Molecular characterization of cancers with NTRK gene fusions

Abstract

Targeted inhibitors of neurotropic tyrosine kinases are highly effective in selected patients with gene fusions involving NTRK1, NTRK2, or NTRK3. These fusions are consistently detected in rare cancer types (e.g., secretory breast carcinoma and congenital infantile fibrosarcoma), but the occurrence of NTRK fusions in common cancers and their relationship to other therapy biomarkers are largely unexplored. Tissue samples from 11,502 patients were analyzed for 53 gene fusions and sequencing of 592 genes, along with an immunohistochemical evaluation of TrkA/B/C and PD-L1. Thirty-one cases (0.27% of the entire cohort) had NTRK fusions. The most common fusions were ETV6:NTRK3 (n = 10) and TPM3:NTRK1 (n = 6). Gliomas had the highest number of NTRK fusions (14/982, 1.4%), most commonly involving NTRK2 (n = 9). Seventeen non-glioma cases with NTRK fusions included carcinomas of the lungs, thyroid, breast, cervix, colon, nasal cavity, cancer of unknown primary and soft tissue sarcomas. Strong and uniform Trk expression detected with a pan-Trk immunohistochemistry characterized 7/8 NTRK1 fusion cases and 8/9 NTRK2 fusion cases, while NTRK3 fused cases were positive in 6/11 (55%) of cases. 29% of NTRK fusion cases had no other pathogenic genomic alteration. PD-L1 expression was observed in 23% of NTRK fused cases while high tumor DNA microsatellite instability was detected in two cases. We confirm the rarity of NTRK genes fusions outside the brain malignancies. NTRK inhibitors alone or combined with immune checkpoint inhibitors may be a therapeutic option for a substantial proportion of these patients. Strategies for detection of the NTRK fusion-driven cancers may include immunohistochemistry, but gene fusion detection remains the most reliable tool.

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

“…Not only can the presence of NTRK3 rearrangement confirm the diagnosis of secretory carcinoma in the appropriate histomorphological context, but this renders the patients eligible for TRK‐targeted therapy such as treatment with larotrectinib, which was recently approved by the FDA in the USA irrespective of tumour site and histology . In addition to secretory carcinoma, NTRK fusions have been identified in most cases of infantile fibrosarcoma, cellular mesoblastic nephroma, lipofibromatosis‐like neural tumour and other paediatric mesenchymal tumours, along with a small subset of uterine sarcomas and gliomas, and rare carcinomas from the thyroid, lung, cervix, breast, and colon …”

Non‐secretory breast carcinomas lack NTRK rearrangements and TRK protein expression

“…have reported that pan‐TRK IHC was an efficient and reliable screening tool to detect NTRK rearrangements in various tumours. Nevertheless, their study did not provide data about non‐secretory breast carcinomas because only one IHC‐positive ETV6‐NTRK3 rearranged breast carcinoma (of secretory subtype) was include among the 23 NTRK‐ rearranged tumours and the 20 NTRK ‐non rearranged tumours did not comprise any breast carcinoma …”

“…The pan‐TRK monoclonal rabbit antibody clone EPR17341 was used (6 μg/mL dilution, Abcam, Cambridge, MA) which has been reported to be a valuable screening tool searching for NTRK1/2/3 ‐rearranged tumours . IHC was processed on 3 μm‐thick TMA slides using Ventana Benchmark Ultra automated slide preparation system (Roche Diagnostics, Meylan, France) comprised, after deparaffinization, a 64 min CC1 pretreatment step (Roche Diagnostics) followed by antibody incubation during 52 min, washing and OptiView DAB IHC Detection Kit (Roche Diagnostics) before hematoxylin counterstaining and mounting.…”

“…In this rare case of aggressive secretory breast carcinoma but in a wider manner in advanced breast carcinomas of non‐secretory subtype, identifying new targetable molecular events such as NTRK genes rearrangements and related‐TRK proteins expressions could be of crucial importance for an optimal therapeutic management of the patients. To the best of our knowledge, little is known about the frequency of NTRK rearrangements and the expression of TRK proteins in non‐secretory breast carcinomas in the current literature . This was the aim of our present study.…”

Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasising distant metastatic potential

“…Identification of a recurrent chromosomal rearrangement in secretory carcinoma, t(12;15)(p13;q25), resulting in a fusion between E26 transformation‐specific translocation variant 6 ( ETV6 ) and neurotrophic receptor tyrosine kinase 3 ( NTK3 ), allowed for a potentially targeted approach to management . This fusion has thus far been reported in 95.2% (40 of 42) of the cases tested in the literature …”