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

JAMA Oncol
Authors
Keywords
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.

Year of Publication
2015
Journal
JAMA Oncol
Volume
1
Issue
2
Pages
238-44
Date Published
2015 May
ISSN
2374-2445
DOI
10.1001/jamaoncol.2015.34
PubMed ID
26181029
PubMed Central ID
PMC4557203
Links
Grant list
K07 CA137140 / CA / NCI NIH HHS / United States
P50 CA097190 / CA / NCI NIH HHS / United States
R01 CA098372 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States