NTRK3 fusion

Genomic profiling yields clinically actionable information for approved therapies and evidence of resistance, and it may uncover rational therapeutic opportunities regardless of tumor type.

Our standard operating procedure (SOP) was updated to perform orthogonal confirmation testing for stand-alone equivocal NTRK1/2 and equivocal NTRK3 (5' failure), but to ignore equivocal NTRK3 (5' intact) and report as NTRK2/3 indeterminate. Re-verification showed no change to ALK, ROS1, RET, MET ex14, and NTRK1 results. Sensitivity of NTRK2 detection was significantly increased (80% after orthogonal testing).

The routine use of RNA-based CGP analysis allows for the comprehensive detection of oncogenic fusions in patients with cancer. The diversity of tumor types in which actionable fusions were detected supports the broader utilization of CGP to potentially increase targeted therapy usage and improve outcomes across cancer subtypes.

Emerging structural variants (eSVs) were found to have a combined prevalence to be 0.7%, with only 47.5% of eSVs detected by DNA-NGS. In this cohort study, the detection of structural variants via concurrent RNA-NGS and DNA-NGS was higher across multiple NCCN-guideline recommended biomarkers compared with DNA-NGS alone, suggesting that RNA-NGS should be routinely implemented in the care of patients with advanced NSCLC.

P2, N=70, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

P=N/A, N=150, Recruiting, Bayer | N=300 --> 150

P2, N=13, Recruiting, Children's Hospital of Philadelphia | Trial primary completion date: Oct 2024 --> Oct 2026

This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.

Tumours arising on HSGT, share histological similarities with those affecting orthotopic salivary glands. This unique case expands the understanding of SC occurrences on HSGT.

P4, N=14, Pfizer, Inc

Actionable gene fusions are more prevalent in MSI-H, RAS/BRAF wildtype, or RNF43-mutated CRC, as well as in colon cancer. Mapping of these molecular markers can markedly increase the fusion detection rate, which can help clinicians select candidates for fusion testing and targeted therapy.

The patient in case 2 had no other known tumors at the time of diagnosis, but no follow-up is available. We believe the reported cases represent a hitherto unrecognized variant of "NTRK-rearranged spindle cell neoplasms" of the uterine cervix with novel EGFR mutations.

Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors.

As demonstrated in our PTC cohort, DNA CGP and RNA CGP may be complementary for fusion detection in certain tumor types. RNA CGP complements DNA CGP by detecting fusions that cannot be efficiently baited on DNA CGP, while DNA CGP may complement RNA CGP by detecting fusions in poor quality (e.g., old archival) samples when RNA sequencing may not be not technically feasible. Clinically relevant fusions detected in this retrospectively profiled PTC cohort included therapeutically targetable fusion events (e.g., RET, NTRK, ALK) and a PAX8::PPARG fusion, which is suggestive of a follicular variant PTC.

SAMS is on a morphologic and molecular genetic spectrum with EFH, with a similar body site distribution, frequent clinical presentation as an exophytic skin tumor, and invariably benign outcomes; we conclude that SAMS should be considered a histologic variant of EFH. Some morphologically typical examples harbor alternate RET and NTRK3 fusions, such that SAMS is not an appropriate designation for this morphologic class; instead, to highlight the clinicopathologic similarities to EFH, we propose the diagnostic term "myxoid spindle cell variant of epithelioid fibrous histiocytoma."

Among documented cases of thyroid SC, prognostic factors established for salivary SC have shown broad distributions, including a mitotic activity ranging from < 1 to 10 per 10 high-power fields and variable presence of necrosis, awaiting additional case experience to better elucidate their relevance in thyroid SC. We hereby present a 61-year-old female patient with widely metastatic thyroid SC treated with larotrectinib and provide an updated review of the literature on the molecular pathogenesis and clinicopathologic characteristics of this rare entity.

Infantile high-grade glioma should be regarded as a unique tumor entity and a multidisciplinary approach is paramount in improving survival for this group of patients.

Metastases beyond the ipsilateral axillary lymph nodes are rare, with the most common sites involving the lung and liver. Except for the potential addition of targeted drug therapy for NTRK fusion-positive tumors, the treatment approach is otherwise similar to invasive breast carcinomas of similar receptor status.

Clinically, BPI-28592 achieved a complete response in a patient with malignant melanoma carrying an AP3S2-NTRK3 fusion (Clinicaltrials. gov identifier: NCT05302843).

We also demonstrate that EML4-NTRK3 is localized in the cytoplasm and fails to associate with microtubules. These data suggest potential therapeutic strategies for Infantile Fibrosarcoma cases bearing EML4-NTRK3 fusion through inhibition of salt bridge interactions and disruption of multimerization.

The soft tissue tumors with EGFR ITD are not a morphologic match for the low-grade histology of classical CMN. Whether they have a similar favorable biology or behave more like fibrosarcoma with an ETV6::NTRK3 fusion or an alternative fusion involving other kinases remains to be determined.

Importantly, co-occurrence of rare fusions and EGFR classical activating mutations in patients pre-treated with anti-EGFR therapy suggests a potential resistance mechanism and consideration of upfront, dual mutation, targeted treatment to improve outcomes. Further clinical studies are needed to validate the best treatment options for these patients with rare fusions.

In a real-world, retrospective analysis of a cohort of advanced NSCLC patients, most oncologists utilized CGP to identify and treat patients with guideline-recommended variant matched targeted therapy, with adherence rates varying by variant. Importantly, even patients that received CGP results prior to FDA approval of novel therapies, received matched therapy once they were included in guidelines.

This may prove to be an additional therapeutic option for patients with aggressive prostatic carcinomas refractory to initial therapy. We report a case of an aggressive castrate-resistant prostatic adenocarcinoma with a BMP6::NTRK3 gene fusion.

Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

Tyrosine kinase inhibitors i.e, sorafenib and lenvatinib, have been used in cases of progressive, recurrent, or metastatic disease not responsive to 131I therapy. PDTC accounts for 3–5% of all thyroid carcinomas. The 5, 10-, and 15-year survival rates of patients are 50–85%, 34–50%, and 0%, respectively. RAS gene alterations are found in 25–35%, BRAF mutation in 15–27%, TERT promoter mutation in 40% and mutant TP53 in 16–28% of PDTCs.

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