Download PDF
CC BY 4.0 · Brazilian Journal of Oncology 2024; 20: e-20240468
DOI: 10.5935/2526-8732.20240468
Review Article
Clinical Oncology

Gastrointestinal stromal tumors: advances in molecular characterization and therapeutic implications

Tumores estromais gastrointestinais: avanços na caracterização molecular e implicações terapêuticas
Nildevande Firmino Lima  Jr.
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Marcello Moro Queiroz 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Julia Sousa Leal Franco 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Julia Sousa Lins  Junior
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Eduardo Felício de Campos 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Beatriz Mendes Awni 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Luiz Guilherme Cernaglia Aureliano de Lima 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Frederico Teixeira 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Fábio de Oliveira Ferreira 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Eduardo Hiroshi Akaishi 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Fernanda Cunha Capareli 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
,
Rodrigo Ramella Munhoz 
1   Hospital Sirio Libanês, Oncologia Clínica, São Paulo, SP, Brazil
2   Hospital Sirio Libanês, Cutaneous Malignancies and Sarcoma Group, São Paulo, SP, Brazil
› Author Affiliationsnone to declare
› Further Information
   Permissions and Reprints All articles of this category

ABSTRACT

Recognition of the molecular basis of gastrointestinal stromal tumors has paved the way for significant breakthroughs in the diagnosis and treatment of this disease as well as positioned gastrointestinal stromal tumors as a framework for the concept of precision oncology in solid tumors. The incorporation of novel targeted agents for molecularly defined subgroups has led to significant improvements in treatment outcomes; however, the characterization of heterogeneous KIT or PDGFRA mutations and the emergence of resistance mechanisms highlight the need for a broader use of comprehensive molecular profiling and emphasize the importance of molecularly driven adaptive treatment strategies. Such a molecular background is critical for developing personalized and effective interventions and optimizing outcomes. The present review summarizes key studies that provide the basis for standard-of-care management options as well as provides molecular insights into the management of gastrointestinal stromal tumors, with an emphasis on recent advances.

RESUMO

O reconhecimento da base molecular dos tumores estromais gastrointestinais abriu caminho para avanços significativos no diagnóstico e tratamento desta doença, bem como posicionou os tumores estromais gastrointestinais como uma estrutura para o conceito de oncologia de precisão em tumores sólidos. A incorporação de novos agentes direcionados para subgrupos definidos molecularmente levou a melhorias significativas nos resultados do tratamento; no entanto, a caracterização de mutações heterogêneas no KIT ou PDGFRA e o surgimento de mecanismos de resistência destacam a necessidade de um uso mais amplo de perfis moleculares abrangentes e enfatizam a importância de estratégias de tratamento adaptativas orientadas molecularmente. Esse contexto molecular é fundamental para o desenvolvimento de intervenções personalizadas e eficazes e para a otimização dos resultados. A presente revisão resume os principais estudos que fornecem a base para opções de tratamento padrão, bem como fornece insights moleculares sobre o tratamento de tumores estromais gastrointestinais, com ênfase nos avanços recentes.

Keywords:

Gastrointestinal Stromal Tumors - Sarcoma - Tyrosine Kinase Inhibitors - Protooncogene proteins c-ki - Platelet-Derived Growth Factor

Descritores:

Tumores Estromais Gastrointestinais - Sarcoma - Inibidores de Tirosina Quinase - Proteínas proto-oncogênicas c-kit - Factor de crescimento derivado de plaquetas


Publication History

Received: 04 January 2024

Accepted: 22 March 2024

Article published online:
16 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

Bibliographical Record
Nildevande Firmino Lima, Marcello Moro Queiroz, Julia Sousa Leal Franco, Julia Sousa Lins, Eduardo Felício de Campos, Beatriz Mendes Awni, Luiz Guilherme Cernaglia Aureliano de Lima, Frederico Teixeira, Fábio de Oliveira Ferreira, Eduardo Hiroshi Akaishi, Fernanda Cunha Capareli, Rodrigo Ramella Munhoz. Gastrointestinal stromal tumors: advances in molecular characterization and therapeutic implications. Brazilian Journal of Oncology 2024; 20: e-20240468.
DOI: 10.5935/2526-8732.20240468
 

