Journal
JAMA ONCOLOGY
Volume 1, Issue 2, Pages 238-244Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaoncol.2015.34
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Funding
- American Cancer Society
- Patricia L. Knebel Fund of the Pittsburgh Foundation
- National Cancer Institute [K07 CA137140]
- Sheikh Khalifa bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
- Slim Initiative for Genomic Medicine
- US-Mexico project - Carlos Slim Health Institute
- National Cancer Institute Head and Neck Cancer Specialized Program of Research Excellence [P50 CA097190]
- OSI Pharmaceuticals
- Bristol-Myers Squibb
- US Department of Veterans Affairs Career Development Award, Biomedical Laboratory Research and Development
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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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