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Gastrointestinal Stromal Tumors (GISTs), PDGFRA Mutation Analysis

CPT: 81314; 88381
Updated on 06/7/2020

Synonyms

  • Tyrosine Kinase Inhibitor (TKI, Imatinib) Responsiveness

Special Instructions

This assay is currently not available in New York state.

Please provide a copy of the pathology report, and direct any questions regarding this test to oncology customer service at 800-345-4363.


Expected Turnaround Time

10 - 14 days



Specimen Requirements


Specimen

Formalin-fixed, paraffin-embedded (FFPE) tissue or five unstained slides from a paraffin block in 10-μM sections and a matching H&E reference slide


Volume

Formalin-fixed, paraffin-embedded (FFPE) block or five unstained slides from paraffin block in 10-μM sections and a matching H&E reference slide


Minimum Volume

2mm x 2mm tumor area with greater than or equal to 50% tumor


Container

Slides or blocks


Storage Instructions

Maintain blocks and slides at room temperature.


Causes for Rejection

Tumor block containing insufficient tumor tissue or tumor fixed in a heavy metal fixative; broken or stained slides


Test Details


Use

The platelet-derived growth factor receptor alpha (PDGFRA) gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. PDGFRA and c-KIT have approximately 35% homology. They both belong to the PDGFRA subfamily of receptor tyrosine kinases, which are involved in the regulation of cell growth, proliferation, adhesion, migration, differentiation, and apoptosis. Recently, the kinase inhibitor Avapritinib (AYVAKIT™) was approved for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.

The platelet-derived growth factor receptor alpha (PDGFRA) gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. PDGFRA and c-KIT have approximately 35% homology. They both belong to the PDGFRA subfamily of receptor tyrosine kinases, which are involved in the regulation of cell growth, proliferation, adhesion, migration, differentiation, and apoptosis. Recently, the kinase inhibitor Avapritinib (AYVAKIT ™) was approved for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.

The platelet-derived growth factor receptor alpha (PDGFRA) gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. PDGFRA and c-KIT have approximately 35% homology. They both belong to the PDGFRA subfamily of receptor tyrosine kinases, which are involved in the regulation of cell growth, proliferation, adhesion, migration, differentiation, and apoptosis. Recently, the kinase inhibitor Avapritinib (AYVAKIT™) was approved for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.


Limitations

Genomic DNA is purified from the specimen provided. Exons 10, 12, 14, and 18 of PDGFRA gene coding are subjected to PCR amplification and bidirectional sequencing in duplicate to identify sequence variations. This assay has a sensitivity to detect approximately 10% of cells containing the PDGFRA mutations in a background of nonmutant cells. This assay will not detect the mutation below the sensitivity of this assay.

This test was developed and its performance characteristics determined by LabCorp. It has not been cleared or approved by the Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary.

Genomic DNA is purified from the specimen provided. Exons 10, 12, 14, and 18 of PDGFRA gene coding are subjected to PCR amplification and bidirectional sequencing in duplicate to identify sequence variations. This assay has a sensitivity to detect approximately 10% of cells containing the PDGFRA mutations in a background of nonmutant cells. This assay will not detect the mutation below the sensitivity of this assay.

This test was developed, and its performance characteristics determined, by LabCorp. It has not been cleared or approved by the US Food and Drug Administration (FDA). The FDA has determined that such clearance or approval is not necessary.

Genomic DNA is purified from the specimen provided. Exons 10, 12, 14, and 18 of PDGFRA gene coding are subjected to PCR amplification and bidirectional sequencing in duplicate to identify sequence variations. This assay has a sensitivity to detect approximately 10% of cells containing the PDGFRA mutations in a background of nonmutant cells. This assay will not detect the mutation below the sensitivity of this assay.

This test was developed and its performance characteristics determined by LabCorp. It has not been cleared or approved by the Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary.


