While HNSCC tumors are largely negative for RAS mutations at diagnosis [14, 20] and EGFR ectodomain mutations have not been detected by conventional sequencing to date, we reasoned that potential resistance-mediating mutations could be present in rare tumor subclones before treatment (undetectable by conventional sequencing) and would subsequently be amplified under the selective pressure of EGFR-targeted antibody treatment. The gene discussed is EGFR; the disease is head and neck squamous cell carcinoma.