Format

Send to

Choose Destination
JAMA Oncol. 2015 May;1(2):238-44. doi: 10.1001/jamaoncol.2015.34.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts2Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
2
Department of Pharmacology and Pharmacy, Li-Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong4Department of Biochemistry, Li-Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong5Department of Otolaryngology, University of Pittsb.
3
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania6Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
6
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
7
Blueprint Medicines, Cambridge, Massachusetts.
8
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
9
Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
10
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston.
11
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
12
Department of Genome Sciences, University of Washington, Seattle.
13
Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge13Department of Pathology, Massachusetts General Hospital, Boston.
14
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania14Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00779389.

PMID:
26181029
PMCID:
PMC4557203
DOI:
10.1001/jamaoncol.2015.34
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Supplementary concept, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Supplementary concept

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center