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Ref Type Journal Article
PMID (18955451)
Authors Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, Ryan CW, von Mehren M, Blanke CD, Rankin C, Benjamin RS, Bramwell VH, Demetri GD, Bertagnolli MM, Fletcher JA
Title Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.
Journal Vol Issue Date Pages Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26 33 2008 Nov 20 5360-7 J Clin Oncol
URL
Abstract Text Imatinib mesylate is standard treatment for patients who have advanced gastrointestinal stromal tumor (GIST), but not all patients benefit equally. In previous studies, GIST genotype correlated with treatment outcome and optimal imatinib dosing.We examined the relationship between kinase genotype and treatment outcome for 428 patients enrolled on the North American phase III study SWOG S0033/CALGB 150105 and treated with either 400 mg or 800 mg daily doses of imatinib.The presence of KIT exon 11-mutant genotype (n = 283) correlated with improved treatment outcome when compared with KIT exon 9-mutant (n = 32) and wild-type (WT; n = 67) genotypes for objective response (complete response [CR]/partial response [PR], 71.7% v 44.4% [P = .007]; and 44.6% [P = .0002], respectively); time to tumor progression (TTP; median 24.7 months v 16.7 and 12.8 months, respectively); and overall survival (OS; median 60.0 months v 38.4 and 49.0 months, respectively). The survival outcomes for patients with exon 9-mutant, exon 11-mutant or WT GIST were not affected by imatinib dose. However, there was evidence of improved response rates for patients with exon 9-mutant tumors treated with imatinib 800 mg versus 400 mg (CR/PR, 67% v 17%; P = .02). Patients who had CD117-negative GIST had similar TTP but inferior OS compared with patients who had CD117-positive disease, which suggests that patients who have CD117-negative GIST may benefit from imatinib treatment. In addition, we identified novel but rare mutations of the KIT extracellular domain (exons 8 and 9).We confirmed the favorable impact of KIT exon 11 genotype when compared with KIT exon 9 and wild-type genotype for patients with advanced GIST who are treated with imatinib.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT exon11 gastrointestinal stromal tumor sensitive Imatinib Phase III Actionable In a Phase III trial (CALGB 150105), Gleevec (imatinib) treatment resulted in a more favorable objective response (71.7% vs 44.4% (p=0.007) and 44.6% (p=0.002)), median time to tumor progression (24.7 mo vs 16.7 mo and 12.8 mo), and median overall survival (60.0 mo vs 38.4 mo and 49.0 mo) in patients with advanced gastrointestinal stromal tumor harboring KIT exon 11 mutations (n=283) compared to patients with KIT exon 9 mutations (n=32) or wild-type KIT (n=67) (PMID: 18955451). 18955451
KIT exon9 gastrointestinal stromal tumor sensitive Imatinib Case Reports/Case Series Actionable In a Phase III trial (CALGB 150105), Gleevec (imatinib) treatment resulted in a higher objective response rate at a dose of 800mg (n=18) compared to 400mg (n=14) (67% vs 17%, p=0.02) in patients with advanced gastrointestinal stromal tumor harboring KIT exon 9 mutations (PMID: 18955451). 18955451