Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma

Abstract

Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results:RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions

“…Genomically, most patients with classical MEN2A harbor germline mutations in RET exons 10 (C609, C611, C618, or C620) or 11 (C634), whereas sporadic MTC is predominantly driven by activating somatic RET mutations, typically RET M918T . In addition to RET M918T, detected in 71% of the PAYA MTC cases analyzed here, we identified 3 novel indels within the RET ECD: RET C630_D631>CDELCRTVIAAAVLFSFT, RET L633_A639del, and RET D378_G385>E.…”

“…Thyroid carcinoma is notable among cancers due to the high frequency of recurrent fusions involving kinases . Among thyroid carcinomas, oncogenic fusions are most frequently found in PTCs , whereas they are rare in ATC , and, with a notable exception of a RET fusion identified in a patient with MTC, largely absent in MTC .…”

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

“…Nevertheless, promising data have been reported from a phase 2 trial in patients with progressive, advanced thyroid cancer who received everolimus in combination with sorafenib (Sherman et al 2016). In another report, everolimus was prescribed in addition to vandetanib in a patient who presented disease progression and observed a 25% tumor reduction (Heilmann et al 2016). The combination of RET kinase inhibitors and mTOR inhibitors might be an exciting dual targeting strategy, but it awaits further evaluation in clinical trials.…”

Synergistic activity of everolimus and 5‐aza‐2′‐deoxycytidine in medullary thyroid carcinoma cell lines

“…In fact, most of the pro-oncogenic effects of RET and RAS mutations are modulated by the activation of PI3K/Akt/mTOR pathway (Lyra et al, 2014;Manfredi et al, 2015). Few preliminary studies showed promising antitumor effects of mTOR inhibitors, such as everolimus, in MTC (Druce et al, 2012;Faggiano et al, 2012;Heilmann et al, 2016;Lim et al, 2013). A recent phase II study, assessing efficacy and tolerability of everolimus on tumor progression in patients with advanced thyroid cancer, showed stable disease in five (71%) of seven patients with MTC and a low toxicity profile for everolimus (Schneider et al, 2015).…”