[531] Molecular Characterization of Radioactive Iodine Refractory (RAIR) FDG-PET Positive Thyroid Carcinoma (TC)

J Ricarte-Filho, M Rivera, RM Tuttle, JA Fagin, R Ghossein. Memorial Sloan-Kettering Cancer Center, New York

Background: RAIR FDG-PET positive TC represent the major cause of deaths from TC and are therefore the main focus of novel target therapies. Aim: To perform a comprehensive screen for known TC-associated oncogenic mutations in RAIR tumors and correlate genotype with histotype.
Design: Sixty samples of locally recurrent/metastatic (n=56) and primary tissue (n=4) from 43 RAIR PET positive patients were selected for histologic and molecular analysis. At least one biopsied metastatic site corresponded to a FDG-PET positive lesion sampled within 2 years of the PET scan. Poorly differentiated thyroid carcinomas (PDTC) were defined on the basis of high mitotic activity (> 5 mitosis/10 high power fields) and/or tumor necrosis. Paraffin tissue samples were genotyped using a highly multiplexed Sequenom mass spectrometry-based mutation assay that screened for 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, MAP2K1, AKT1, MET, IKBKB, PIK3R5, PRKCZ, RHEB, RPS6AK3, RPS6KB1, FRAP1..
Results: The mutation frequency in primary and locally recurrent/metastatic samples was as follows: BRAF (n=39; 65%), RAS (n=7; 12%), AKT1 (n=3; 5%), PIK3CA (n=2; 3%), MET (n=1; 2%), RET (n=2; 3%). Overall 34/43 (79%) patients had at least one mutation. In 13 patients with multiple tumor specimens, their mutational status was conserved in 7 (54%), and BRAF^T1799A status was homogeneous within patients in 11 individuals (85%). In 34 patients whose FDG-PET positive recurrence/metastases was genotyped, 23 (68%) were positive for any mutations, of which BRAF was the most common (20/34, 59%). The histotype of the 34 FDG-PET positive recurrence /metastases was as follows: PDTC: n=20; 59%-Papillary thyroid carcinoma (PTC) tall cell variant (TCV): n=6;17%- Well differentiated PTC (WDPTC): n=4;12%; Hurthle cell carcinoma (HCC):n=3;9%- Anaplastic carcinoma:n=1;3%. Of the 20 PDTC, 9 (45%) had BRAF^T1799A, 2 (10%) RAS, 1 MET (5%) and 8 (40%) were wild type. All 6 TCV and 3 WDPTC had BRAF^T1799A while 1 WDPTC had a BRAF^V600/K601del. All 3 HCC were wild type and the anaplastic tumor contained BRAF^T1799A. There was a very strong correlation between BRAF mutation and the presence of tall cells in the recurrence/metastatic site (P=0.0003).
Conclusions: 1) BRAF^T1799A is frequently seen in RAIR thyroid carcinomas 2) Distinct RAIR thyroid carcinoma sites are genetically homogeneous for BRAF^T1799A within a patient. 3) The above findings make BRAF an attractive target for therapy in incurable RAIR thyroid carcinomas.
Category: Endocrine

Tuesday, March 10, 2009 9:15 AM

Platform Session: Section H1, Tuesday Morning