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.
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: Richard J Robbins; Qiang Wan; Ravinder K Grewal; Roland Reibke; Mithat Gonen; H William Strauss; R Michael Tuttle; William Drucker; Steven M Larson Journal: J Clin Endocrinol Metab Date: 2005-11-22 Impact factor: 5.958
Authors: C Durante; N Haddy; E Baudin; S Leboulleux; D Hartl; J P Travagli; B Caillou; M Ricard; J D Lumbroso; F De Vathaire; M Schlumberger Journal: J Clin Endocrinol Metab Date: 2006-05-09 Impact factor: 5.958
Authors: Marina N Nikiforova; Paul W Biddinger; Christy M Caudill; Todd G Kroll; Yuri E Nikiforov Journal: Am J Surg Pathol Date: 2002-08 Impact factor: 6.394
Authors: M Schlumberger; M Tubiana; F De Vathaire; C Hill; P Gardet; J P Travagli; P Fragu; J Lumbroso; B Caillou; C Parmentier Journal: J Clin Endocrinol Metab Date: 1986-10 Impact factor: 5.958
Authors: Marco Volante; Paola Collini; Yuri E Nikiforov; Atsuhiko Sakamoto; Kennichi Kakudo; Ryohei Katoh; Ricardo V Lloyd; Virginia A LiVolsi; Mauro Papotti; Manuel Sobrinho-Simoes; Gianni Bussolati; Juan Rosai Journal: Am J Surg Pathol Date: 2007-08 Impact factor: 6.394
Authors: Alan L Ho; Ravinder K Grewal; Rebecca Leboeuf; Eric J Sherman; David G Pfister; Desiree Deandreis; Keith S Pentlow; Pat B Zanzonico; Sofia Haque; Somali Gavane; Ronald A Ghossein; Julio C Ricarte-Filho; José M Domínguez; Ronglai Shen; R Michael Tuttle; Steve M Larson; James A Fagin Journal: N Engl J Med Date: 2013-02-14 Impact factor: 91.245
Authors: David Hiltzik; Diane L Carlson; R Michael Tuttle; Shaokun Chuai; Nicole Ishill; Ashok Shaha; Jatin P Shah; Buvanesh Singh; Ronald A Ghossein Journal: Cancer Date: 2006-03-15 Impact factor: 6.860
Authors: Bryan R Haugen; Erik K Alexander; Keith C Bible; Gerard M Doherty; Susan J Mandel; Yuri E Nikiforov; Furio Pacini; Gregory W Randolph; Anna M Sawka; Martin Schlumberger; Kathryn G Schuff; Steven I Sherman; Julie Ann Sosa; David L Steward; R Michael Tuttle; Leonard Wartofsky Journal: Thyroid Date: 2016-01 Impact factor: 6.568