Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma | Genetics and Genomics | JAMA Oncology | JAMA Network
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Brief Report
May 2015

Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma

Author Affiliations
  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 2Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge
  • 3Department of Pharmacology and Pharmacy, Li-Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
  • 4Department of Biochemistry, Li-Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
  • 5Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 6Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 7Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 8Blueprint Medicines, Cambridge, Massachusetts
  • 9Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 10Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston
  • 11Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
  • 12Department of Genome Sciences, University of Washington, Seattle
  • 13Department of Pathology, Massachusetts General Hospital, Boston
  • 14Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
JAMA Oncol. 2015;1(2):238-244. doi:10.1001/jamaoncol.2015.34
Abstract

Importance  Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response.

Objective  To determine a mechanism of exceptional response to erlotinib therapy in HNSCC.

Design, Setting, and Participants  Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response.

Intervention  A brief course of erlotinib monotherapy followed by surgical resection.

Main Outcomes and Measures  Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants.

Results  No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells.

Conclusions and Relevance  Selective erlotinib use in HNSCC may be informed by precision oncology approaches.

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