Optimal Use of Targeted Agents for Advanced Gastrointestinal Stromal Tumours

HELIOS Klinikum Bad Saarow, Bad Saarow, Germany.
Oncology (Impact Factor: 2.42). 04/2010; 78(2):130-40. DOI: 10.1159/000312655
Source: PubMed


Imatinib is the recommended 1st-line treatment for a KIT-positive unresectable and/or metastatic gastrointestinal stromal tumour (GIST). However, some patients experience intolerance to imatinib and most patients will eventually experience disease progression while on imatinib treatment. Sunitinib is approved for treatment of a GIST after disease progression on, or intolerance to, imatinib therapy. Progression may occur early or later on, in treatment and is determined by factors including initial GIST genotype and mutational status. GISTs with KIT exon 11 mutations appear to be sensitive to standard dose imatinib, and patients with GISTs exhibiting KIT exon 9 mutations whose disease has progressed on imatinib 400 mg/day have been shown to respond to imatinib 800 mg/day, albeit with a higher incidence of adverse events. Sunitinib has shown clinical benefit in all major GIST mutational subtypes, particularly in patients with wild-type or KIT exon 9 genotype and against GISTs with secondary KIT exon 13 or 14 mutations. The choice between higher-dose imatinib and sunitinib after progression on standard dose imatinib is unclear, and apart from the GIST primary resistance genotype and mutational status, individual patient factors such as tumour characteristics, drug pharmacokinetics, and other clinical factors may affect response to treatment. Individualisation of therapy may help to maximise clinical benefit of therapy in these patients.

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    • "Approximately 75–85% of GIST patients express activating mutations of KIT of which exon 11 is the most common (57–70%), followed by exon 9 (5–18%) and rarely exon 13 and 17 domains (<2%). Only 5% of patients exhibit mutations in PDGFR and some patients exhibit neither KIT nor PDGFR (10–15%) [29]. Work with a c-KIT expressing human myeloid leukemia cell line proved that STI 571 (imatinib mesylate) was able to block c-KIT autophosphorylation [30]. "
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    • "The identification of specific cellular markers has led to the development of effective targeted agents, namely, tyrosine kinase inhibitor (TKI) therapy (e.g., imatinib). These have had dramatic effects in prolonging progression free survival in advanced unresectable disease [15]. Most Kit positive tumors are sensitive to imatinib; however, the majority (80%) of PDGFRA mutations are resistant to treatment [16]. "
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    • "The results lead us to the assumption that KIT exon 9 mutated GIST play a special role compared to GIST carrying other mutations. Interestingly, KIT exon 9 mutated GIST need a double daily dose of the tyrosine kinase inhibitor imatinib to be effectively treated [48]. Furthermore, they develop preferentially in the small intestine but only rarely in the stomach where the majority of GIST are detected [49]. "
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    ABSTRACT: Gastrointestinal stromal tumors (GIST) represent the most common mesenchymal tumors of the gastrointestinal tract. About 85% carry an activating mutation in the KIT or PDGFRA gene. Approximately 10% of GIST are so-called wild type GIST (wt-GIST) without mutations in the hot spots. In the present study we evaluated appropriate reference genes for the expression analysis of formalin-fixed, paraffin-embedded and fresh frozen samples from gastrointestinal stromal tumors. We evaluated the gene expression of KIT as well as of the alternative receptor tyrosine kinase genes FLT3, CSF1-R, PDGFRB, AXL and MET by qPCR. wt-GIST were compared to samples with mutations in KIT exon 9 and 11 and PDGFRA exon 18 in order to evaluate whether overexpression of these alternative RTK might contribute to the pathogenesis of wt-GIST. Gene expression variability of the pooled cDNA samples is much lower than the single reverse transcription cDNA synthesis. By combining the lowest variability values of fixed and fresh tissue, the genes POLR2A, PPIA, RPLPO and TFRC were chosen for further analysis of the GIST samples. Overexpression of KIT compared to the corresponding normal tissue was detected in each GIST subgroup except in GIST with PDGFRA exon 18 mutation. Comparing our sample groups, no significant differences in the gene expression levels of FLT3, CSF1R and AXL were determined. An exception was the sample group with KIT exon 9 mutation. A significantly reduced expression of CSF1R, FLT3 and PDGFRB compared to the normal tissue was detected. GIST with mutations in KIT exon 9 and 11 and in PDGFRA exon 18 showed a significant PDGFRB downregulation. As the variability of expression levels for the reference genes is very high comparing fresh frozen and formalin-fixed tissue there is a strong need for validation in each tissue type. None of the alternative receptor tyrosine kinases analyzed is associated with the pathogenesis of wild-type or mutated GIST. It remains to be clarified whether an autocrine or paracrine mechanism by overexpression of receptor tyrosine kinase ligands is responsible for the tumorigenesis of wt-GIST.
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