JCO Early Release, published online ahead of print Oct 27 2008
Journal of Clinical Oncology, 10.1200/JCO.2008.17.4284
Received March 28, 2008
Accepted June 30, 2008
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 C. Heinrich,* Kouros Owzar, Christopher L. Corless, Donna Hollis, Ernest C. Borden, Christopher D.M. Fletcher, Christopher W. Ryan, Margaret von Mehren, Charles D. Blanke, Cathryn Rankin, Robert S. Benjamin, Vivien H. Bramwell, George D. Demetri, Monica M. Bertagnolli, and Jonathan A. Fletcher
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.
* To whom correspondence should be addressed. 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.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Facebook  Reddit  Technorati  Twitter What's this?
Related Articles
- Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor
Michael C. Heinrich, Robert G. Maki, Christopher L. Corless, Cristina R. Antonescu, Amy Harlow, Diana Griffith, Ajia Town, Arin Mckinley, Wen-Bin Ou, Jonathan A. Fletcher, Christopher D.M. Fletcher, Xin Huang, Darrel P. Cohen, Charles M. Baum, and George D. Demetri
JCO 2008 26: 5352-5359
[Abstract]
[Full Text]
- Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor
Michael C. Heinrich, Robert G. Maki, Christopher L. Corless, Cristina R. Antonescu, Amy Harlow, Diana Griffith, Ajia Town, Arin Mckinley, Wen-Bin Ou, Jonathan A. Fletcher, Christopher D.M. Fletcher, Xin Huang, Darrel P. Cohen, Charles M. Baum, and George D. Demetri
JCO 2008 26: 5352-5359
[Abstract]
[Full Text]
Related Editorial
- Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype
Ian R. Judson
JCO 2008 26: 5322-5325
[Full Text]
This article has been cited by other articles:
|
|
|
|
 
J. Verweij
Soft Tissue Sarcoma Trials: One Size No Longer Fits All
J. Clin. Oncol.,
July 1, 2009;
27(19):
3085 - 3087.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Cohen, A. Farrell, R. Justice, and R. Pazdur
Approval Summary: Imatinib Mesylate in the Treatment of Metastatic and/or Unresectable Malignant Gastrointestinal Stromal Tumors
Oncologist,
February 1, 2009;
14(2):
174 - 180.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Heinrich, S. George, S. Bauer, and J. A. Fletcher
Optimizing the Treatment of Gastrointestinal Stromal Tumors: The Roles of Tumor Genotyping, Imatinib Blood-level Testing, and New Therapeutic Strategies
ASCO Educational Book,
January 1, 2009;
2009(1):
694 - 699.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. R. Judson
Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype
J. Clin. Oncol.,
November 20, 2008;
26(33):
5322 - 5325.
[Full Text]
[PDF]
|
|
|
|
