Clinicopathologic Features of Non–Small-Cell Lung Cancer Harboring an NTRK Gene Fusion

Abstract

Purpose Gene rearrangements involving NTRK1/2/3 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 NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized. Methods We compiled a database of NSCLC cases harboring NTRK fusions. We characterized the clinical, molecular, and histologic features of these cases with central review of histology. Results We identified 11 NSCLC cases harboring NTRK gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data, forming the study cohort. Fusions involved NTRK1 (7 cases) and NTRK3 (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 KRAS, EGFR, ALK, ROS1, 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 NTRK fusions in NSCLC of 0.23% (95% CI 0.11–0.40). Conclusion NTRK 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 NTRK fusions using a multiplexed NGS-based fusion assay.

Updated guidelines for predictive biomarker testing in advanced non-small-cell lung cancer: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

“…Several drugs are the subject of clinical trials, and at least two of them are approved or in the process of approval: larotrectinib (LOXO-101, a selective inhibitor) and entrectinib (also a ROS1 and ALK inhibitor) [78]. There is a very small proportion of lung carcinoma patients (especially with adenocarcinomas) that present rearrangements in NTRK1, NTRK2 or NTRK3 [79]. Although early studies showed higher percentages, recent publications suggest a prevalence of less than 1% [78].…”

Optimizing Mutation and Fusion Detection in NSCLC by Sequential DNA and RNA Sequencing

“…The 5-year survival rate in metastatic disease is only 4.7%, making lung cancer the number one cause of cancer deaths globally. 1,2 In current practice, all patients with locally advanced or metastatic NSCLC (nonsquamous type) should be tested for pathogenic driver mutations in EGFR, 3,4 BRAF, [5][6][7] ERBB2, 8,9 KRAS, 10,11 and MET (including exon 14 skipping) [12][13][14][15] ; amplifications in EGFR, 16,17 ERBB2, and MET 12 ; fusions in RET, [18][19][20] ALK, [21][22][23] NTRK, 24,25 and ROS1 26,27 ; and for programmed death-ligand 1 (PD-L1) expression. [28][29][30][31] This is especially important in NSCLC in nonsmokers, who, as a group, are a distinct molecular entity harboring different driver mutations.…”

Japan society of clinical oncology/Japanese society of medical oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese society of pediatric hematology/oncology

“…As for lung cancer, in a study in 4872 patients at 7 institutions, NTRK fusions were found in 11 patients (0.23%). Of them, six patients (55%) were male, eight patients (73%) were non-smokers/light smokers, and the median age was 47.6 years [30]. Nine of the 11 patients had adenocarcinoma.…”