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

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.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

“…As shown in Figure 3A, baseline pMAPK expression was associated with erlotinib sensitivity (P = 0.099). One patient experienced an exceptional, near-complete histologic response of an oral cavity primary tumor to single-agent erlotinib, which we found to be associated with a MAPK1 E322K mutation (28). Identifying biomarkers of resistance is also critical to guide the use of targeted therapies.…”

“…In this trial, baseline pMAPK expression was associated with erlotinib response, irrespective of the presence of dasatinib. Moreover, one patient who demonstrated an exceptional response to erlotinib harbored an activating MAPK1 E322K mutation (28). Collectively, these findings suggest that basal MAPK activation, as established by IHC or whole exome sequencing, indicates EGFR pathway dependence and represents a predictive biomarker for the EGFR tyrosine kinase inhibitor.…”

The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome

“…Notably, the MAPK1 p.Glu322Lys mutation has been reported as an activating allele 15 and expression of both MAPK1 E322K and E322A resulted in increased ERK1/2 activation (Supplementary Fig. 3).…”

EGFR-targeted therapies in the post-genomic era

“…In a window-of-opportunity clinical trial, a patient with a stage IVA tongue carcinoma who received a 13-day course of erlotinib experienced remarkable disease reduction from initial clinical T1N2c disease with bulky lymphadenopathy to pathological T1N0 disease. Following surgery, the patient has remained disease-free for more than 4 years without additional treatment [59]. No EGFR mutation was identified in this patient.…”