Zeynep Sagnak Yilmaz, Zeynep Turkmen Usta, Gizem Teoman, Rumeysa Beyzanur Gulcebi, Sevdegul Aydin Mungan, Safak Ersoz
Medicine Science - 2026;15(1):370-376
NTRK gene fusions are rare but actionable oncogenic drivers of non-small cell lung cancer (NSCLC). Although receptor tyrosine kinase (TRK) inhibitors show high efficacy, the relationship between NTRK status, concurrent mutations, and immune biomarkers, such as PD-L1, remains to be fully elucidated. We retrospectively evaluated 413 NSCLC cases that underwent comprehensive profiling for NTRK fusions and other somatic alterations using targeted next-generation sequencing (NGS). PD-L1 expression was assessed using immunohistochemistry at 1%, 10%, and 50% cut-off levels. NTRK fusions were identified in 12 (2.9%) patients. The median age of the NTRK fusion-positive group was 65 years, with male predominance (83.3%). Adenocarcinoma was the most common histological type (50.0%). Genomic analysis revealed a high rate of co-occurring mutations, particularly in EGFR (25.0%) and TP53 (33.3%), whereas fusions in BRAF (8.3%) and FGFR (8.3%) were also detected. Notably, NTRK fusion-positive tumors showed a significantly lower rate of PD-L1 expression at the 1% cut-off compared to NTRK fusion-negative tumors (11.1% vs. 58.0%, p=0.006). Our study revealed that NTRK fusion-positive NSCLC frequently exhibits a complex molecular architecture characterized by concurrent alterations, most notably in EGFR and TP53. These findings align with the recent literature challenging the traditional "single-driver" model and suggest that such genomic complexity may mediate bypass signaling pathways. The presence of these co-occurring mutations underscores the clinical necessity of comprehensive NGS profiling to identify potential resistance mechanisms and guide personalized therapeutic strategies beyond solitary TRK inhibition.
