LMNA-NTRK1 fusion

Clinical, histopathological, immunohistochemical, and molecular analyses were performed to diagnose these patients. This report adds to the growing body of knowledge on NTRK-rearranged Spitz lesions and underscores the importance of integrating molecular findings with morphological and immunohistochemical data for the accurate classification and understanding of these neoplasms.

Identifying patients with NTRK gene fusions is crucial, as they could benefit from targeted therapy using TRK inhibitors. This requires a detailed description of emerging entities like NTRK-RSCNs because testing for NTRK rearrangement is not routinely performed. In two cases, we report a spectrum of histological grades, including a high-grade phenotype.

FISH could complement NGS detection, particularly when NTRK fusion is detected by DNA sequencing. NTRK fusion in GC may not be limited to specific subtypes.

The correlations between the MAPK pathway G1-G7 subgroups and the PI3-kinase/PTEN, TERT, cell cycle G1 phase and p53 pathways defined characteristic subgroup pathway profiles amenable to personalized targeted therapy. This analysis validated the first all-inclusive molecular classification of glioblastoma, showed significant demographic and molecular differences between subgroups, and provided the first ethnic molecular comparison of glioblastoma.

DNA- and RNA-based screening systems may be useful for detecting tyrosine kinase fusion genes in specific fusion-negative sarcomas and identifying key therapeutic targets, leading to possible breakthroughs in the treatment of bone and soft tissue sarcomas. Given that current DNA sequencing misses fusion genes, RNA-based screening systems should be widely considered as a worldwide test for sarcoma. If standard treatments such as chemotherapy are not effective, or even if the sarcoma is of bone, RNA sequencing should be considered to identify as many therapeutic targets as possible.

The statistical significance was limited to NTRK3 alterations but a trend for better mOS was evident in NTRK1 and NTRK2. Propsective validation and efforts to understand the underlying mechansims are warranted.

The spectrum of fusion-driven melanocytic lesions is rapidly expanding with the democratization of molecular testing. Tumors with CRTC1 :: TRIM11 are now known for their metastatic potential. Precise characterization of these entities may inform patient follow-up and management, including the opportunity for kinase inhibitor therapies.

All the findings confirmed the diagnosis of LMNA-NTRK1 rearranged spindle cell neoplasm, a recently described and rare molecularly-defined soft tissue tumor that may have a wide spectrum of morphologies and histological grades, with frequent co-expression of CD34 and S100. Due to the highly infiltrative growth pattern, the tumor has a propensity for local recurrence, if incompletely excised, but none has been shown to metastasize. In our patient, there was no recurrence more than 3 years after the excision.

"Gene fusions represent crucial targets in the context of precision medicine. NGS testing for fusion detection not only allows analysis of multiple targets but also saves time and material. The identification of novel fusions in this study also highlights the potential for future therapeutic targets."

Regarding break-apart FISH, NTRK detection is difficult because of the diversity of signal patterns. Further research is warranted to identify the characteristics of NTRK-fusion CRCs.

Here, we present a recently encountered intestinal spindle cell neoplasm harbouring an LMNA::NTRK1 gene fusion in a woman in her early 20s, which was initially thought to represent a GIST or a solitary fibrous tumour. Awareness of this emerging tumour type in the gastrointestinal tract is important due to treatment implications.

NTRK1, NTRK2, and NTRK3 fusions are clinically relevant driver alterations across solid tumor types. These fusions are difficult to detect, as the breakpoints occur across large intronic regions and they have many partner genes, with 10 novel fusion partners identified in this study. These data emphasize how important CGP with RNA sequencing is to identify all NTRK fusions for optimal patient treatment.

Interestingly, pan-TRK positivity was observed in one case with precursor lesions in both precancerous and cancerous regions, whereas MLH1 loss was restricted to the cancerous region. In summary, an optimized multi-step algorithm using pan-TRK IHC as a screening method was proposed to identify CRC patients harboring NTRK fusions.

"Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS."

All 3 patients are alive without the disease (median follow-up, 9 mo; range, 4 to 87 mo). The cases present herein demonstrate that NTRK-rearranged spindle cell neoplasms may occur primarily in the lung, albeit extremely rare, and should be included in the differential diagnosis of primary pulmonary spindle cell neoplasms.

NTRK fusion-positive entities presented with a wide clinical and histologic spectrum, in a third of which the finding was unexpected. Uncommon/novel NTRK fusions may be present in classic entities negative for canonical fusions by targeted testing and comprehensive fusion detection should be pursued in such cases. Positivity for pan-TRK IHC, diffuse or focal, may be helpful in uncommon clinical presentations.

The CANTRK study demonstrated a high level of agreement in detection of NTRK fusions by NGS RNA testing across different NGS panels. Fusions not detected by certain panels were due either to absence of targets in amplicon primer panels, or potential bioinformatic challenges. Issues encountered during the study, such as defining quality criteria for reporting a positive result, types of results requiring confirmation, and reporting requirements, will be used to formulate a best practice guideline for analysis and reporting of gene fusions detected by NGS methods.

