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|Ref Type||Journal Article|
|Authors||Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, Blay JY, Leyvraz S, Stul M, Casali PG, Zalcberg J, Verweij J, Van Glabbeke M, Hagemeijer A, Judson I, null null, null null, null null|
|Title||KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.|
|Journal||European journal of cancer (Oxford, England : 1990)|
|Abstract Text||A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|PDGFRA||D846V||missense||unknown||PDGFRA D846V lies within the protein kinase domain of the Pdgfra protein (UniProt.org). D846V is associated with resistance to Gleevec (imatinib) (PMID: 16624552), but has not been biochemically characterized and therefore, its effect on Pdgfra protein function is unknown (PubMed, Mar 2020).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PDGFRA D846V||gastrointestinal stromal tumor||predicted - resistant||Imatinib||Case Reports/Case Series||Actionable||In a clinical study, none of 4 gastrointestinal stromal tumor patients harboring PDGFRA D842V (n=3) or PDGFRA D846V (n=1) mutations treated on a Phase III clinical trial demonstrated a response to treatment with Gleevec (imatinib), compared to 5 of 6 patients harboring PDGFRA sensitizing mutations (PMID: 16624552).||16624552|