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.

Fig 1.

(A) Schematic of the human NTRK loci. Exon numbers are shown below their respective boxes for reference sequence NTRK1 transcript variant 1 (NM_001012331.1), NTRK2 transcript variant a (NM_006180.4), and NTRK3 transcript variant 1 (NM_001012338.2). Fusion breakpoints are shown as dotted lines for the indicated patients. Patient 7 has an exonic breakpoint; all other breakpoints are intronic. Note that exons are drawn at a larger scale than introns and that introns are not drawn to the same scale for each gene (NTRK1 locus is approximately 21 kilobases [kb], NTRK2 is approximately 358 kb, and NTRK3 is approximately 384 kb). (B) Schematic of predicted fusion protein products (see also Tables 2 and 3). Triangles and E notation indicate the fusion breakpoints and subsequent TRK exon. Purple-shaded domains are those predicted or shown to induce dimerization in the fusion partner (C4ZF, C4 zinc finger; PB1, Phox and Bem1p interaction domain; CC, coiled coil; Pointed, sterile alpha motif [SAM]/helix loop helix [HLH] oligomerization domain; RRM, RNA recognition motif). Green-shading indicates domains are other annotated sequence features (ZF, zinc finger; PH, pleckstrin homology). Gray shading indicates the transmembrane domain (TM). The kinase domains of TRKA/B/C are indicated and shown in light red, blue, and gold, respectively. Proteins are drawn to scale (MPRIP-NTRK1 fusion = 1,332 amino acids). Ig, immunoglobulin.

Fig 2.

Histology of select patient tumors; original magnification x100 unless otherwise specified. (A) Patient 2 had an adenocarcinoma with solid growth pattern, diffuse neuroendocrine differentiation, and signet ring cells; inset shows high magnification (x400). (B) Patient 1 had poorly differentiated adenocarcinoma with solid and single-cell growth patterns. (C) Patient 4 had mucinous adenocarcinoma, and patient 6 had similar histology (data not shown). (D) Patient 8 had squamous cell carcinoma. (E) Patient 11 had neuroendocrine carcinoma with well-differentiated morphology and increased mitotic activity (left); high magnification (x400) shown in middle.

Fig 3.

Overall survival of the 10 patients with metastatic disease measured from the date of stage IV diagnosis to date of death or last known follow-up. Censored patients are marked on the curve.