The Outcome of Targeted Therapy in Advanced Gastrointestinal Stromal Tumors (Gist) with Non-Exon 11 Kit Mutations

• Authors: Czesław Osuch , Piotr Rutkowski , Karolina Brzuszkiewicz , Elżbieta Bylina , Janusz Limon , Janusz A. Siedlecki
• Languages of publication: EN

Abstracts

EN

GIST is the most common mesenchymal tumour of gastrointestinal tract arising from mutation of KIT or PDGFRA gene. Surgery is the primary method of treatment, however a targeted therapy with imatinib is necessary due to recurrence. The aim of the study was to evaluate efficacy of the targeted chemotherapy in advanced gastrointestinal stromal tumours with non-exon 11 KIT mutations. Material and methods. Data from 279 patients with advanced GIST treated with imatinib between 2001 and 2011 were analysed in the study. Exon 11 KIT mutation was found in 192 patients (68.7%), non-exon 11 KIT mutation was found in 87 patients (31.3%): this group included lack of mutation - wild-type, exon 9 KIT mutations, exon 18 PDGFRA D842V mutations, non-D842V PDGFRA mutations as well as non-exon 9 and 11 KIT mutations. Analysis of progression-free survival and overall survival were done for the entire group of patients and for patients with particular mutations, and then effects on progression-free survival and overall survival of such factors as sex, age, imatinib dose were evaluated. Results. Occurrence of non-exon 11 KIT mutation increases the risk of disease progression by 20% in comparison to the presence of exon 11 KIT mutation, however it does not increase the risk of patient’s death. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation. Percentage of 5-year survivals in case of the presence of D842V PDGFRA mutation is more than twice worse than in the case of the other mutations. Lesion location in the gastrointestinal tract affected the risk of death, with the greatest percentage of 5-year survival for lesions located in the stomach. Such factors as sex, age at diagnosis (<50, ≥50 years) and imatinib dose did not affect the risk of disease progression and the risk of patient’s death. Conclusions. The ratio of overall survival of patients with advanced GIST with a mutation other than exon 11 KIT mutation treated with imatinib is similar to the ratio of overall survival of patients with GIST with exon 11 KIT mutation. An exception is the group of patients with GIST in whom the presence of D842V PDGFRA mutation was found. In general, longer survival has been found in patients with GIST located in the stomach in comparison to the small intestine or other less frequent locations. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation.

Keywords

EN

GIST; KIT mutations; imatinib

• Publisher: De Gruyter Open
• Journal: Polish Journal of Surgery
• Year: 2015
• Volume: 86
• Issue: 7
• Pages: 325-332

Dates

published

1 - 7 - 2014

online

12 - 9 - 2014

received

30 - 6 - 2014

Contributors

author

Czesław Osuch

• Department of General Surgery, Jagiellonian University Collegium Medicum in Cracow

author

Piotr Rutkowski

• Department of Soft Tissue/ Bone Sarcoma and Melanoma Memorial Cancer Center and Institute of Oncology in Warsaw

author

Karolina Brzuszkiewicz

• Department of General Surgery, Jagiellonian University Collegium Medicum in Cracow

author

Elżbieta Bylina

• Department of Soft Tissue/ Bone Sarcoma and Melanoma Memorial Cancer Center and Institute of Oncology in Warsaw

author

Janusz Limon

• Department of Biology and Genetics, Medical University in Gdańsk

author

Janusz A. Siedlecki

• Department of Molecular Biology, Memorial Cancer Center and Institute of Oncology in Warsaw

