title: BRAF(V600E) Mutation is Associated with Decreased Disease-Free Survival in Papillary Thyroid Cancer.
abstract: BACKGROUND
  The BRAF (V600E) mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80 %. BRAF(V600E) aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAF(V600E) on clinicopathological features of PTC. The study aims to determine whether BRAF(V600E) is useful as a prognostic biomarker in PTC.
  
  
  METHODS
  A cohort study of patients undergoing surgery for PTC was undertaken. The primary outcome measure was disease-free survival. Secondary outcome measures were tumour size, nodal positivity and radioactive iodine ablation rate. All cases were re-examined to confirm PTC. Immunohistochemistry for BRAF(V600E) was performed on tissue microarrays. A single endocrine pathologist, blinded to clinicopathological data, interpreted staining.
  
  
  RESULTS
  496 patients with PTC were included, and 309 (62 %) were BRAF(V600E) positive. Tumour size was similar for BRAF(V600E)-positive and -negative tumours (21.3 vs. 23.2 mm, p = 0.23). BRAF(V600E)-positive patients were significantly older at first operation (mean age 45 versus 49 years, p = 0.003). BRAF(V600E)-positive PTCs had a higher rate of disease recurrence (12.9 vs. 5.6 %, p = 0.004), lymph node metastasis (44 vs. 29.4 %, p = 0.004) and extra-thyroidal extension (44 vs. 22 %, p < 0.001). Five-year disease-free survival was 89.6 % for BRAF(V600E) positive and 96.3 % for negative tumours, p < 0.001. There was no difference between groups for vascular invasion or multifocality. The mean follow-up was 57 months for both groups.
  
  
  CONCLUSIONS
  BRAF(V600E) in PTC predicts an increased risk of lymph node metastasis, extra-thyroidal extension and reduced disease-free survival. It is an additional useful prognostic biomarker.
authors.affiliation: Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia. sheilafraser@doctors.org.uk.
authors.forename: S
authors.initials: S
authors.lastname: Fraser
authors.affiliation: Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Go
authors.affiliation: Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Aniss
authors.affiliation: Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Sidhu
authors.affiliation: Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Delbridge
authors.affiliation: Department of Endocrinology, Royal North Shore Hospital and Sydney Medical School, University of Sydney, St Leonards, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Learoyd
authors.affiliation: Department of Endocrinology, Royal North Shore Hospital and Sydney Medical School, University of Sydney, St Leonards, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Clifton-Bligh
authors.affiliation: Department of Endocrinology, Royal North Shore Hospital and Sydney Medical School, University of Sydney, St Leonards, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Tacon
authors.affiliation: Department of Endocrinology, Royal North Shore Hospital and Sydney Medical School, University of Sydney, St Leonards, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Tsang
authors.affiliation: Department of Endocrinology, Royal North Shore Hospital and Sydney Medical School, University of Sydney, St Leonards, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Robinson
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital and Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Surgical Endocrine Unit, Royal North Shore Hospital, University of Sydney, Level 3, Acute Services Building, Reserve Road, St Leonards, NSW, 2065, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Sywak
mesh_terms: D055011:Ablation Techniques; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary* / Q000601:surgery; D002291:Carcinoma, Papillary; D002648:Child; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000032:analysis / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D047368:Tumor Burden / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D007457:Iodine Radioisotopes; D048493:Proto-Oncogene Proteins B-raf