Methodology

Polymerase chain reaction (PCR) and DNA sequencing


Additional Information

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, located mostly in the stomach (60%) and small intestine (35%). Approximately 80% of GISTs have a mutation in c-KIT and 5% to 10% of GISTs have a mutation in PDGFRA. PDGFRA mutations are mutually exclusive with c-KIT mutations but active similar signal transduction pathways that support GIST oncogenesis. The location of c-KIT and PDGFRA mutations in GISTs is associated with the site of origin, histological phenotype, and treatment response to tyrosine kinase inhibitors (TKI, such as imatinib and sunitinib). Patients with mutations in c-KIT exon 11 have been shown to have significantly better response rates to imatinib treatment when compared with patients who have the c-KIT exon 9 mutations or no mutation. Patients with mutations in c-KIT exon 9 may benefit from dose escalation depending on tolerance. Secondary mutations usually occur in c-KIT kinase domains in patients after imatinib treatment resulting in resistance to this drug. Other TKI inhibitors, such as sunitinib and sorafenib, could be used as a replacement drug for selected mutations. Most known mutations in the PDGFRA gene are associated with imatinib response with the exception of D842V mutation. In a subset of intestinal high-risk GISTs lacking c-KIT/PDGFRA mutations, 7% have a mutation in BRAF. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset.


References

Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005 Aug 10; 23(23):5357-5364.15928335
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced GIST after failure of imatinib: A randomized controlled trial. Lancet. 2006 Oct 14;368(9544):1329-1338.17046465
Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010 Mar 1;28(7):1247-1253.20124181
Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res. 2009 Dec 15;15(24):7510-7518.20008851
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-4349.14645423
Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008 Nov 20;26(33):5352-5359.18955458
Heinrich MC, Owzar K, Corless CL, et al. 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. 2008 Nov 20;26(33):5360-5367.18955451
Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008 Sep;53(3):245-266.18312355
Maleddu A, Pantaleo MA, Nannini M, et al. Mechanisms of secondary resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumours (Review). Oncol Rep. 2009 Jun;21(6):1359-1366.19424610
National Comprehensive Cancer Network. Soft Tissue Sarcoma. Plymouth Meeting, PA: NCCN Guidelines, Version 6.2019.
Penzel R, Aulmann S, Moock M, Schwarzbach M, Rieker RJ, Mechtersheimer G. The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumors is site and phenotype associated. J Clin Pathol. 2005 Jun;58:634-639.15917417
US Food & Drug Administration. FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors. FDA web site. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-rare-mutation-patients-gastrointestinal-stromal-tumors. Accessed June 2020.
Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008 Sep;53(3):245-266.1831235
Soft Tissue Sarcoma. NCCN Guidelines, Version 6.2019.
US Food and Drug Administration. FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors. FDA web site. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-rare-mutation-patients-gastrointestinal-stromal-tumors. Accessed April 2020.
Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005 Aug 10; 23(23):5357-5364.15928335
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced GIST after failure of imatinib: A randomized controlled trial. Lancet. 2006 Oct 14;368(9544):1329-1338.17046465
Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010 Mar 1;28(7):1247-1253.20124181
Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res. 2009 Dec 15;15(24):7510-7518.20008851
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-4349.14645423
Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008 Nov 20;26(33):5352-5359.18955458
Heinrich MC, Owzar K, Corless CL, et al. 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. 2008 Nov 20;26(33):5360-5367.18955451
Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008 Sep;53(3):245-266.18312355
Maleddu A, Pantaleo MA, Nannini M, et al. Mechanisms of secondary resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumours (Review). Oncol Rep. 2009 Jun;21(6):1359-1366.19424610
National Comprehensive Cancer Network. Soft Tissue Sarcoma. Plymouth Meeting, PA: NCCN Guidelines, Version 6.2019.
Penzel R, Aulmann S, Moock M, Schwarzbach M, Rieker RJ, Mechtersheimer G. The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumors is site and phenotype associated. J Clin Pathol. 2005 Jun;58:634-639.15917417
US Food & Drug Administration. FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors. FDA web site. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-rare-mutation-patients-gastrointestinal-stromal-tumors. Accessed June 2020.

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