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INTRODUCTION

Tissue-agnostic cancer therapeutics treat cancers based on the mutations they harbor, and it is this genetic change and not the tissue of origin that has led to their regulatory approvals. To date, tissue-agnostic therapeutics have been developed for tumors harboring NTRK mutations, those with mismatch repair deficiencies, and those with high tumor mutational burden. Tissue-agnostic cancer therapeutics are the ultimate goal of precision oncology, and it is hoped additional targets will be added and the number of such drugs will grow

Expert Opinion

 

NTRK Fusions

  • NTRK gene fusions, also called neurotrophic tyrosine receptor kinase gene fusions, lead to abnormal proteins called TRK fusion proteins. NTRK gene fusions involve either NTRK1NTRK2, or NTRK3—the genes that encode the neurotrophin receptors TRKA, TRKB, and TRKC, respectively

  • Usually intra- and inter-chromosomal rearrangements result in hybrid genes with the 3′ sequences of NTRK1NTRK2, or NTRK3 containing the kinase domain juxtaposed to the 5′ sequences of a different gene. The fusion results in a chimeric oncoprotein characterized by ligand-independent constitutive activation of the TRK kinase

  • The fusions result in oncogenic drivers in both adult and pediatric tumors

  • NTRK fusions were originally identified in colorectal and papillary thyroid carcinomas but have since been found in multiple tumors from both adult and pediatric patients. These cancers can be grouped into two general categories according to the frequency at which these fusions are detected. For example, in select series of patients the prevalence of the ETV6–NTRK3 fusion exceeds 90% in mammary analogue secretory carcinoma (MASC), secretory breast carcinoma, congenital mesoblastic nephroma (cellular or mixed subtypes), and infantile fibrosarcomas. NTRK fusions are also found at lower and much lower frequencies in other cancers

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    Frequency of NTRK Fusions in Cancer
    Tumor Type NTRK Gene Fusions Involved Frequency
    Breast secretory carcinoma NTRK3 96%
    Infantile fibrosarcoma NTRK3 95.5%
    Mammary analogue secretory carcinoma (MASC)’ NTRK3 89.1%
    (Cellular and mixed) Congenital mesoblastic nephroma NTRK3 72%
    Spitz tumors and spitzoid melanoma NTRK1 16.4%
    Papillary thyroid carcinoma NTRK1,3 8.8%
    Intrahepatic cholangiocarcinoma NTRK1 3.6%
    Astrocytoma NTRK2 3.1%
    High-grade glioma NTRK1,2,3 2.1%
    Uterine sarcoma NTRK1,3 2.1%
    GIST (pan-negative) NTRK3 1.9%
    Lung cancer NTRK1,2 1.7%
    Thyroid carcinoma NTRK1,3 1.2%
    Glioblastoma NTRK1,2 1.2%
    Sarcoma NTRK1 1.0%
    Ph-like ALL NTRK3 0.7%
    Colorectal cancer NTRK1,3 0.61%
    Melanoma NTRK3 0.3%
    Head and neck cancer NTRK2,3 0.24%
    Invasive breast cancer NTRK3 <0.1%
    Other: Renal cell carcinoma, pancreatic cancer, breast cancer, histiocytosis, multiple myeloma, and dendritic cell neoplasms Various <1%
    Adapted from: https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/targeting-ntrk-gene-fusions/overview-of-cancers-with-ntrk-gene-fusion/ntrk-gene-fusions-as-oncogenic-drivers/epidemiology-of-cancers-with-ntrk-gene-fusion

  • These fusions can be detected using a variety of methods, including tumor DNA and RNA sequencing and plasma cell–free DNA profiling

  • The clinical detection of NTRK fusions has predominantly been based on NGS

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    ...
    Techniques to Detect NTRK Gene Fusions
    Technique Use
    NGS Detects known and novel fusions with breakpoints in DNA or RNA

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