Retrospective study of prevalence and characteristics of NTRK fusions in two cohorts of patients with non-small cell lung cancer

Functional NTRK1-2-3 fusions are rare, tumor-agnostic, targetable alterations. Accurate detection is essential to ensure optimal treatment. A study by the European Thoracic Oncology Platform (ETOP) investigated the prevalence of NTRK fusions in two cohorts of patients with NSCLC: the Lungscape Cohort, comprising of tissue microarrays from 1703 resected stage I-III NSCLC cases (52% adenocarcinomas, 40% squamous cell carcinomas) and the NGS Cohort of 24,243 NSCLC patients. The Lungscape Cohort was screened using pan-TRK immunohistochemistry (IHC) and positive cases were confirmed by next-generation sequencing (NGS). The NGS Cohort was screened by NGS and positive cases were retested using IHC. In the Lungscape Cohort, panTRK IHC was found positive in 69 patients (4%; 60 squamous cell carcinoma, 5 adenocarcinoma, 4 large cell carcinoma; median H-score 37; range 5-200). Sixty-five samples underwent confirmatory testing by NGS, and one fusion was found, which after manual review was classified as non-functional. The NGS Cohort yielded 11 fusions of which eight were functional (0.03%; 5 in NTRK1, 1 in NTRK2, and 2 in NTRK3) and five were retested using IHC (median H-score 200; range 50-300). Of the three non-functional fusions, two were IHC negative, an one weakly positive (H-score 30). The authors conclude that pant-TRK IHC has a false-positive rate of approximately 4%, particularly in squamous cell carcinomas, underscoring the need for confirmatory NGS to validate IH findings and assess fusion functionality. Functional NTRK1/2/3 fusions remain exceedingly rare in NSCLC, with a detection rate of 0.03% across both cohorts.