Efficacy of Gleevec in metastatic gastrointestinal stromal tumors in correlation with C-KIT/PDGFRA mutational status

Purpose. To evaluate the efficacy of Gleevec in patients (pts) with metastatic gastrointestinal stromal tumors (GIST) in according to C-KIT/PDGFRA mutational status. Patients and Methods. 101 patients with metastatic GIST were treated at the N.N. Blokhin Russian Cancer Research Center from 2002 to 2013. Patients received Gleevec 400 mg/day as first line therapy. 25 (37,9%) patients received surgical cytoreduction during imatinib therapy. Tumor specimens were tested for KIT exons 9, 11, 13, 17 and PDGFRA exons 18, 12, 14 mutations by direct sequencing of PCR products. DNA samples were isolated from paraffin-embedded tissues. Tumor response was assessed using RECIST 1.1. The survival curves were estimated using Kaplan-Meier method by SPSS v. 13.0 for Windows. Results. KIT/PDGFRA mutational status was determined in 66 (65,3%) patients with metastatic GIST. C-KIT mutations were found in 54 (81,8%) patients, PDGFRA - 2 (3%), wild type - 10 (15,2%). С-KIT mutation spectrum was presented by exon 11 mutations in 42 (77,8%) pts, exon 9 - 10 (18,5%) pts, exon 13 - 1 (1,9%) pts, exon 17 - 1 (1,9%) pts. Both PDGFRA mutations were found in 18 exon. Tumor response of imatinib was assessed in 56 (84,4%) pts. Objective response (complete response + partial response) in patients with C-KIT exon 11, exon 9 were 70,3% and 22,2%, respectively; median time-to-progression - 29 and 9, respectively (p=0,000); median overall survival - 79 and 26, respectively (p=0,006). Conclusion. The most common GIST mutation was C-KIT exon 11. Efficacy of Gleevec therapy was superior in C-KIT exon 11 mutations.

гастроинтестинальные стромальные опухоли, C-KIT, PDGFRA, гливек, иматиниб, gastrointestinal stromal tumors, GIST, C-KIT, PDGFRA, Gleevec, imatinib

1. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of Two Doses of Imatinib for the Treatment of Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Meta-Analysis of 1,640 Patients. J. Clin. Oncol. 2010, v. 28 (Nov. 7), p. 1247-1253.

2. Michael C. Heinrich, Kouros Owzar, Christopher L. Corless, et al. Correlation of Kinase Genotype and Clinical Outcome in the North American Intergroup Phase III Trial of Imatinib Mesylate for Treatment of Advanced Gastrointestinal Stromal Tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J. Clin. Oncol. 2008, v. 20, p. 5360-5367.

3. Julien Domont, Sylvie Chabaud, Isabelle Ray Coquard et al. Impact of mutational status and other prognostic factors on survival in patients with advanced GIST treated with standarddose imatinib (IM): Results from the BFR14 phase III trial of the French Sarcoma Group. ASCO 2013, abstr. 10548.

4. Javier Martin-Broto, Luis Rubio, Regina Alemany et al. Clinical implications of KIT and PDGFRA genotyping in GIST Clin. Transl. Oncol. 2010, v. 12, p. 670-667.

5. Беляков И.С., Анурова О.А., Снигур П.В., Цыганова И.В., Сельчук В.Ю., Мазуренко Н.Н. Мутации генов C-KIT и PDGFRA и клинико-морфологические особенности стромальных опухолей желудочно-кишечного тракта. Вопросы онкологии. 2007, т. 53 (6), с. 677-681.

6. Цыганова И.В. Мутации генов C-KIT и PDGFRA и клинико-морфологические особенности стромальных опухолей желудочно-кишечного тракта». Автореферат диссертации канд. мед. наук. 2010, 26 с.

7. Мазуренко Н.Н., Беляков И.С., Цыганова И.В., Гагарин И.М., Анурова О.А. Значение молекулярно-генетических маркеров для прогноза и лечения стромальных опухолей ЖКТ Достижения и перспективы лекарственного лечения злокачественных опухолей. Этюды химиотерапии III. М.: «Фармарус Принт Медиа». 2011, с. 111-126.