Neurotrophic Tropomyosin Kinase Receptor 1 (NTRK1) gene encodes for the protein Tropomyosin-related kinase A (TRKA). A deregulated activity of TRKA has been detected in cancer, leading to oncogenic activity. This can result from translocations, amplifications, deletions and point mutations involving the NTRK1 gene. The incidence of NTRK1 gene copy number gain (GCN) across solid tumors has not been investigated. We present here the results of an immunohistochemistry (IHC) screening for TRKA expression within the phase I ALKA-001 clinical trial. Clinical results of ALKA-001 clinical trial are not presented here.
Formalin-fixed paraffin-embedded (FFPE) consecutive samples of different solid tumors were tested for TRKA IHC staining. Samples showing TRKA IHC staining in at least 10% of cells were further studied by fluorescence in situ hybridization (FISH) to assess whether NTRK1 gene rearrangements were present and to assess GCN. All patients signed informed consent for molecular screening according to the phase I ALKA-001 clinical trial.
1043 samples were tested; annotation for histology was available in 1023. Most of the samples were colorectal adenocarcinoma (CRC) (n = 550, 53.8%) or lung adenocarcinoma (312, 30.5%). 24 samples (2.3%) were biliary tract carcinoma (BTC). Seventeen (1.6%) samples were characterized by TRKA IHC expression (4 weak, 8 moderate, 5 strong). By FISH, 1/17 (5.9%) displayed NTRK1 gene rearrangement and 15 (88.2%) NTRK1 GCN gain. Among samples harboring NTRK1 GCN gain, 8 (53%) were lung adenocarcinoma, 3 (20.0%) BTC and 2 (13.3%) CRC. Five (33.3%) samples had concomitant ALK and ROS1 GCN gain. None of the lung adenocarcinoma (n = 8) had concomitant EGFR mutations. Both CRC samples (n = 2) harbored KRAS mutation. No correlation was found between grading of TRKA IHC staining and the number of NTRK1 GCN.
NTRK1 GCN gain can be found in 1.6% of solid tumors. In particular, we found GCN gain in 2.6% of lung adenocarcinomas, without EGFR mutations, 0.4% of CRC and 17.6% of BTC even though a limited number of the latter histology was included in the analysis. The prognostic and translational therapeutic impact of this genetic alteration remains to be established.
Clinical trial identification
Legal entity responsible for the study
The molecular screening was funded by Ignyta within ALKA-372-001 study. Investigators are supported by Fondazione Oncologia Niguarda Onlus - Project: “Terapia molecolare dei tumori” (G.M., S.S. A.S-B.). This project has received funding from the European Union's Horizon 2020 research and innovation programma under grant agreement No 635342
S. Siena: Consultant/advisory board member for Amgen, Bayer, Eli Lilly, Merck, Merrimack, and Roche.All other authors have declared no conflicts of interest.