  P. Ladenson,et al.  BRAF mutation in papillary thyroid carcinoma. , 2003, Journal of the National Cancer Institute.

[18]  Dagmara Rusinek,et al.  Occurrence of BRAF mutations in a Polish cohort of PTC patients - preliminary results. , 2010, Endokrynologia Polska.

[19]  P. Ladenson,et al.  BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  P. Hou,et al.  Genome-wide alterations in gene methylation by the BRAF V600E mutation in papillary thyroid cancer cells. , 2011, Endocrine-related cancer.

[21]  R. Kodet,et al.  BRAFV600E mutation in the pathogenesis of a large series of papillary thyroid carcinoma in Czech Republic , 2010, Journal of endocrinological investigation.

[22]  N. Wada,et al.  Clinical significance of BRAF (V600E) mutation and Ki-67 labeling index in papillary thyroid carcinomas. , 2007, Anticancer research.

[23]  A. Toniato,et al.  BRAF analysis by fine needle aspiration biopsy of thyroid nodules improves preoperative identification of papillary thyroid carcinoma and represents a prognostic factor. A mono-institutional experience , 2011, Clinical chemistry and laboratory medicine.

[24]  Louise Davies,et al.  Increasing incidence of thyroid cancer in the United States, 1973-2002. , 2006, JAMA.

[25]  P. Beck‐Peccoz,et al.  BRAF mutations in an Italian cohort of thyroid cancers , 2004, Clinical endocrinology.

[26]  Y. Youn,et al.  The association of the BRAFV600E mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer , 2012, Cancer.

[27]  S Lemeshow,et al.  Confidence interval estimation of interaction. , 1992, Epidemiology.

[28]  Robert A. Smith,et al.  Correlation between BRAF mutation and the clinicopathological parameters in papillary thyroid carcinoma with particular reference to follicular variant. , 2011, Human pathology.

[29]  A. Chou,et al.  BRAF(V600E) mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer. , 2010, Surgery.