Journal of Clinical Oncology Precision Oncology | July, 2018
Anna F. Farago, Martin S. Taylor, Robert C. Doebele, Viola W. Zhu, Shivaani Kummar, Alexander I. Spira, Theresa A. Boyle, Eric B. Haura, Maria E. Arcila, Ryma Benayed, Dara L. Aisner, Nora K. Horick, Jochen K. Lennerz, Long P. Le, A. John Iafrate, Sai-Hong I. Ou, Alice T. Shaw, Mari Mino-Kenudson, and Alexander Drilon
Gene rearrangements that involve NTRK1/2/3 can generate fusion oncoproteins that contain 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.
We compiled a database of patients with NSCLCs that harbor NTRK fusions. We characterized clinical, molecular, and histologic features with central review of histology.
We identified 11 patients with NSCLCs that harbor NTRK gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data. Fusions involved NTRK1 (n = 7) and NTRK3 (n = 4), with five and two distinct fusion partners, respectively. Fifty-five percent of cohort patients were male with a median age at diagnosis of 47.6 years (range, 25.3 to 86.0 years) and a median smoking history of 0 pack-years (range, 0 to 58 pack-years). Seventy-three percent of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known oncogenic drivers were identified. Nine patients had adenocarcinoma, including two with invasive mucinous adenocarcinoma and one with adenocarcinoma with neuroendocrine features; one had squamous cell carcinoma; and one had neuroendocrine carcinoma. By collating data on 4,872 consecutively screened, unique patients with NSCLC, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI, 0.11% to 0.40%).
NTRK fusions occur in NSCLCs across sexes, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions by using a multiplexed next-generation sequencing (NGS)–based fusion test.