MET Genomic Alterations in Head and Neck Squamous Cell Carcinoma (HNSCC): Rapid Response to Crizotinib in a Patient with HNSCC with a Novel MET R1004G Mutation

Lisa Pei Chu, Debra Franck, Christine A. Parachoniak, Jeffrey Gregg, Michael Moore, D Gregory Farwell, Shyam Rao, Andreas M. Heilmann, Rachel L. Erlich, Jeffrey S. Ross, Vincent A. Miller, Siraj Ali, Jonathan Riess

Research output: Contribution to journalArticle

Abstract

Identification of effective targeted therapies for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains an unmet medical need. A patient with platinum-refractory recurrent oral cavity HNSCC underwent comprehensive genomic profiling (CGP) that identified an activating MET mutation (R1004). The patient was treated with the oral MET tyrosine kinase inhibitor crizotinib with rapid response to treatment. Based on this index case, we determined the frequency of MET alterations in 1,637 HNSCC samples, which had been analyzed with hybrid capture-based CGP performed in the routine course of clinical care. The specimens were sequenced to a median depth of >500× for all coding exons from 182 (version 1, n = 24), 236 (version 2, n = 326), or 315 (version 3, n = 1,287) cancer-related genes, plus select introns from 14 (version 1), 19 (version 2), or 28 (version 3) genes frequently rearranged in cancer. We identified 13 HNSCC cases (0.79%) with MET alterations (4 point mutation events and 9 focal amplification events). MET-mutant or amplified tumors represent a small but potentially actionable molecular subset of HNSCC. Key Points: This case report is believed to be the first reported pan-cancer case of a patient harboring a MET mutation at R1004 demonstrating a clinical response to crizotinib, in addition to the first documented case of head and neck squamous cell carcinoma (HNSCC) with any MET alteration responding to crizotinib. The positive response to MET inhibition in this patient highlights the significance of comprehensive genomic profiling in advanced metastatic HNSCC to identify actionable targetable molecular alterations as current treatment options are limited.

Original languageEnglish (US)
JournalOncologist
DOIs
StateAccepted/In press - Jan 1 2019

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Mutation
Neoplasms
Neoplasm Genes
crizotinib
Carcinoma, squamous cell of head and neck
Platinum
Point Mutation
Protein-Tyrosine Kinases
Introns
Mouth
Exons
Therapeutics
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MET Genomic Alterations in Head and Neck Squamous Cell Carcinoma (HNSCC) : Rapid Response to Crizotinib in a Patient with HNSCC with a Novel MET R1004G Mutation. / Chu, Lisa Pei; Franck, Debra; Parachoniak, Christine A.; Gregg, Jeffrey; Moore, Michael; Farwell, D Gregory; Rao, Shyam; Heilmann, Andreas M.; Erlich, Rachel L.; Ross, Jeffrey S.; Miller, Vincent A.; Ali, Siraj; Riess, Jonathan.

In: Oncologist, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Identification of effective targeted therapies for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains an unmet medical need. A patient with platinum-refractory recurrent oral cavity HNSCC underwent comprehensive genomic profiling (CGP) that identified an activating MET mutation (R1004). The patient was treated with the oral MET tyrosine kinase inhibitor crizotinib with rapid response to treatment. Based on this index case, we determined the frequency of MET alterations in 1,637 HNSCC samples, which had been analyzed with hybrid capture-based CGP performed in the routine course of clinical care. The specimens were sequenced to a median depth of >500× for all coding exons from 182 (version 1, n = 24), 236 (version 2, n = 326), or 315 (version 3, n = 1,287) cancer-related genes, plus select introns from 14 (version 1), 19 (version 2), or 28 (version 3) genes frequently rearranged in cancer. We identified 13 HNSCC cases (0.79{\%}) with MET alterations (4 point mutation events and 9 focal amplification events). MET-mutant or amplified tumors represent a small but potentially actionable molecular subset of HNSCC. Key Points: This case report is believed to be the first reported pan-cancer case of a patient harboring a MET mutation at R1004 demonstrating a clinical response to crizotinib, in addition to the first documented case of head and neck squamous cell carcinoma (HNSCC) with any MET alteration responding to crizotinib. The positive response to MET inhibition in this patient highlights the significance of comprehensive genomic profiling in advanced metastatic HNSCC to identify actionable targetable molecular alterations as current treatment options are limited.",
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