Solid Tumors PDGFRA - GIST

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.

The most common mutation in PDGFRA is D842V, which generates a mutant form of the kinase that is fully resistant to imatinib in vitro.¹  Tumors with this mutation are generally slow to recur or progress. There are only limited data on patients whose GIST harbored this mutation and were treated with imatinib. Combining data from the B2222 phase II trial, the SWOG 0033 phase III trial and the EORTC phase III trial of imatinib for advanced GIST, there were no objective responses among 10 patients with this mutation.^2-4 One patient had stable disease.  In another recent report of 19 patients with D842V-mutant GIST, 26% had stable disease and 74% had progressive disease as their best response to imatinib.⁶
 
Other PDGFRA mutations occurring in exons 12, 14 and 18 are nearly all predicted to be sensitive to inhibition by imatinib based on pre-clinical data.⁴  This is supported by the limited clinical trial data that are available.^3-5

This test is performed as a reflex for GISTs that are negative for a cKIT mutation. The testing protocol involves the following steps.
1. Microscopic examination of the specimen and macrodissection of tumor-rich areas.
2. DNA extraction and purification.
3. PCR amplification of selected PDGFRA exons 12, 14 & 18. 
4. Screening for mutations by one of two methods: direct, bidirectional sequencing, or real-time PCR with high resolution melting curve analysis. DNA sequencing is used to confirm any mutations picked up by melting curve analysis. 
5. The estimated sensitivity of these methods is 20% mutant allele. 

• A paraffin block or
• 10 unstained sections of tumor (4-5 microns) (15 sections for small biopsies)

Contact Client Services for shipping materials and procedures at (855) 535-1522.

A REQUISITION FORM MUST ACCOMPANY ALL SAMPLES.  Please include detailed clinical information.

Mon - Fri

10 - 14 days

• Keep specimen cool during transit, but do not ship on dry ice.
• Please use the cold pack provided in the KDL shipping kit.
• Ship the specimen overnight express, using the FedEx priority overnight label provided. 
• Contact Client Services for shipping materials and procedures at (855) 535-1522.

1. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 22:3813-3825, 2004.

2. Debiec-Rychter M, 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, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD, Ryan CW, von Mehren M, Blanke CD, Rankin C, Benjamin RS, Bramwell VH, Demetri GD, Bertagnolli MM, Fletcher JA. 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. J Clin Oncol 26:5360-7, 2008.

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.

6. P. Biron, P. A. Cassier, E. Fumagalli, A. Blesius, M. Debiec-Rychter, A. Adenis, J. Verweij, P. Hohenberger, J. Blay, P. G. Casali, EORTC Soft Tissue and Bone Sarcoma Group. Outcome of patients (pts) with PDGFRAD842V mutant gastrointestinal stromal tumor (GIST) treated with imatinib (IM) for advanced disease. J Clin Onc 2010 ASCO Meeting Abstract 10051.