Background: Tyrosine Kinase Inhibitors show great promise in the management of metastatic Medullary Thyroid Carcinoma.Somatic mutations are considered to play a major role in the response/resistance to therapies.RET-somatic mutations are present in 45-75% of sporadic MTCs while RAS are rarer.
Objectives: The aim of this study is to investigate the mutational profile of 18 spMTC pts, with metastatic/biochemical persistent disease and to look into possible associations with the response to TKIs treatment.
Methods: 37/191 spMTC pts, presented with biochemical persistent or metastatic disease.In 18/37pts, FFPEs were obtained. DNA was extracted & NGS libraries were constructed for the sequencing. Data analysis, including alignment to the hg19 human reference genome and variant calling, was performed using the Torrent Suite Software(ThermoFisher).
Results: 11/18pts(61.1%) harboured a RET somatic mutation(RET-pos),(Variant Allele Frequency:19.17-42.39%), while 5/11 carried also Variants of Uncertain Significance. The majority of our mutated spMTCs harboured the RET-M918T mutation (8/11,72.72%); in 3 pts the following RET mutations were detected: C634A, C630A, V804M. Coexistence of (a) RET-M918T & MTOR (b) RET-V804M & TP53 mutation with presentation of brain metastases, was detected in 2 patients. 5 pts (3/5 RET-pos) presented with biochemical persistent disease while distant metastases were present in 13 (8/13 RET-pos). 9 pts (5/9 RET-pos & 4/9 without mutation) are under TKIs treatment (Vandetanib n=6, Cabozatinib, Lenvatinib, Selpercatinib). Out of 9pts under TKIs, 4/5 harbouring the RET-M918T & 2/4 without mutation, show partial response. 3 pts developed resistance to Vandetanib; one with the "gatekeeper" RET-V804M and two without mutation.
Conclusions: The frequency of RET somatic mutations found in our cohort is consistent with literature.Tumor molecular profiling can provide crucial information regarding disease progression and response to targeted therapies in metastatic MTC patients.