KIT & PDGFRA Gene Mutation Screening For GI Stromal Tumors

How to order KIT and PDGFRa test How test is performed

Approximately 80% of gastrointestinal stromal tumors (GISTs) have an oncogenic mutation in the gene encoding KIT tyrosine kinase.1,2 Another 5-7% of GISTs have a mutation in the gene encoding the related kinase PDGFRA (platelet-derived growth factor receptor alpha).3 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 7-12% of GISTs have no detectable KIT or PDGFRA gene mutation.

Testing for mutations in the KIT and PDGFRA genes is available through the Molecular Diagnostics Laboratory of Oregon Health & Science University (OHSU). This testing can provide physicians and their patients information on the likelihood of response to therapy with imatinib mesylate (Gleevec™), as detailed below. Regardless of the test results, however, all patients eligible for treatment should undergo a therapeutic trial with the drug. Even among patients with tumors lacking a detectable KIT or PDGFRA gene mutation, the response to imatinib mesylate is higher than the response to traditional chemotherapy (<5%).

Based on analysis of the CSTI-B2222 phase II trial of imatinib mesylate for the treatment of non-operable malignant GI stromal tumor, there is a relationship between the kinase mutation status of a GIST and the likelihood of drug response, as summarized in the table below.4

In addition to having a higher rate of response to therapy, patients with GISTs harboring an exon 11 mutation have more durable responses and better overall survival than those with exon 9 mutations or those with no mutation detected in either kinase gene. Patients without detectable KIT or PDGFRA mutation had a median event-free survival of 82 days. For patients with an KIT exon 9-mutant tumor the median event-free survival was 200 days, while for patients with an exon 11-mutant tumor it was 687 days.4 The findings in the CSTI-B2222 trial have been supported by a similar phase I/II trial performed in Europe.5

References

1. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118-8121, 2001.

2. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Human Pathology 33:484-495, 2002

3. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen C-J, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri G, Fletcher CDM, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708-710, 2003.

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.