10.1245/s10434-006-9288-1
Annals of Surgical Oncology 14:1123-1128 (2007)
© 2007 Society of Surgical Oncology
Kinase Mutations and Imatinib Mesylate Response for 64 Taiwanese with Advanced GIST: Preliminary Experience from Chang Gung Memorial Hospital
Chun-Nan Yeh, MD,
Tsung-Wen Chen, MD,
Hsiang-Lin Lee, MD,
Yu-Yin Liu, MD,
Tzu-Chieh Chao, MD, PhD,
Tsann-Long Hwang, MD, FACS,
Yi-Yin Jan, MD, FACS and
Miin-Fu Chen, MD, FACS
Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, 5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan
Correspondence: Address correspondence and reprint requests to: Chun-Nan Yeh, MD; E-mail: ycn{at}adm.cgmh.org.tw
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ABSTRACT
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Purpose: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutation of kit or platelet-derived growth factor receptor alpha (PDGFRA), which are therapeutic targets for imatinib. Results of 64 Taiwanese with advanced GIST treated with imatinib were reported.
Method and materials: Between 2001 and May 2006, a prospective, non-randomized, and a single center trial containing 64 Taiwanese patients with advanced GIST treated with imatinib was conducted. Each tumor was investigated for mutations of kit or PDGFRA.
Results: The median follow-up time after imatinib administration was 16.1 months. 12 patients (18.8%) had complete response (CR), 24 (37.5%) had a partial response (PR), 12 stationary disease (18.8%), 16 progressive disease (25.0%). The 64 Taiwanese with advanced GIST had an estimated median survival of 48.0 months and 4-year survival rate for 76.1%. Kit mutation was found in 49 of 54 (90.7%) test patients and five of them had no mutation (9.3%). No PDGFRA mutant was identified. In 40 patients harboring kit exon 11 mutations, the CR and PR rates (ORR) were 57.5%, nine patients with tumors containing kit exon 9 mutation had ORR rates of 22.2%, and five patients with no mutation had ORR rates of 60.0% (not significant; P = 0.149).
Conclusions: Activated mutation of kit constituted 90.7% genetic alteration of Taiwanese with advanced GIST and no PDGFRA mutation was detected. Imatinib induced a sustained objective response in more than half of Taiwan advanced GIST patients. ORR did not differ between patients whose GISTs had no mutation, kit exon 9, and 11 mutations.
Key Words: Kinase mutation • Imatinib mesylate • GIST
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INTRODUCTION
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Gastrointestinal stromal tumors (GISTs) are soft-tissue sarcomas primarily arising from mesenchymal tissue in the gastrointestinal (GI) tract and abdomen. They are rare neoplasms, estimated to represent 0.1–3% of all gastrointestinal tract tumors.1 However, GISTs are the most common mesenchymal malignancy of the GI tract with precise incidence unknown.2 Approximately 5,000 GISTs are diagnosed annually in the USA and are distributed equally between men and women. GISTs appear to be related the interstitial cells of Cajal of the mesenteric plexus.3 GISTs express the cell-surface transmembrane receptor kit with a tyrosine kinase activity. There are frequent gain-of-function mutations of kit in GISTs. These mutations result in constitutive activation of kit signaling, which leads to uncontrolled cell proliferation and resistance to apoptosis.4,5 Because the availability of the kit tyrosine kinase inhibitor, imatinib mesylate (Glivec, formerly known as STI571, Novartis Pharma AG, Basel, Switzerland) has shown a promising clinical result for an advanced GIST patient,6 identification of GIST by kit immunopositivity has become paramount. Since then, several trials have shown a promising effect of this target therapy.7 As shown in our previous study, Glivec had a significant impact on survival in patients with advanced small bowel GISTs.8
Although, surgical resection remains the mainstay of therapy for GIST, recurrence is common and the 5-year survival rates after complete resection ranges from 40 to 65%.6,9–12 Unresectable or metastatic GIST is a fatal disease that resists conventional chemotherapy. The effectiveness of radiation therapy for unresectable or metastatic GIST has not been proven. The median length of survival for patients with a metastatic GIST is approximately 20 months, and 9–12 months for patients with local recurrence.3 Before the development of imatinib mesylate, the outlook for patients with advanced GIST was extremely poor.
