• Determine eligibility and potential for response to imatinib in patients with gastrointestinal stromal tumors (GISTs)

Although rare (≈7 cases per million in the U.S.), GISTs are the most common mesenchymal tumor of the gastrointestinal tract.¹ They usually occur in the stomach (60%) or small intestine (35%) and manifest with gastrointestinal bleeding, abdominal swelling, and/or palpable mass.² Patients may also be asymptomatic. Diagnostic procedures include imaging studies and exploratory surgery followed by excision of the primary tumor when appropriate (ie, ≥2 cm in size without metastases).³ In lieu of tumor excision, patients with advanced GISTs (unresectable tumors or metastatic disease) may be treated with protein tyrosine kinase inhibitors such as imatinib.

Approximately 80% of GISTs harbor an activating mutation in the KIT gene and another 5% to 7% have a mutation in the PDGFRA gene; such mutations result in tumorigenesis, predict treatment response to imatinib, and provide prognostic information.³ In patients with advanced GISTs, 69% to 86% of patients respond to imatinib when their tumors have a c-KIT exon 11 mutation.^4-6 On the other hand, only 17% to 48% of patients respond when their tumors harbor a c-KIT exon 9 mutation; in these patients, the likelihood of response improves with the use of 800 mg imatinib rather than the standard 400 mg dose.^4,5 Most known mutations in the PDGFRA gene are associated with imatinib response; the most notable exception is D842V.⁷ When negative for both c-KIT and PDGFRA mutations, advanced GISTs have only a 0% to 45% likelihood of responding to imatinib.^4-6

When patients with advanced disease were treated with imatinib, c-KIT exon 11 mutations were associated with improved outcomes: median time to progression (TTP) was 25, 17, and 13 months for patients with tumor mutations in c-KIT exon 11, c-KIT exon 9, and neither c-KIT nor PDGFRA genes, respectively.⁴ Median overall survival (OS) was 60, 38, and 49 months, respectively.⁴ OS for patients with tumors that had exon 9 mutation was the same as those without a c-KIT or PDGFRA mutation.

Since c-KIT and PDGFRA mutations are believed to be mutually exclusive (ie, mutations from only 1 of these genes occur within a single tumor), Quest Diagnostics tests first for mutations in c-KIT and, if negative, then tests for PDGFRA mutations. PDGFRA mutations have been reported in 33% of c-KIT mutation-negative GISTs.⁸

• Patients with advanced GISTs who are candidates for imatinib therapy

• Polymerase chain reaction (PCR) and gene sequencing

–   PCR amplification of exons 8, 9,11,13, and 17 of c-KIT gene and exons 12 and 18 of PDGFRA gene

–   Bidirectional gene sequencing of purified products

–   Computer analysis of sequencing data to determine mutation presence or absence

• Analytical sensitivity: 20% mutant allele in background of wild-type allele

Not detected
Silent polymorphisms P567 and V824 may be present in PDGFRA exon 12 and 18, respectively.

Presence of a c-KIT mutation in exon 11 is associated with a more favorable prognosis and greater likelihood of response to imatinib therapy in patients with advanced GIST. Presence of a c-KIT mutation in exon 9 predicts a less likelihood of response and an increased dose should be considered. PDGFRA mutations in exon 18 (eg, D842V, double point mutation DI842-843IM, and RD841-842KI) predict imatinib resistance,⁷ as do negative c-KIT and PDGFRA mutations. Alternative drugs (eg, sunitinib) may be considered if imatinib resistance or failure is suspected.⁹

Polymorphisms or mutations at locations other than those mentioned in the Methods section will not be detected. Results should be interpreted in conjunction with other laboratory and clinical findings.