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Originally published as JCO Early Release 10.1200/JCO.2008.17.4284 on October 27 2008 © 2008 American Society of Clinical Oncology. 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
From the Oregon Health and Science University Cancer Institute; and Portland Veterans Affairs Medical Center, Portland, OR; Cancer and Leukemia Group B Statistical Center; and Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC; Cleveland Clinic Foundation, Cleveland, OH; Dana-Farber/Harvard Cancer Center; and Departments of Surgery and of Pathology, Brigham and Women's Hospital, Boston, MA; Fox Chase Cancer Center, Philadelphia, PA; Southwest Oncology Group Statistical Center, Seattle, WA; The University of Texas M. D. Anderson Cancer Center, Houston, TX; and Tom Baker Cancer Centre, Calgary, Alberta, Canada Corresponding author: Michael C. Heinrich, MD, Portland VA Medical Center and Oregon Health and Science University, Division of Hematology/Oncology, 3710 SW US Veterans Hospital Road, R&D-19, Portland, OR 97239; e-mail: heinrich{at}ohsu.edu 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. published online ahead of print at www.jco.org on October 27, 2008 Supported in part by Grants No. CA33601, CA04919, CA32291, CA27525, CA31946, CA32102, and CA77202 from the National Cancer Institute (NCI); by Grants No. U01-CA70172-01 and N01-CM-17003 from the NCI; by a Veterans Affairs Merit Review Grant (M.H.); and by research funding from Novartis Pharmaceuticals. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors‘ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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