LAUSR

Depending on the clinical scenarios, merely 0.1–3.3% NTRK fusions are demonstrated in lung cancer, but the remarkable efficacy of Trk inhibitors offers a possibility to use NTRK fusion as antitumorigenic target (Harada et al. 2020). NTRK fusions are worthy of great concern. Herein, a novel NTRK1 fusion (EPS15–NTRK1) was first detected in a patient with advanced lung adenocarcinoma. A 74-year-old male patient was admitted to the hospital complaining for irregular cough with blood tinged sputum over 6 months, having smoked for 40 years and cigarette quitting 6 months. Computed tomography (CT) on chest revealed space-occupying lesion in upper right lobe and multiple nodules in right lung. Pleural effusion in both lungs was also observed. CT-guided percutaneous lung biopsy was conducted and the patient was pathologically diagnosed as invasive lung adenocarcinoma with intrapulmonary metastasis (Fig. 1a–c). Next-generation sequencing (NGS) analysis via DNA-based hybrid capture based on a pan-cancer 539-gene panel of the biopsy of primary foci and blood sample identified a novel NTRK1 fusion (EPS15–NTRK1; Fig. 2a). The fusion of EPS15–NTRK1 included exons 1–21 of EPS15 and exons 10–17 of NTRK1 (Fig. 2b). This novel NTRK1 fusion retained the complete kinase domain of NTRK1, and might lead to abnormal NTRK 1 activation. Fluorescence In Situ Hybridization (FISH) and Immunohistochemistry (IHC) results confirmed the NTRK1 fusion (Fig. 2c, d). Fusions involving NTRK and a wide range of partner genes were observed in various tumor entities, although in very rare frequency. NTRKs encodes Trks (TrkA, TrkB, and TrkC), which could initiate consecutive activation of downstream signal transduction pathways like MAPK/ ERK, PI3K/AKT, and PLCγ/PKC upon homo-dimerization (Märkl et al. 2019; Cocco et al. 2018). Migration, proliferation, and cancer cell transformation were all modulated by Trk-dependent pathways (Märkl et al. 2019). More importantly, NTRK fusion would lead to constitutive Trk heterodimerization and activation, contributing to tumorigenesis.2 In our case, a new fusion with NTRK1 and EPS15 (EGFR pathway substrate 15) is detected in an elderly patient with advanced lung adenocarcinoma. It may imply a specific subtype of NSCLC, which could receive positive clinical response to the Trk inhibitors. Currently, there are two substances available that achieved FDA approval for NTRK-positive cancers. The one is Larotrectinib, a selective Trk inhibitor that can be applied in all cancers with proven NTRK fusion; another is Entrectinib, which has been one major novelty of precision tumor therapy with marked effects achieved (e.g., Larotrectinib ORR 71% in lung cancer with NTRK fusion; Entrectinib ORR 57.4% in NTRK-fusion cancer) (Harada et al. 2020; Okamura et al. 2018). On the other hand, compared to the significant falsepositive data happened on the classical test approaches, NGS, regardless of DNAor RNA-based, is a popular tool to search for a low pre-test probability of NTRK fusions in practice. NGS can detect all forms of NTRK fusion at once with high sensitivity and other potential deleterious mutations (Table 1). All in all, our case report expands the spectrum of NTRKfusion types and may recommend a promising option, besides IHC and FISH, to tumor patients intending to targeting therapy, and, therefore, provide possible NTRK–TKI for consideration. * Lei Xian [email protected]