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Somatic Ret Indels In Sporadic Medullary Thyroid Cancer: Prevalence And Response To Selpercatinib.

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.