Initial and Late Resistance to Imatinib in Advanced Gastrointestinal Stromal Tumors Are Predicted by Different Prognostic Factors: A European Organisation for Research and Treatment of Cancer–Italian Sarcoma Group–Australasian Gastrointestinal Trials Group Study

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Abstract
Purpose: The aim of this study was to identify factors predicting initial and late resistance of GI stromal tumor (GIST) patients to imatinib and to document the dose-response relationship in the prognostic subgroups. This study is based on the European Organisation for Research and Treatment of Cancer–Italian Sarcoma Group–Australasian Gastrointestinal Trials Group randomized trial comparing two doses of imatinib in advanced disease. Patients and Methods: Initial resistance was defined as progression within 3 months of randomization, and late resistance was defined as progression beyond 3 months. Investigated cofactors include imatinib dose, age, sex, performance status, original disease site, site and size of lesions at trial entry, and baseline hematologic and biologic parameters. Results: Initial resistance was recorded for 116 (12%) of 934 assessable patients and was independently predicted by the presence of lung and absence of liver metastases, low hemoglobin level, and high granulocyte count. Among 818 patients who were alive and progression free at 3 months, 347 subsequent progressions were recorded, and late resistance was independently predicted by high baseline granulocyte count, primary tumor outside of the stomach, large tumor size, and low initial imatinib dose. The impact of initial dose on late resistance was mainly significant in patients with a high baseline granulocyte count (> 5.109/L) and in patients with tumors of GI origin outside of the stomach and small intestine. Conclusion: Our study identifies patients for whom initial and/or long-term treatment needs to be improved and patients who require a high initial dose. Correlation of these results with immunohistochemistry and molecular parameters may further help to understand the biologic mechanisms of resistance.