Purpose: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes.Experimental Design: Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes.Results: PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n ¼ 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P ¼ 0.0006). Oncogenic RAS mutations (n ¼ 13) were associated with significantly poorer progression-free survival (P ¼ 0.0001) and lower overall survival (P ¼ 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response.Conclusions: Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort.

Cabozantinib was poorly tolerated and did not demonstrate activity in patients with recurrent/metastatic, platinum-failure MCC. It is unclear whether preselection of patients with the specific upregulation or genetic alteration in the targets for cabozantinib would have changed the results of this study. (Clinical trial identification number: NCT02036476) IMPLICATIONS FOR PRACTICE: This phase II study demonstrated poor tolerability and lack of activity of cabozantinib in an unselected group of patients with advanced Merkel cell carcinoma. Although it is unclear whether preselection of patients with the specific upregulation and genetic alterations in targets for cabozantinib would have changed the results of this study, this would have likely led to an extremely rare patient population that would take many years to accrue.

<p>Correlation with Number of Alterations per Sample and Progression-Free Survival.</p>

<div>Abstract<p><b>Purpose:</b> The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes.</p><p><b>Experimental Design:</b> Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes.</p><p><b>Results:</b> PI3K/RTK pathway activation occurred frequently [activating <i>PIK3CA</i> mutation or amplification (13%), <i>PTEN</i> inactivation (3%), <i>RAS</i> activation (6%), <i>EGFR</i> or <i>ERBB2</i> activation (9%)]. Alterations in pathways affecting cell-cycle regulation [<i>CCND1</i> amplification (9%), <i>CDKN2A</i> inactivation (17%), <i>BRCA2</i> inactivation (2%)] and squamous differentiation [<i>NOTCH1</i> inactivation (8%) and<i>EP300</i> inactivation (6%)] were identified. <i>PIK3CA</i> amplification (<i>n</i> = 43), not <i>PIK3CA</i> mutation, was associated with significantly poorer progression-free survival (<i>P</i> = 0.0006). Oncogenic <i>RAS</i> mutations (<i>n</i> = 13) were associated with significantly poorer progression-free survival (<i>P</i> = 0.0001) and lower overall survival (<i>P</i> = 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response.</p><p><b>Conclusions:</b> Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. <i>PIK3CA</i> amplification and <i>RAS</i> mutations were frequently identified and associated with poorer prognosis in this cohort. <i>Clin Cancer Res; 22(12); 2939–49. ©2016 AACR</i>.</p></div>