Somatic RET Indels in Sporadic Medullary Thyroid Cancer: Prevalence and Response to Selpercatinib

Abstract

Context Although the majority of RET alterations are single nucleotide variants (SNV), small deletions and/or insertions have been reported at variable prevalence. No information about the efficacy of RET specific inhibitors in patients harboring RET indels, has been provided. Objective To present an update on the prevalence of RET indels in MTC and describe the efficacy of selpercatinib in patients with advanced RET indels MTC. Patients and Methods MTC tissues of 287 patients were analyzed using an Ion S5 targeted sequencing. The functional role of the reported indels have been evaluated by Mutation-Taster. Clinical and pathological data of MTC patients harboring a RET indel were collected and analyzed. Two patients with a RET indel have been treated with selpercatinib. Results Among 178 RET positive cases, 147 (82.6%) harbored a SNV and 31 (17.4%) a RET in-frame indel. Nine indels were not previously reported and were found to be disease causing by Mutation-Taster. Patients harboring an indel were found to have an aggressive disease and 2 of them were treated with selpercatinib, experiencing a good response to the treatment. Conclusions These data show that RET indels are not infrequent and correlate with an aggressive disease. Two RET indels positive patients showed a partial response to the treatment with highly selective RET inhibitor thus these RET indels can be considered actionable mutations. In order to not miss these alterations, the analysis of the full gene is recommended.

Precision oncology for RET-related tumors

“…The prognostic role of the RET deletions (including indels) has not been clearly proved due to the few available data. However, in a recent paper, Elisei R. et al observed that MTC harboring RET indels, show a more aggressive phenotype with a high prevalence of advanced cases at diagnosis (45).…”

“…However, in a recent paper, Elisei R. et al. observed that MTC harboring RET indels, show a more aggressive phenotype with a high prevalence of advanced cases at diagnosis ( 45 ).…”

“…Seven are germline deletions and are mainly located in the cysteine-rich domain, at exons 11 and 10 ( 18 – 24 ), and two are in the cadherin-like coding regions, at exons 6 and 7 ( 25 , 26 ). Most RET deletions have been found in the tumor tissue of sporadic MTCs, mainly at exons 11 and 15 ( 3 , 4 , 25 , 27 – 49 ), and to a lesser extent at exons 10 and 8 ( 30 , 45 , 49 – 51 ). Although only a few deletions have been reported in non-”hotspot” exons (i.e., exons 6 and 7), we cannot exclude that their frequency may be higher since those exons are not routinely studied.…”

“…Recently, two MTC patients with the p.E632_L633del and p.D631_L633delinsS RET deletion, respectively, who were previously treated with cabozantinib and/or vandetanib, experienced a treatment benefit with selpercatinib, with a rapid biochemical response. In particular, the first patient showed a partial response in the target lesions and stable disease in non-target lesions, while the second patient showed stable disease and a partial response in target and non-target lesions, respectively ( 45 ). An in vitro study provided evidence that the p.C630del RET alteration is sensitive to pralsetinib ( 23 ).…”

Initial Experiences of Selective RET Inhibitor Selpercatinib in Adults with Metastatic Differentiated Thyroid Carcinoma and Medullary Thyroid Carcinoma: Real-World Case Series in Korea

“…Selpercatinib also showed good efficacy in studies using a Chinese population [ 13 ]. It has been suggested that other RET alterations with less frequency, such as indels which indicate complex alterations such as small deletions or insertions or both, can also be treated with selpercatnib [ 14 ].…”