NTRK3 fusion

Case Presentation and We report two cases with RAI-resistant lung metastases treated with larotrectinib: 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation)...In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered...The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.

Our findings document that RAF1 gene rearrangements represent a recurrent event in ETV6::NTRK3-negative IFS/CMN and provide a rationale for the use of inhibitors directed to suppress MAPK and PI3K-AKT signaling in these cancers.

Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

P2, N=60, Not yet recruiting, Teligene US | Initiation date: Jan 2024 --> May 2024

P2, N=70, Active, not recruiting, Children's Oncology Group | Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

P2, N=146, Recruiting, Genentech, Inc. | N=85 --> 146

P2, N=85, Recruiting, Genentech, Inc. | Trial primary completion date: Mar 2024 --> Dec 2025

This study highlights the benefits of combining morphological and immunohistochemical analyses for gene detection and posits that lymph node metastases are more suitable for genetic analysis owing to their mild calcification. Our results emphasize the importance of accurate sample processing in diagnosing and treating thyroid carcinomas.

Moreover, multigene detection is superior to single gene detection. For BSRTC Ⅲ lesion with wild-type BRAF, multigene detection can be considered with a repeated FNA.

Fourteen eligible articles were analysed, which revealed predominant immunostaining pattern of S100 + /Mammaglobin + /SOX10 + /DOG1- by nearly all ETV6::NTRK3 fusion prevalent SCs alongside with other gene fusions like RET, MET and MAML3 with 98.4% sensitivity as well as 86.1% specificity. The evidence supports that S100/Mammaglobin/SOX10/DOG1 combined immunostaining can serve as a reliable diagnostic method to differentiate secretory from acinic cell carcinoma.

Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

This is the first report of an MYO5A::NTRK3 fusion in a pediatric GNT. GNT kinase-fused is a provisional methylation class not currently included in the WHO classification of CNS tumors. This case highlights the impact of thorough molecular characterization of CNS tumors, especially with the increasing availability of novel gene targeting therapies.

Conclusion Congenital infantile fibrosarcoma is a rare entity that has no specific MRI findings. However, it should be always considered as part of the differential diagnosis of congenital soft tissue masses with aggressive behavior.

A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified.

P1/2, N=69, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Mar 2023 --> Jun 2025

Despite the rare occurrence, these alterations have gained importance owing to approval of drugs like entrectinib and larotrectinib targeting the kinase domain of the gene. Detection of these rests on the use of conventional modalities like Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH); however, accurate characterization requires direct sequencing methods. We report an interesting case of an NTRK fusion-positive NSCLC, exhibiting good response to entrectinib.

P2, N=13, Recruiting, Children's Hospital of Philadelphia | Not yet recruiting --> Recruiting

Combined with the results of previous studies, we proposed that the combination of all five markers, S100, mammaglobin, DOG1, ADFP and CA6, could contribute more to differential diagnosis of SCs with other salivary carcinomas, especially with AciCC. The prognosis of SCs is optimistic in most cases, but larger patient cohort and long-term follow-up are still needed.

P2, N=215, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting

Recognition of subtle cytomorphological patterns, i.e., papillary formation, clusters and singly dispersed cells along with presence of fine intracytoplasmic vacuolations were the characteristic findings in majority of cases, confirmed with diagnostic molecular profiling. This may be helpful in identification of this rare entity with limited published literature and help in increasing diagnostic accuracy.

Pan-TRK IHC shows some utility as a diagnostic and surrogate marker for NTRK screening however, physiologic or non-specific expression may lead to false-positive results.

P2, N=32, Active, not recruiting, The University of Sydney | Recruiting --> Active, not recruiting

We also advocate the use of molecular techniques in rare tumors of uncertain type or differentiation, to increase understanding and possibilities of reproducible classification of these rare neoplasms. Pathologists and oncologists should recognize this entity, which leads to a direct approach for detecting NTRK fusion for appropriate treatment.

To the best of our knowledge, we reported the first case demonstrating anti-tumor activity of repotrectinib in a patient with AC carring an ETV6-NTRK3 gene fusion, indicating that repotrectinib may be an efficient therapeutic option for tumors with NTRK gene rearrangements.

