Lung cancer (Amsterdam, Netherlands) · 2026
Prevalence and characteristics of NTRK fusions in 25,946 patients with non-small cell lung cancer.
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Radonic Teodora, Rahmani-Khajouei Sepehr, Dafni Urania, Stenzinger Albrecht, Haberecker Martina, Madsen Line Bille, Monkhorst Kim, Kowalski Jacek, Hernandez-Losa Javier, Kerr Keith M, Speel Ernst Jan M, Bubendorf Lukas, Joseph Leena, Navarro Atilio, Thunnissen Erik, Sansano Irene, Hillen Lisa M, Biernat Wojciech, Christoffel Miriam, Tsamtsouri Lydia, Kammler Roswitha, Peters Solange, Zoche Martin, Stahel Rolf A, Finn Stephen P, ETOP Lungscape consortium
Аннотация
BACKGROUND: Functional NTRK1-2-3 fusions are rare, tumor-agnostic, targetable alterations. Accurate detection is essential to ensure optimal treatment. We investigated the prevalence of NTRK fusions in two cohorts of patients with NSCLC.
METHODS: The Lungscape Cohort, comprising of tissue microarrays from 1703 resected stage I-III NSCLC cases (52% adenocarcinomas, 40% squamous cell carcinomas), was screened using pan-TRK immunohistochemistry (IHC, EPR17341, Ventana) and positive cases were confirmed by next-generation sequencing (NGS). The NGS Cohort of 24,243 NSCLC was screened by NGS within the European Lungscape Center Network and positive cases were retested using IHC. Functional fusions were defined as in-frame fusions containing an intact NTRK kinase domain.
RESULTS: In the Lungscape Cohort of resected NSCLC panTRK IHC was found positive in 69 (60squamous cell carcinoma, 5 adenocarcinoma, 4 large cell carcinoma) of 1703 patients (4%, 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 in tumors of 24,243 patients 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 and 1 weakly positive (H-score 30).
CONCLUSION: Pan-TRK IHC has a false-positive rate of ∼4%, particularly in squamous cell carcinomas, underscoring the need for confirmatory NGS to validate IHC findings and assess fusion functionality. Functional NTRK1/2/3 fusions remain exceedingly rare in NSCLC, with a detection rate of 0.03% across our combined cohorts.
METHODS: The Lungscape Cohort, comprising of tissue microarrays from 1703 resected stage I-III NSCLC cases (52% adenocarcinomas, 40% squamous cell carcinomas), was screened using pan-TRK immunohistochemistry (IHC, EPR17341, Ventana) and positive cases were confirmed by next-generation sequencing (NGS). The NGS Cohort of 24,243 NSCLC was screened by NGS within the European Lungscape Center Network and positive cases were retested using IHC. Functional fusions were defined as in-frame fusions containing an intact NTRK kinase domain.
RESULTS: In the Lungscape Cohort of resected NSCLC panTRK IHC was found positive in 69 (60squamous cell carcinoma, 5 adenocarcinoma, 4 large cell carcinoma) of 1703 patients (4%, 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 in tumors of 24,243 patients 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 and 1 weakly positive (H-score 30).
CONCLUSION: Pan-TRK IHC has a false-positive rate of ∼4%, particularly in squamous cell carcinomas, underscoring the need for confirmatory NGS to validate IHC findings and assess fusion functionality. Functional NTRK1/2/3 fusions remain exceedingly rare in NSCLC, with a detection rate of 0.03% across our combined cohorts.
Предметные рубрики MeSH
HumansCarcinoma, Non-Small-Cell LungLung NeoplasmsFemaleReceptor, trkAMaleOncogene Proteins, FusionAgedMiddle AgedHigh-Throughput Nucleotide SequencingReceptor, trkCPrevalenceMembrane GlycoproteinsImmunohistochemistryNeoplasm StagingReceptor, trkBAdultAged, 80 and overBiomarkers, TumorCohort Studies