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

Michael Heinrich, Kouros Owzar, Christopher Corless, Donna Hollis, Ernest C. Borden, Christopher D M Fletcher, Christopher Ryan, Margaret Von Mehren, Charles Blanke, Cathryn Rankin, Robert S. Benjamin, Vivien H. Bramwell, George D. Demetri, Monica M. Bertagnolli, Jonathan A. Fletcher

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    Abstract

    Purpose: 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. Patients and Methods: 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. Results: 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). Conclusion: 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.

    Original languageEnglish (US)
    Pages (from-to)5360-5367
    Number of pages8
    JournalJournal of Clinical Oncology
    Volume26
    Issue number33
    DOIs
    StatePublished - Nov 20 2008

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    Gastrointestinal Stromal Tumors
    Leukemia
    Phosphotransferases
    Genotype
    Exons
    Neoplasms
    Therapeutics
    Imatinib Mesylate
    Survival
    Mutation

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    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. / Heinrich, Michael; Owzar, Kouros; Corless, Christopher; Hollis, Donna; Borden, Ernest C.; Fletcher, Christopher D M; Ryan, Christopher; Von Mehren, Margaret; Blanke, Charles; Rankin, Cathryn; Benjamin, Robert S.; Bramwell, Vivien H.; Demetri, George D.; Bertagnolli, Monica M.; Fletcher, Jonathan A.

    In: Journal of Clinical Oncology, Vol. 26, No. 33, 20.11.2008, p. 5360-5367.

    Research output: Contribution to journalArticle

    Heinrich, Michael ; Owzar, Kouros ; Corless, Christopher ; Hollis, Donna ; Borden, Ernest C. ; Fletcher, Christopher D M ; Ryan, Christopher ; Von Mehren, Margaret ; Blanke, Charles ; Rankin, Cathryn ; Benjamin, Robert S. ; Bramwell, Vivien H. ; Demetri, George D. ; Bertagnolli, Monica M. ; Fletcher, Jonathan A. / 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. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 33. pp. 5360-5367.
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    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",
    abstract = "Purpose: 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. Patients and Methods: 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. Results: 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). Conclusion: 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.",
    author = "Michael Heinrich and Kouros Owzar and Christopher Corless and Donna Hollis and Borden, {Ernest C.} and Fletcher, {Christopher D M} and Christopher Ryan and {Von Mehren}, Margaret and Charles Blanke and Cathryn Rankin and Benjamin, {Robert S.} and Bramwell, {Vivien H.} and Demetri, {George D.} and Bertagnolli, {Monica M.} and Fletcher, {Jonathan A.}",
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    TY - JOUR

    T1 - 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

    T2 - CALGB 150105 study by cancer and leukemia group B and southwest oncology group

    AU - Heinrich, Michael

    AU - Owzar, Kouros

    AU - Corless, Christopher

    AU - Hollis, Donna

    AU - Borden, Ernest C.

    AU - Fletcher, Christopher D M

    AU - Ryan, Christopher

    AU - Von Mehren, Margaret

    AU - Blanke, Charles

    AU - Rankin, Cathryn

    AU - Benjamin, Robert S.

    AU - Bramwell, Vivien H.

    AU - Demetri, George D.

    AU - Bertagnolli, Monica M.

    AU - Fletcher, Jonathan A.

    PY - 2008/11/20

    Y1 - 2008/11/20

    N2 - Purpose: 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. Patients and Methods: 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. Results: 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). Conclusion: 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.

    AB - Purpose: 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. Patients and Methods: 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. Results: 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). Conclusion: 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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