P1/2, N=50, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=13, Not yet recruiting, Children's Hospital of Philadelphia | Initiation date: Nov 2023 --> Feb 2024

The results of the current study highlight the cytomorphological features which may help in clinching the diagnosis SC on cytology itself. They also highlight certain cytological features which help to rule out the other differential diagnoses.

The concordance rate between IHC and RNA-based NGS was 33.4%, and between immunohistochemistry and nCounter was 40%. Our findings indicate that NTRK fusions in Brazilian NSCLC patients are relatively rare (1.3%), and RNA-based nCounter methodology is a suitable approach for NRTK fusion identification in small biopsies.

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.

Gounder showed thar CGP could lead to refinement or reassignment of 10.5% of diagnoses and 32% of the patients harbored potentially actionable alterations. In this study, 2.8% of patients were reclassified and the actionable gene mutations were found in 25% of the patients with sarcoma by the CGP. Although few patients could receive genotype-matched therapy, they could achieve relatively good control.

Next-generation sequencing revealed t(12;15)(p13;q25) ETV6-NTRK3 translocation. Because SC/MASCs harbor the ETV6-NTRK3 translocation, molecular studies and immunostains are crucial to confirm the diagnosis and direct therapy.

These modifications altered the response to TKI treatment both in vitro and in vivo. Overall, these models serve as valuable tools for studying the biology of NTRK fusion tumors, their treatment response in a treatment-naïve or -experienced state, and the mechanisms underlying treatment resistance.

P1/2, N=500, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Dec 2024 --> Feb 2028 | Trial primary completion date: Jun 2024 --> Feb 2028

CGIP for breast cancer patients identified one or more clinically significant Tier IA genomic alterations that directs targeted therapy in ~ 37.5% of patients in a cohort of real world patients tested during the standard course of clinical care. This highlights the need for comprehensive genomic testing in breast cancer patients to drive therapeutic decision making.

Introduction: Trastuzumab deruxtecan (T-DXd), an anti-HER2 antibodydrug conjugate (ADC), is now the standard of care for patients with HER2- positive metastatic breast and gastric/gastroesophageal cancers, and those with ERBB2-mutated metastatic non-small-cell lung cancer (NSCLC)... HER2 expression is not routinely assessed in solid tumors with no approved indications for an anti-HER2 antibody. Many patients will undergo CGP to determine eligibility for approved targeted therapies, where genomic ERBB2 alterations will also be identified. As additional anti-HER2 ADCs emerge, CGP can identify ERBB2 genomic alterations which may be sensitive to these targeted therapies, providing additional opportunities in cancers with limited treatment options.

Here we report a large cohort of NTRK fusions detected in a broad range of tumor types during routine clinical care in the community setting. The number of unique and novel fusion partners identified highlights the value of RNAbased NGS, and demonstrates that when performed along with DNA NGS, provides a comprehensive assessment of NTRK fusions and actionable gene alterations to inform the routine clinical care of cancer patients.

P1/2, N=75, Recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Mar 2025 --> Sep 2027 | Trial primary completion date: Mar 2025 --> Sep 2026

No abstract available

In summary, emphasizing the risk of misdiagnosis is pivotal in the context of SC of the salivary gland, which can manifest across diverse glandular sites. Accurate diagnosis, underscored by the assessment of NTRK3 gene rearrangements, assumes a critical role in guiding effective management and treatment decisions.

SBC is highly prevalent among the multiple pathological types of pediatric breast cancer. Almost all pediatric SBC patients are characterized by the ETV6-NTRK3 fusion gene, which has a good prognosis and a 10-year survival rate of more than 90% when compared with other TNBC subtypes. According to the patient, we performed local mass resection and a postoperative pathological diagnosis of SBC (a subtype of BL-TNBC). The TNBC case had a good prognosis and differed from basal TNBC in several aspects, including clinical presentation, treatment, and prognosis. It is necessary to exclude SBC from BL-type TNBC, enhance understanding of the disease, and individualize the treatment plan, so as to avoid medical errors.

Variant-specific PCR was performed for 744 tumors with a normal 5'/3'-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/MET-negative lung cancers and 125 pediatric tumors, while NTRK3 fusions were detected in 2/447 (0.5%) non-lung adult malignancies. In conclusion, this study describes a diagnostic pipeline that can be used as a cost-efficient alternative to conventional methods of NTRK1-3 analysis.