Clinicopathologic Features of Non-Small-Cell Lung Cancer Harboring an <i>NTRK</i> Gene Fusion.

Abstract

Gene rearrangements involving <i>NTRK1/2/3</i> can generate fusion oncoproteins containing the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small cell lung cancer (NSCLC), with frequency previously estimated to be <1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with <i>NTRK</i> fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of <i>NTRK</i> fusion-positive NSCLCs are not well characterized. We compiled a database of NSCLC cases harboring <i>NTRK</i> fusions. We characterized the clinical, molecular, and histologic features of these cases with central review of histology. We identified 11 NSCLC cases harboring <i>NTRK</i> gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data, forming the study cohort. Fusions involved <i>NTRK1</i> (7 cases) and <i>NTRK3</i> (4 cases), with 5 and 2 distinct fusion partners, respectively. Cohort patients were 55% male, with a median age at diagnosis of 47.6 years (range 25.3-86.0) and a median pack year history of 0 (range 0-58). 73% of patients had metastatic disease at diagnosis. No concurrent alterations in <i>KRAS</i>, <i>EGFR</i>, <i>ALK</i>, <i>ROS1</i>, or other known oncogenic drivers were identified. Nine cases were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features; one was squamous cell carcinoma; and one was neuroendocrine carcinoma. By collating data on 4872 consecutively screened NSCLC cases from unique patients, we estimate a frequency of <i>NTRK</i> fusions in NSCLC of 0.23% (95% CI 0.11-0.40). <i>NTRK</i> fusions occur in NSCLCs across genders, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for <i>NTRK</i> fusions using a multiplexed NGS-based fusion assay.