title: Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases.
abstract: BACKGROUND
  Radioiodine (RAI) remains the mainstay of therapy for RAI-avid (RAIA) distant metastatic thyroid carcinoma. We previously demonstrated that RAI-refractory distant metastatic thyroid cancers commonly harbor BRAF mutations. However, the molecular profile of RAIA metastatic thyroid cancer is unknown. Here we describe the mutational profile of thyroid tumors from follicular cell-derived cancer (FCDTC) patients presenting with RAIA distant metastases. In addition, we aimed to correlate clinical outcomes of RAI therapy with clinicopathological factors and tumor mutational status.
  
  
  METHODS
  We retrospectively identified 43 patients with FCDTC who had RAI uptake in the lungs and/or bones on their initial ¹³¹I postablation scan. Primary tumors were genotyped for known mutations in thyroid cancer genes. Structural response to RAI was assessed 6-18 months after each administered RAI activity and at the end of follow-up.
  
  
  RESULTS
  RAS, BRAF, RET/PTC, and PIK3CA mutations were found in 42, 23, 10, and 2% of tumors, respectively, and the remaining 23% were wild type. None of these patients achieved cure after repeat RAI therapies, and most patients (54%) experienced disease progression despite repeated RAI administration. There was an increased prevalence of RAS mutations in these RAIA tumors. RAS-mutant cancers were more likely to concentrate iodine on diagnostic whole body scans. Despite this, structural response to RAI was not influenced by tumor genotype.
  
  
  CONCLUSIONS
  RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations. Despite a seemingly preserved ability to concentrate iodine, RAI therapy is ineffective in achieving cure in most patients with RAIA metastatic FCDTC, even in RAS-mutant disease. These poor outcomes may be improved based on recent evidence that pretreatment with MAPK kinase 1/2 inhibitors enhances responses to RAI, particularly in patients with RAS-mutant tumors.
authors.affiliation: Endocrinology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill-Cornell College of Medicine, New York, New York 10065, USA. sabram@mskcc.org
authors.forename: M M
authors.initials: MM
authors.lastname: Sabra
authors.forename: J M
authors.initials: JM
authors.lastname: Dominguez
authors.forename: R K
authors.initials: RK
authors.lastname: Grewal
authors.forename: S M
authors.initials: SM
authors.lastname: Larson
authors.forename: R A
authors.initials: RA
authors.lastname: Ghossein
authors.forename: R M
authors.initials: RM
authors.lastname: Tuttle
authors.forename: J A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000378:metabolism / Q000556:secondary* / Q000628:therapy; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D012189:Retrospective Studies; D016019:Survival Analysis; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy* / Q000601:surgery; D013965:Thyroidectomy; D055815:Young Adult
chemical_list: D007457:Iodine Radioisotopes; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D019275:Radiopharmaceuticals