Prognostic Value of Neurotrophic Tyrosine Receptor Kinase Gene Fusions in Solid Tumors for Overall Survival: A Systematic Review and Meta-Analysis

Lassen, Ulrik; Bokemeyer, Carsten; García‐Foncillas, Jesús; Italiano, Antoîne; Vassal, Gilles; Paracha, Noman; Marian, Marisca; Chen, Y.; Linsell, Louise; Abrams, Keith R.

doi:10.1200/po.22.00651

Cited by 2 publications

References 19 publications

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Analytical performance of OncoPrism-HNSCC, an RNA-based assay to inform immune checkpoint inhibitor treatment decisions for recurrent/metastatic head and neck squamous cell carcinoma

Hiken,

Earls,

Flanagan

et al. 2024

Preprint

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Background While immune checkpoint inhibitor (ICI) therapies can significantly improve outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC), only about 15–20% benefit from such treatments. Clinical tests that guide the use of ICIs are therefore critically needed. OncoPrism-HNSCC was developed to address this need. The assay combines next generation RNA sequencing-based immunomodulatory gene expression signatures with machine learning algorithms to generate an OncoPrism Score that classifies patients as having low, medium, or high likelihood of disease control in response to ICI treatment. Also, OncoPrism-HNSCC leverages the same FFPE patient tumor RNA used for ICI response prediction to identify rare cases where oncogenic rearrangements in NTRK1/2/3 or ALK genes, which may indicate the use of potentially highly effective targeted therapies. The clinical performance of OncoPrism-HNSCC has been validated. Here, we report its analytical performance in the presence of potentially confounding sources of variation. Methods The assay’s analytical sensitivity was assessed by varying RNA input quantity and quality, observing the effect on ICI response prediction scores. Analytical specificity was tested by spiking increasing percentages of genomic DNA into input RNA. Intra-assay and inter-assay precision were evaluated, and the analytical sensitivity, specificity, and precision of gene fusion detection were assessed. Concordance with orthogonal methods of gene fusion detection was tested on 67 FFPE clinical samples. Results Varying RNA inputs as low as four-fold below the nominal input amount had little effect on ICI response prediction scores. RNA quality levels below the test threshold had no significant effect. Genomic DNA spike-ins up to 30% had only a small effect on scores. The pooled standard deviation for multiple operators, reagent lots, batches, and sequencers yielded an overall variance represented by just 0.87% of the score range of the test (0–100). NTRK and ALK gene fusion detection was 100% concordant with orthogonal methods. Conclusions Robust and reliable analytical performance of the OncoPrism-HNSCC assay supports its clinical use, even in the presence of variation typically encountered in the laboratory setting.

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Analytical performance of OncoPrism-HNSCC, an RNA-based assay to inform immune checkpoint inhibitor treatment decisions for recurrent/metastatic head and neck squamous cell carcinoma

Hiken,

Earls,

Flanagan

et al. 2024

Preprint

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Neurotrophic tyrosine receptor kinase gene fusions in adult and pediatric patients with solid tumors: a clinicogenomic biobank and record linkage study of expression frequency and patient characteristics from Finland

Zhang,

Schmitz,

Kallionpää

et al. 2024

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Background: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers. Using the Auria Biobank in Finland, we aimed to identify and characterize patients with these gene fusions, and describe their clinical and tumor characteristics, treatments received, and outcomes. Material and methods: We evaluated pediatrics with any solid tumor type and adults with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), sarcoma, or salivary gland cancer. We determined tropomyosin receptor kinase (TRK) protein expression by pan-TRK immunohistochemistry (IHC) staining of tumor samples from the Auria Biobank, scored by a certified pathologist. NTRK gene fusion was confirmed by next generation sequencing (NGS). All 2,059 patients were followed-up starting 1 year before their cancer diagnosis. Results: Frequency of NTRK gene fusion tumors was 3.1% (4/127) in pediatrics, 0.7% (8/1,151) for CRC, 0.3% (1/288) for NSCLC, 0.9% (1/114) for salivary gland cancer, and 0% (0/379) for sarcoma. Among pediatrics there was one case each of fibrosarcoma (TPM3::NTRK1), Ewing’s sarcoma (LPPR1::NTRK2), primitive neuroectodermal tumor (DAB2IP::NTRK2), and papillary thyroid carcinoma (RAD51B::NTRK3). Among CRC patients, six harbored tumors with NTRK1 fusions (three fused with TPM3), one harbored a NTRK3::GABRG1 fusion, and the other a NTRK2::FXN/LPPR1 fusion. Microsatellite instability was higher in CRC patients with NTRK gene fusion tumors versus wild-type tumors (50.0% vs. 4.4%). Other detected fusions were SGCZ::NTRK3 (NSCLC) and ETV6::NTRK3 (salivary gland cancer). Four patients (three CRC, one NSCLC) received chemotherapy; one patient (with CRC) received radiotherapy. Conclusion: NTRK gene fusions are rare in adult CRC, NSCLC, salivary tumors, sarcoma, and pediatric solid tumors.

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Prognostic Value of Neurotrophic Tyrosine Receptor Kinase Gene Fusions in Solid Tumors for Overall Survival: A Systematic Review and Meta-Analysis

Cited by 2 publications

References 19 publications

Analytical performance of OncoPrism-HNSCC, an RNA-based assay to inform immune checkpoint inhibitor treatment decisions for recurrent/metastatic head and neck squamous cell carcinoma

Analytical performance of OncoPrism-HNSCC, an RNA-based assay to inform immune checkpoint inhibitor treatment decisions for recurrent/metastatic head and neck squamous cell carcinoma

Neurotrophic tyrosine receptor kinase gene fusions in adult and pediatric patients with solid tumors: a clinicogenomic biobank and record linkage study of expression frequency and patient characteristics from Finland

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