GIST Background Information

Approximately 80% of gastrointestinal stromal tumors (GISTs) have an oncogenic mutation in the gene encoding KIT tyrosine kinase.¹ Another 5-7% of GISTs have a mutation in the gene encoding the related kinase PDGFRA (platelet-derived growth factor receptor alpha).¹ KIT and PDGFRA mutations are mutually exclusive in GISTs. In both genes, the observed mutations are invariably in-frame and result in expression of a mutant kinase isoform that has constitutive tyrosine kinase activity. Approximately 10-15% of GISTs have no detectable KIT or PDGFRA gene mutation.

Screening for kinase mutations in suspected GISTs is important for the following reasons.

1. The presence of a mutation provides molecular confirmation of the diagnosis.
2. Clinical response to treatment with imatinib mesylate (Gleevec™) is predicted by the kinase mutation status, as detailed in the table below.
3. The progression-free survival of patients with KIT exon 9-mutant GIST is significantly longer when they are treated with 800mg/d imatinib as opposed to 400mg/d.² In contrast, the PFS of patients with KIT exon 11-mutant tumor is not influenced by drug dosage.

Additional testing performed if initial testing is negative
     KIT exons (9), 13 & 17
     PDGFRA exons 12, 14 & 18

		Mutation Status*
	KIT exon 11	KIT exon 9	No mutation
Objective response#	65-67%	34-40%	23-40%
Progressive disease	3%	17%	19%
Progression-free survival	19-27 mo	9-10 mo	8-15 mo

#Defined as complete or partial response by RECIST criteria.
*Compilation of data from the SWOG S0033 and EROTC phase III trials of imatinib for advanced GIST.2,3
Similar data were previously published from phase II trials.4,5

References

1. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 22:3813-3825, 2004.
2. Debiec-Rychter M, Raf Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, Blay J-Y, Leyvraz S, Stul M, Casali PG, Zalcberg J, Verweij J, Van Glabbeke M, Hagemeijer A, Judson I. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-103, 2006
3. Heinrich MC, Shoemaker JS, Corless CL, Hollis D, Demetri GD, Bertagnolli MM, Fletcher JA. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: Abstract 7.
4. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen C-J, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CDM, Silberman S, Dimitrijevic S, Fletcher JA. Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 21:4342-4349, 2003.
5. Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, Dimitrijevic S, Sciot R, Stul M, Vranck H, Scurr M, Hagemeijer A, Van Glabbeke M, Van Oosterom AT. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40:689-95, 2004.

Links: Pathology Translational Research, Research Tests Available, GIST, Mastocytosis/MPD/AML, Melanoma

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