Clinical and Pathological Characteristics of <i>KEAP1</i> - and <i>NFE2L2</i> -Mutated Non–Small Cell Lung Carcinoma (NSCLC)

Abstract

<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.<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.<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.<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>.