A Study of Outcome of Metastatic Gastrointestinal Stromal Tumors Treated with Imatinib and Correlation with C-Kit Mutation Status.

Sanju, Cyriac (2011) A Study of Outcome of Metastatic Gastrointestinal Stromal Tumors Treated with Imatinib and Correlation with C-Kit Mutation Status. Masters thesis, Cancer Institute (WIA), Chennai.


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Introduction: Gastrointestinal Stromal Tumors (GIST) are the most common mesenchymal Tumors of the gastrointestinal tract.[1] They are very rare tumors and can arise Anywhere in the gastrointestinal tract but most commonly arise from the stomach (40- 65%), the small intestine (20-40%) and rectum (2-15%). Majority of the patients are Asymptomatic. The molecular hallmark of entity was discovered only 10 years back. Approximately 95% of GIST stain positive for CD117 on immunohistochemistry.[1] KIT is the cell surface transmembrane tyrosine kinase receptor of the stem cell factor. In1998, Hirota et al identified activated mutations of the KIT receptor gene in familial And sporadic cases of GIST, which were later found to occur very frequently. [2] Approximately 80 – 90% of the GIST exhibit activating KIT mutations. [3] The most common KIT mutations affect the juxtamembrane domain encoded By exon 11 which is seen in 80% of the cases. [4,5] In addition, 12% of gists have a Mutation in an extracellular domain encoded by exon 9. More rarely, mutations occur In the split kinase domain encoded by exon 13 or 17. Approximately 30% of gists That are wild type for KIT, and 5% to 8% of gists overall, have PDGFRA gene Mutations. KIT and PDGFRA mutations are mutually exclusive in GIST. Wild-type Gists (i.e., gists lacking mutations of KIT or PDGFRA) account for 12% to 15% of All adult gists but is more prevalent in pediatric gists (uptp 90%). The molecular Pathogenesis and underlying biology of wild-type gists is a subject of ongoing Research. The prognosis of metastatic GIST was considered dismal and hardly any Patient survived beyond 1 - 2 years. Traditionally, GIST is considered to be Chemoresistant. The discovery of Imatinib and its use against Chronic Myeloid Leukemia led to more researches for targeted therapy. [6] Subsequently, the ability of Imatinib to inhibit KIT and PDGFR was noted. In two large phase III studies Comparing imatinib dose levels (400 mg/day vs. 800 mg/day), the median Progression-free survival (PFS) for either arm was approximately 20 months, and Median overall survival (OS) was approximately 50 months.[7,8] So the fact that the Natural history of GIST has changed was clear. Since then, there are fascinating Research activities going on in the field of GIST. Secondary resistance mechanisms eventually ensue and many patients Progress after Imatinib. Several second line agents are available now to salvage such Patients. These include drugs like Sunitinib, Dasatinib, Nilotinib etc. Newer pathways Like mtor inhibition are explored to add drugs to the second line list. The clinical studies of imatinib for treatment of gists consistently Demonstrated that genotypically defined subsets of gists have different outcomes During imatinib treatment. [7, 9] The presence of a KIT exon 11 mutation is associated With a significantly improved clinical outcome during imatinib therapy when Compared with patients with metastatic gists with KIT exon 9-mutant or wild-type Genotypes. Patients with KIT exon 9-mutant GIST had significantly improved PFS, But not OS, when treated with high-dose imatinib. The relative imatinib resistance of The KIT exon 9 mutant kinase when compared with KIT exon 11 mutant kinase might Explain the benefit of high-dose imatinib in KIT exon 9-mutant GIST. Based on the Previous data, many GIST experts now recommend routine tumor genotyping and Dose selection based on the presence or absence of a KIT exon 9 mutation. Metastatic GIST management has taken a new turn in our country also after The introduction of Imatinib. Support programmes like GIPAP (Glivec International Patient Assistance Programme) provide free drugs to all patients with metastatic GIST. There is hardly any data about the treatment outcome of metastatic GIST in India. It Would be interesting to check whether our patients behave similar to the reported Series. The genotype pattern in our population also is largely unknown. This study is Conducted to address both these important issues. AIM The aims of the study are 1. To analyse clinicopathological profile of patients with metastatic GIST 2. To determine the prognostic factors associated with treatment outcome 3. To assess the survival patterns 4. To study the genotype of tumors of patients with metastatic GIST 5. To study the relationship of genotype with treatment outcome, if any.

Item Type: Thesis (Masters)
Uncontrolled Keywords: Metastatic ; Gastrointestinal ; Stromal Tumors ; Imatinib ; C-Kit Mutation Status.
Subjects: MEDICAL > Medical Oncology
Depositing User: Subramani R
Date Deposited: 19 Aug 2017 03:37
Last Modified: 19 Aug 2017 03:37
URI: http://repository-tnmgrmu.ac.in/id/eprint/2036

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