References

• 1. Rutkowski P, Nowecki ZI, Debiec-Rychter M et al.: Predictive factors for long-term effects of imatinib therapy in patients with inoperable/metastatic CD117(+) gastrointestinal stromal tumors (GISTs). J Cancer Res Clin Oncol 2007 Sep; 133(9):589-97. Epub 2007 Apr 26.[WoS]
• 2. 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 28:1247-1253. © 2010 by American Society of Clinical Oncology.
• 3. Chun-Nan Yeh, Yen-Yang Chen, Jeng-Hwei Tseng et al.: Imatinib Mesylate for Patients with Recurrent or Metastatic Gastrointestinal Stromal Tumors Expressing KIT: A Decade Experience from Tajwan. Translational Oncology Volume 4 Number 6 December 2011; pp. 328-35.
• 4. Xiaofei Zhi, Xiaoying Zhou, Weizhi Wang, Zekuan Xu: Practical Role of Mutation Analysis for Imatinib Treatment in Patients With Advanced Gastrointestinal Stromal Tumors: A Meta-Analysis. PLOS ON E | www.plosone.org 1 November 2013 | Volume 8 | Issue 11 | e79275.
• 5. Zhang XH, Wu H, He YL et al.: Clinical analysis of imatinib in patients with advanced gastrointestinal stromal tumor. Zhonghua Wei Chang Wai Ke Za Zhi 2012 Mar; 15(3): 243-46.[PubMed]
• 6. Kang HJ, Ryu MH, Kim KM et al.: Imatinib efficacy by tumor genotype in Korean patients with advanced gastrointestinal stromal tumors (GIST): The Korean GIST Study Group (KGSG) study. Acta On c o l 2 0 1 2 A p r ; 5 1 ( 4 ) : 5 2 8 - 3 6 . d o i : 10.3109/0284186X.2011.636753. Epub 2011 Dec 7.
• 7. Gao J, Dang Y, Sun N, Li J, Shen L.: C-KIT mutations were closely associated with the response to Imatinib in Chinese advanced gastrointestinal stromal tumor patients.Med Oncol 2012 Dec; 29(5):3039-45. doi: 10.1007/s12032-012-0308-7. Epub 2012 Jul 20.[WoS][Crossref][PubMed]
• 8. Maleddu A, Pantaleo MA, Nannini M, Biasco G: The role of mutational analysis of KIT and PDGFRA in gastrointestinal stromal tumors in a clinical setting. J Transl Med 2011 May 23;9:75. doi: 10.1186/1479-5876-9-75.[Crossref]
• 9. Cassier PA, Fumagalli E, Rutkowski P et al.: and Hohenberger Pfor the European Organisation for Research and Treatment of Cancer. Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era. Clin Cancer Res 2012;18:4458-4464. Published Online- First June 20, 2012.
• 10. Cassier PA, Fumagalli E, Rutkowski P et al.: Kinase Inhibitor Era Alpha-Mutated Gastrointestinal Stromal Tumors in the Tyrosine Outcome of Patients with Platelet-Derived Growth Factor Receptor. Clin Cancer Res 2012;18:4458-4464. Published OnlineFirst June 20, 2012.[Crossref]
• 11. Corless CL, Schroeder A, Griffith D et al.: PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005; 23: 5357-64.[Crossref][PubMed]
• 12. Lasota J, Miettinen M: Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology 2008; 53: 245-66.[WoS][PubMed][Crossref]
• 13. Woźniak A, Rutkowski P, Piskorz A et al.: Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience. Ann Oncol 2012 Feb; 23(2):353-60. doi: 10.1093/annonc/mdr127. Epub 2011 Apr 28.[WoS][PubMed][Crossref]
• 14. Gronchi A, Blay JY, Trent JC: The Role of High- Dose Imatinib in the Management of Patients With Gastrointestinal Stromal Tumor. Cancer April 15, 2010; 1847-58.[Crossref]
• 15. Mehmet Ali Nahit Şendur, Nuriye Yıldırım Özdemir, Muhammed Bülent Akıncı et al.: Is exon mutation analysis needed for adjuvant treatment ofgastrointestinal stromal tumor? World J Gastroenterol 2013 January 7; 19(1): 144-46.[WoS]
• 16. Dewaele B, Wasag B, Cools J et al.: Activity of Dasatinib, a Dual SRC/ABL Kinase Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal Stromal Tumor-Associated PDGFRAD842V Mutation. Clin Cancer Res 2008; 14: 5749-58.
• 17. Michael C. Heinrich, Adrian Marino-Enriquez, Ajia Presnell et al.: Sorafenib Inhibits Many Kinase Mutations Associated with Drug-Resistant Gastrointestinal Stromal Tumors. Mol Cancer Ther 2012;11:1770-1780. Published OnlineFirst June 4, 2012.[WoS]
• 18. Italiano A, Bui B: Aspects moléculaires et stratégies thérapeutiques des tumeurs stromales gastrointestinales. Bull Cancer 2008; 95 (1): 107-16.
• 19. Weisberg E, Wright RD, Jiang J et al.: Effects of PKC412, nilotinib and imatinib against GISTassociated PDGFRA mutants with differential imatinib sensitivity: Mutant PDGFRA: PKC412, nilotinib, imatinib. Gastroenterology. 2006 December; 131(6): 1734-1742. doi:10.1053/j.gastro .2006.09.017.[Crossref]
• 20. Debiec-Rychter M, Cools J, Dumez H et al.: Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 2005 Feb;128(2): 270-79.
• 21. Ménard C, Blay JY, Borg C et al.: Tumor-Bearing Patients with Imatinib Mesylate Therapy in Gastrointestinal Stromal Natural Killer Cell IFN-g Levels Predict Long-term Survival. Cancer Res 2009; 69: 3563-3569. Published OnlineFirst April 7, 2009.[Crossref]
• 22. Rutkowski P, Kulig J, Krzakowski M i wsp.: Nowotwory podścieliskowe przewodu pokarmowego (GIST). Aktualne (2010) zasady postępowania diagnostyczno-terapeutycznego. Medycyna Praktyczna Chirurgia 2011/01.

Identifiers

DOI

10.2478/pjs-2014-0057