Endocrine Abstracts

Objectives: Distant metastases in MTC adversely affect disease prognosis. Somatic mutations in spMTC as well as Variant Allele Frequency (VAF) have been related to tumor burden, disease course and the response to TKIs. The aim of this study is to report three cases of nucleotide (nt) insertions/deletions (indels) in the RET oncogene in relation to disease course/response to TKIs.

Methods: Of 195 spMTC patients followed-up in Dept. Clinical Therapeutics (Athens), 39 presented with persistent/metastatic disease. In 11/39 FFPEs were obtained. DNA was extracted and NGS libraries were prepared. In silico tools were used to estimate the pathogenic effect of novel mutations.

Results: 8/11 patients-72.7%, harbored RET somatic mutations while 3/11-27.3% HRAS. In 3 female patients RET-indels were detected. A: 32 y.o, diagnosed in 2018, stage IVA. Disease progression two-years later (mediastinum); thoracic surgery was performed. PET-CT following surgery revealed persistent disease (pre-carinal LNs). Due to threatening of vital structures, Vandetanib was initiated. Despite disease stabilization SAEs were recorded. NGS: deletion of 54 nts (RET-exon-10, p.Ile590_Gly607del, VAF: 36.34%), not previously reported. Therefore, treatment with Selpercatinib was initiated and a remarkable disease remission was documented. B: 80 y.o, diagnosed in 1990. Disease progression 20-years later, when the patient was referred to our Unit (metastases: cervical/mediastinal LNs, right breast-lump, liver, bones). LN-dissection, excision of the right breast-lump and local treatments, were performed. After a 12-months disease stabilization, enlargement in liver metastases was documented. Vandetanib was initiated achieving stabilization. NGS: deletion/insertion of 2 nts (RET-exon-11, p. [Leu633 =; Cys634Arg], VAF: 48.85%). C: 72 y.o, MTC diagnosis-2008, stage I. Disease progression two years later (cervical-LNs); LN-dissection was performed. During a 12yrs f-up, biochemical persistence (Calcitonin ~ 500 pg/ml) in the absence of metastases has been documented. NGS: insertion of 21 nts (RET-exon-11, p.Cys634_Ala640dup, VAF: 8.79%), not previously reported.

Conclusions: Deletions in the cysteine-rich region of RET are related to disease aggressiveness. Molecular mechanisms possibly involved may be related to the shortening of crucial for the oncogenic activity RET protein cysteine residues and the formation of stronger disulfide bonds. NGS, beyond of providing pivotal information regarding disease progression and response to TKIs, contributes to the identification of novel mutations even of low VAF, thus being an indispensable tool in precision medicine implementation.