Genetic Testing To Select Melanoma Or Glioma Patients For Targeted Therapy

The identification of specific, targetable oncogenic “driver mutations” in a subset of melanomas and gliomas has resulted in a reclassification of solid tumors to include molecular subtypes that may direct targeted therapy depending on the presence of specific variants. B-raf proto-oncogene, serine/threonine kinase (BRAF) and mitogen-activated protein kinase (MEK) inhibitors are drugs designed to target a somatic variant in the BRAF gene. BRAF and MEK inhibitors were originally developed for patients with advanced melanoma. BRAF encodes a kinase component in the rapidly accelerated fibrosarcoma (RAF)-MEK-extracellular signal-regulated kinase (ERK) signal transduction phosphorylation cascade. Variants in BRAF cause constitutive kinase activity, which is believed to promote oncogenic proliferation. Direct and specific inhibition of the mutated kinase has been shown to retard tumor growth significantly and may improve patient survival. The neurotrophic receptor tyrosine kinase (NTRK) gene fusions are uncommon kinase fusion events that drive tumorigenesis in a small fraction of solid tumors, regardless of tissue type.1, The tropomyosin receptor kinases (TRK) proteins A, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 respectively. In healthy tissue, the TRK pathway is involved in the development and functioning of the nervous system as well as cell survival. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that are oncogenic, promoting tumor cell proliferation and their survival. Larotrectinib and entrectinib is a kinase inhibitor of TRK A, B, and C protein. Entrectinib additionally inhibits 2 other kinases: anaplastic lymphoma kinase and proto-oncogene tyrosine-protein kinase. The presence of NTRK gene fusions can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry.2, Mutations in isocitrate dehydrogenase-1 (IDH1) or -2 (IDH2) genes lead to accumulation of the proto-oncogenic metabolite D-2-hydroxyglutarate, disrupting gene expression and cellular differentiation. WHO grade 2 and 3 astrocytomas and oligodendrogliomas are defined by IDH mutations, distinguishing lower-grade gliomas from glioblastomas. IDH1 and IDH2 mutations are generally associated with a favorable prognosis, and have been important biomarkers for stratification in clinical trials. IDH mutations are detected in over 50% of gliomas in patients aged 55 or older.3,