Imatinib mesylate (formerly STI571, now referred to as Gleevec in the United States and Glivec in Europe [Novartis]) selectively inhibits certain protein tyrosin kinases: intracellular ABL kinase, chimeric BCR-ABL fusion oncoprotein of chronic myeloid leukemia, transmembrane receptor kit, and platelet-derived growth factor (PDRGF) receptors.13–16 Imatinib induced a sustained objective response in more than half of patients in the West with advanced GISTs.7 However, the implication of imatinib on patient survival and patient response to imatinib in terms of kinase mutation for Taiwanese with advanced GIST has not been elucidated. This study examined the impact of imatinib on patient response, survival, and the correlation of the response rate with the kit gene mutation status.
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PATIENTS AND METHODS
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During 2001–May 2006, 64 histologically confirmed, recurrent, unresectable or metastatic GIST patients that expressed CD117 or CD34 (a marker of KIT-receptor tyrosine kinase) were enrolled in this study. Criteria for inclusion were as follows: at least one measurable tumor; normal hepatic, renal, and cardiac function; a normal platelet count; and an Eastern Cooperative Oncology Group (ECOG) performance status of three or less. Patients could have previously received chemotherapeutic regimens (the last chemotherapy treatment must have been at least 4 weeks before study entry) and undergone radio-therapy, or surgery, or both. The study was approved by the local institutional review board of Chang Gung Memorial Hospital in the clinical study and written informed consent for drug administration and the analysis of tumor-associated genetic alteration was obtained independently from each patient.
Study Design and Follow-up Study
A prospective, non-randomized, and a single center trial was conducted to evaluate the effect of imatinib mesylate in inducing objective response in Taiwanese GIST patients. Patients were administered 400 mg of imatinib in 100 mg capsules, taken orally in divided doses daily with food. Patients had regular physical examinations and evaluations of performance status, body weight, complete blood count, and serum chemistry. The administration of each dose and any adverse events were recorded for each patient. Standard computed tomography (CT) was performed on each patient every 3 months the first 3 years and every 6 months the following 2 years to assess patient response. Standard [18F] fluoro-2-deoxy-D-glucose positron-emission tomography (PET) scanning was performed on selected patients to complement standard computed tomography (CT) and assess changes in the metabolic profiles of the tumors. Overall survival is defined as survival after administration of i-matinib mesylate and death is the end point of the study.
Efficacy Evaluation
The response of the tumor to imatinib was evaluated if needed or after 3 months, and every 3 months thereafter or whenever medical need was indicated. Assessments were performed according to the standard Southwest Oncology Group criteria and based solely on CT.17 Responses were classified as follows: complete response (CR) (disappearance of all disease that could be measured and evaluated); partial response (PR) (>50% decrease in the sum of the products of the perpendicular diameters of all measurable lesions, the absence of progression, and the absence of new lesions); stationary disease (SD) (a response that did not qualify as a complete response, a partial response, or disease progression); and disease progression (DP) (>50% increase or an increase of 10 cm [whichever was smaller]) in the sum of the products of the perpendicular diameter of all measurable lesions, worsening of a lesion that could be evaluated, the reappearance of any lesion or the presence of a new lesion, or failure of the patients to return for evaluation because of disease progression. Time to response (TTR) was defined as interval for better drug response during imatinib treatment. Time to progression (TTP) was defined as interval for worse drug response during imatinib treatment.
Analysis of KIT and PDGFRA Mutations
Sections were prepared from formalin-fixed, par-affin-embedded pretreatment specimens trimmed to enrich tumor cells. Polymerase chain reaction amplification of genomic DNA for KIT and PDG-FRA was performed and amplification was analyzed for mutations as previously described.18
Statistical Analysis
All data were presented as percentages of patients or means with standard deviation. Numerical data were compared by an independent two-sample t test. Pearson Chi-square test and Fisher exact test were used for nominal variables. Survival rate was calculated and plots constructed by the Kaplan–Meier method and compared between groups with a log-rank test. All statistical analyses were performed using SPSS computer software package (Version 10.0, Chicago, IL, USA). A P-value <0.05 was considered statistically significant.
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RESULTS
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Clinical Features
Table 1
presents a summary of clinical features. There are 39 male and 25 female patients with a median age of 58.8-years-old (range from 27 to 89-years-old). The median tumor size was 12.0 cm, ranging from 4.5 to 35.0 cm. Stomach was the most common site for GISTs treated with imatinib mesylate (17/64; 26.6%), followed by jejunum (15/64; 23.4%), ileum (9/64; 14.1%), and duodenum (8/64; 12.5%). (Table 1)
Received for publication April 22, 2006.
Accepted for publication August 18, 2006.
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ABSTRACT
INTRODUCTION