A BaF3 xenograft model encoding the LMNA-NTRK1 gene fusion and G595R solvent front mutation showed superior efficacy with PBI-200 relative to first-generation compounds larotrectinib and entrectinib, and equivalent efficacy to the second-generation compound selitrectinib, in terms of tumor growth inhibition. Together, these data suggest that PBI-200 has potential as a best-in-class, highly CNS-penetrant next generation TRKi. A Phase 1/2 clinical trial evaluating PBI-200 in NTRK fusion-positive patients, including patients with PBT, is ongoing (NCT04901806).

NTRK fusions were detected only in SSLs of patients aged ?50?years, whereas BRAF mutation was found in younger age-onset SSLs. In conclusion, NTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without BRAF/KRAS mutations prior to full occurrence of MSI-high/CIMP-high.

"Our study shows that Pan-Trk IHC detects NTRK1 fusions with 100% specificity in CRC. Our results confirm that NTRK1 fusions are frequently detected in dMLH1/BRAFV600Ewt (11%) and especially in dMLH1/MLH1ph/BRAFV600Ewt (16%) CRCs justifying screening for NTRK fusions in these subsets of CRCs. Our findings of NTRK1 fusions with partners LMNA, PLEKHA6 and TPM3 in CRC are consis- tent with previous studies but noteworthy, we introduce a novel IRF2BP2-NTRK1 fusion in CRC."

NTRK gene fusions occur with many partners with the majority occurring at a low frequency across multiple tumour types, supporting the need for validated and appropriate testing methodologies that work agnostic of 5’ partners.

Both NTRK1 fusion-positive cases lacked activating mutations in KRAS and BRAF and were mismatch repair-deficient with loss of MLH1 and PMS2 expression and MLH1 promoter methylation. Our results show that receptor tyrosine kinase fusions are rare but present in colorectal cancers in Japanese patients, with a prevalence similar to that reported in other countries.

Kinase fusions in breast cancers are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating MAPK signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.

Pan-TRK (clone EPR17341, Roche/Ventana) immunhistochemistry is a reliable, highly sensitive but less specific diagnostic marker that can be expressed in non-NTRK-rearranged mesenchymal neoplasms. Conclusion Pan-TRK (clone EPR17341, Roche/Ventana) can be used as a surrogate marker for an identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement if patients are undergoing targeted therapy.

Pan-TRK (clone EPR17341, Roche/Ventana) immunhistochemistry is a reliable, highly sensitive but less specific diagnostic marker that can be expressed in non-NTRK-rearranged mesenchymal neoplasms. Conclusion Pan-TRK (clone EPR17341, Roche/Ventana) can be used as a surrogate marker for an identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement if patients are undergoing targeted therapy.

Pan-TRK (clone EPR17341, Roche/Ventana) immunhistochemistry is a reliable, highly sensitive but less specific diagnostic marker that can be expressed in non-NTRK-rearranged mesenchymal neoplasms. Conclusion Pan-TRK (clone EPR17341, Roche/Ventana) can be used as a surrogate marker for an identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement if patients are undergoing targeted therapy.

Histologic examination revealed a spindle cell neoplasm with fascicular proliferation of relatively plump, bland, fibroblastic to somewhat neural-appearing cells growing in an infiltrative fashion through the preexisting connective tissue (Figure 212, B and C). Immunohistochemistry showed coexpression of S100 protein, CD34, and TRK, and the lesion was found to be positive for the LMNA-NTRK1 fusion by next-generation sequencing.

All cases of NTRK1 and NTRK3 fusion-positive pediatric tumors robustly expressed the Trk protein. A Trk immunopositive pattern and CD34/S100/nestin/CD10/SMA immunohistochemical expression may suggest the presence of NTRK fusion partner genes. LMNA-NTRK1 fusion sarcoma might be a low-grade subtype of infantile fibrosarcoma. Interestingly, more than half of the infantile fibrosarcoma cases were positive for S100 protein and CD10. The follow-up period of TPR-NTRK1 and LMNA-NTRK1 fusion-positive tumors are not enough to predict prognosis. However, ETV6-NTRK3 fusion-positive infantile fibrosarcomas showed an excellent prognosis with no evidence of disease for an average of 11.7 years, after gross total resection of the tumor.

"It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin."

More than 20 different fusion partner genes of NTRK have been reported and most of these NTRK fusions respond well to NTRK inhibitors larotrectinib and/or entrectinib. Legal entity responsible for the study: The authors. Funding: Has not received any funding.

TRK inhibitors such as LOXO-101, entrectinib, X396, AB-106, TL118 had remarkable and durable antitumor activities in patients (pts) with TRK fusion-positive cancers, regardless of age or tumor type. NTRK fusions are a rare molecular subtype in Chinese solid tumors. The NTRK gene fusions more commonly occurred in NSCLC (0.3%), CRC (0.4%) and BC (0.2%), and may occur without other targetable alterations such as EGFR, ALK, ROS1. The clinical evidence for responsiveness of NTRK fusions driven solid tumors provides an opportunity to personalize treatments and improve clinical outcomes for patients (pts).