Abstract
<div>Abstract<p><b>Purpose:</b> <i>KEAP1</i> and <i>NFE2L2</i> mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.</p><p><b>Experimental Design:</b> Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with <i>KEAP1</i> or <i>NFE2L2</i> mutations were assessed.</p><p><b>Results:</b> <i>KEAP1</i> mutations occurred with a frequency of 11.3% (<i>n</i> = 157) and <i>NFE2L2</i> mutations with a frequency of 3.5% (<i>n</i> = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. <i>KEAP1</i> mutations were found mainly in adenocarcinoma (AD; 72%), while <i>NFE2L2</i> mutations were more common in squamous cell carcinoma (LSCC; 59%). <i>KEAP1</i> mutations were spread over the whole protein, whereas <i>NFE2L2</i> mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating <i>EGFR</i> mutations or <i>MET</i> amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with <i>KEAP1</i> mutation had a response on systemic treatment in first-, second-, or third-line setting. Of <i>NFE2L2</i>-mutated patients, none responded to second- or third-line therapy.</p><p><b>Conclusions:</b> <i>KEAP1</i>- and <i>NFE2L2</i>-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. <i>Clin Cancer Res; 24(13); 3087–96. ©2018 AACR</i>.</p></div>
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