  • REFERENCES

  • 1 Søreide K, Sandvik OM, Søreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies. Cancer Epidemiol 2016; Feb 40: 39-46
    Search in Google Scholar
  • 2 Parab TM, DeRogatis MJ, Boaz AM, Grasso SA, Issack PS, Duarte DA. et al. Gastrointestinal stromal tumors: a comprehensive review. J Gastrointest Oncol 2018; Feb 10 (01) 144-54
    Search in Google Scholar
  • 3 Mazur MT, Clark HB. Gastric stromal tumors. Reappraisal of histogenesis. Am J Surg Pathol 1983; Sep 7 (06) 507-20
    Search in Google Scholar
  • 4 Patel N, Benipal B. Incidence of Gastrointestinal Stromal Tumors in the United States from 2001-2015: A United States Cancer Statistics Analysis of 50 States. Cureus 2019; Feb 11 (02) e4120
    Search in Google Scholar
  • 5 Stanek M, Pisarska M, Budzyńska D, Rzepa A, Pędziwiatr M, Major P. et al. Gastric gastrointestinal stromal tumors: clinical features and short- and longterm outcomes of laparoscopic resection. Wideochir Inne Tech Maloinwazyjne 2019; Apr 14 (02) 176-81
    Search in Google Scholar
  • 6 Cajal SR. Sobre la existencia de células nerviosas especiales en la primera capa de las circunvoluciones cerebrales. Gaceta Médica Catalana 1890; Dec 13 (23) 737-9
    Search in Google Scholar
  • 7 Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; Jan 279 (5350) 577-80
    Search in Google Scholar
  • 8 Graadt van Roggen JF, van Velthuysen ML, Hogendoorn PC. The histopathological differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001; Feb 54 (02) 96-102
    Search in Google Scholar
  • 9 Shi E, Chmielecki J, Tang CM, Wang K, Heinrich MC, Kang G. et al. FGFR1 and NTRK3 actionable alterations in “Wild-Type” gastrointestinal stromal tumors. J Transl Med 2016; Dec 14 (01) 339
    Search in Google Scholar
  • 10 Güler B, Özyılmaz F, Tokuç B, Can N, Taştekin E. Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis. Balkan Med J 2015; Oct 32 (04) 388-96
    Search in Google Scholar
  • 11 Lech G, Korcz W, Kowalczyk E, Guzel T, Radoch M, Krasnodębski IW. Giant gastrointestinal stromal tumour of rare sarcomatoid epithelioid subtype: case study and literature review. World J Gastroenterol 2015; Mar 21 (11) 3388-93
    Search in Google Scholar
  • 12 Corless CL. Gastrointestinal stromal tumors: what do we know now?. Mod Pathol 2014; Jan 27 Suppl 1 S1-16
    Search in Google Scholar
  • 13 Suresh PK, Sahu KK, Pai RR, Sridevi HB, Ballal K, Khandelia B. et al. The Prognostic Significance of Neuroendocrine Differentiation in Colorectal Carcinomas: Our Experience. J Clin Diagn Res 2015; Dec 9 (12) EC01-4
    Search in Google Scholar
  • 14 Huizinga JD, Thuneberg L, Klüppel M, Malysz J, Mikkelsen HB, Bernstein A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 1995; Jan 373 (6512) 347-9
    Search in Google Scholar
  • 15 Cioffi A, Maki RG. GI Stromal Tumors: 15 Years of Lessons From a Rare Cancer. J Clin Oncol 2015; Jun 33 (16) 1849-54
    Search in Google Scholar
  • 16 Venkataraman V, George S, Cote GM. Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor. Oncologist 2023; Aug 28 (08) 671-681
    Search in Google Scholar
  • 17 Martín J, Poveda A, Llombart-Bosch A, Ramos R, López-Guerrero JA, García del Muro J. et al. Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol 2005; Sep 23 (25) 6190-8
    Search in Google Scholar
