Clinical and pathological characteristics of KEAP1- and NFE2L2- mutated non-small cell lung carcinoma (NSCLC)

Background: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in many cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, few is known about frequency, histology-dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Patients and methods: Tumor tissue of 1391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n=157) and NFE2L2 mutations with a frequency of 3.5% (n=49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD) (72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC) (59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in hot-spot regions. In over 80% of patients both mutations co-occurred with other cancer-related mutations, among them targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage and performance state. No patient with KEAP1 mutation had a response on systemic treatment in 1st-, 2nd- or 3rd-line setting. Of NFE2L2 mutated patients, none responded to 2nd- or 3rd-line therapy. Conclusion: KEAP1 and NFE2L2 mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and are found together with other cancer-related, partly targetable, aberrations. Both markers seem to be predictive for chemotherapy resistance. 

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