  • 18 Wardelmann E, Hrychyk A, Merkelbach-Bruse S, Pauls K, Goldstein J, Hohenberger P. et al. Association of platelet-derived growth factor receptor alpha mutations with gastric primary site and epithelioid or mixed cell morphology in gastrointestinal stromal tumors. J Mol Diagn 2004; Aug 6 (03) 197-204
    Search in Google Scholar
  • 19 Bannon AE, Klug LR, Corless CL, Heinrich MC. Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromal tumors. Expert Rev Mol Diagn 2017; May 17 (05) 445-57
    Search in Google Scholar
  • 20 Moosavi B, Zhu XL, Yang WC, Yang GF. Molecular pathogenesis of tumorigenesis caused by succinate dehydrogenase defect. Eur J Cell Biol 2020; Jan 99 (01) 151057
    Search in Google Scholar
  • 21 Nannini M, Biasco G, Astolfi A, Urbini M, Pantaleo MA. Insulin-like Growth Factor (IGF) system and gastrointestinal stromal tumours (GIST): present and future. Histol Histopathol 2014; Feb 29 (02) 167-75
    Search in Google Scholar
  • 22 Italiano A, Chen CL, Sung YS, Singer S, DeMatteo RP, LaQuaglia MP. et al. SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors. BMC Cancer 2012; Sep 12: 408
    Search in Google Scholar
  • 23 Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S. et al. Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2016; Jul 2 (07) 922-8
    Search in Google Scholar
  • 24 Blay JY, Kang YK, Nishida T, von Mehren M. Gastrointestinal stromal tumours. Nat Rev Dis Primers 2021; Mar 7 (01) 22
    Search in Google Scholar
  • 25 Agaram NP, Wong GC, Guo T, Maki RG, Singer S, DeMatteo RP. et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 2008; Oct 47 (10) 853-9
    Search in Google Scholar
  • 26 Napolitano A, Ostler AE, Jones RL, Huang PH. Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas. Cells 2021; Jun 10 (06) 1533
    Search in Google Scholar
  • 27 Nishida T, Tsujimoto M, Takahashi T, Hirota S, Blay JY, Wataya-Kaneda M. Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. J Gastroenterol 2016; Jun 51 (06) 571-8
    Search in Google Scholar
  • 28 DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; Jan 231 (01) 51-8
    Search in Google Scholar
  • 29 Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ. et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002; May 33 (05) 459-65
    Search in Google Scholar
  • 30 Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008; Oct 39 (10) 1411-9
    Search in Google Scholar
  • 31 Gold JS, Gönen M, Gutiérrez A, Broto JM, García-del-Muro X, Smyrk TC. et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009; Nov 10 (11) 1045-52
    Search in Google Scholar
  • 32 Rossi S, Gasparotto D, Miceli R, Toffolatti L, Gallina G, Scaramel E. et al. KIT, PDGFRA, and BRAF mutational spectrum impacts on the natural history of imatinibnaive localized GIST: a population-based study. Am J Surg Pathol 2015; Jul 39 (07) 922-30
    Search in Google Scholar
  • 33 Paganini AM, Quaresima S, Balla A, Palmieri L, Corallino D, Di Saverio S, Morales-Conde S. Clinicopathological Features and Surgical Management of Gastrointestinal Stromal Tumors: State-of-the-Art. In: Morgado-Diaz JA. editor. Gastrointestinal Cancers Brisbane (AU): Exon Publications; 2022: 43-56
    Search in Google Scholar
  • 34 Nishida T, Blay JY, Hirota S, Kitagawa Y, Kang YK. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer 2016; Jan 19 (01) 3-14
    Search in Google Scholar
  • 35 Winder A, Strauss DC, Jones RL, Benson C, Messiou C, Chaudry MA. et al. Robotic surgery for gastric gastrointestinal stromal tumors: A single center case series. J Surg Oncol 2020; Sep 122 (04) 691-8
    Search in Google Scholar
  • 36 Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S. et al. Corrections to “Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up”. Ann Oncol 2018; 29: iv68-iv78
    Search in Google Scholar
  • 37 von Mehren M, Randall RL, Benjamin RS, Boles S, Bui MM, Ganjoo KN. et al. Soft Tissue Sarcoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018; May 16 (05) 536-63
    Search in Google Scholar
  • 38 Mayr P, Märkl B, Agaimy A, Kriening B, Dintner S, Schenkirsch G. et al. Malignancies associated with GIST: a retrospective study with molecular analysis of KIT and PDGFRA. Langenbecks Arch Surg 2019; Aug 404 (05) 605-13
    Search in Google Scholar
  • 39 Iwatsuki M, Harada K, Iwagami S, Eto K, Ishimoto T, Baba Y. et al. Neoadjuvant and adjuvant therapy for gastrointestinal stromal tumors. Ann Gastroenterol Surg 2018; Sep 3 (01) 43-49
    Search in Google Scholar
  • 40 Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD. et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009; Mar 373 (9669) 1097-104
    Search in Google Scholar
  • 41 Corless CL, Ballman KV, Antonescu CR, Kolesnikova V, Maki RG, Pisters PW. et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol 2014; May 32 (15) 1563-70
    Search in Google Scholar
  • 42 Casali PG, Le Cesne A, Poveda Velasco A, Kotasek D, Rutkowski P, Hohenberger P. et al. Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol 2015; Dec 33 (36) 4276-83
    Search in Google Scholar
  • 43 Casali PG, Le Cesne A, Poveda A, Kotasek D, Rutkowski P, Hohenberger P. et al. Time to definitive failure to the first tyrosine kinase inhibitor in localized gastrointestinal stromal tumors (GIST) treated with imatinib as an adjuvant: Final results of the EORTC STBSG, AGITG, UNICANCER, FSG, ISG, and GEIS randomized trial. Ann Oncol 2017; Sep 28: v645
    Search in Google Scholar
  • 44 Rutkowski P, Przybył J, Zdzienicki M. Extended adjuvant therapy with imatinib in patients with gastrointestinal stromal tumors: recommendations for patient selection, risk assessment, and molecular response monitoring. Mol Diagn Ther 2013; Feb 17 (01) 9-19
    Search in Google Scholar
  • 45 Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J. et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012; Mar 307 (12) 1265-72
    Search in Google Scholar
  • 46 Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hermes B, Schütte J. et al. Survival Outcomes Associated With 3 Years vs 1 Year of Adjuvant Imatinib for Patients With High-Risk Gastrointestinal Stromal Tumors: An Analysis of a Randomized Clinical Trial After 10-Year Follow-up. JAMA Oncol 2020; Aug 6 (08) 1241-6
    Search in Google Scholar
  • 47 Chibon F, Lagarde P, Salas S, Pérot G, Brouste V, Tirode F. et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med 2010; Jul 16 (07) 781-7
    Search in Google Scholar
  • 48 Raut CP, Espat NJ, Maki RG, Araujo DM, Trent J, Williams TF. et al. Efficacy and Tolerability of 5-Year Adjuvant Imatinib Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal Stromal Tumor: The PERSIST-5 Clinical Trial. JAMA Oncol 2018; Dec 4 (12) e184060
    Search in Google Scholar
  • 49 ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000. Feb 29. Identifier NCT02413736, Three Versus Five Years of Adjuvant Imatinib as Treatment of Patients With Operable GIST; 2023 November 09. Available from https://clinicaltrials.gov/study/NCT02413736
    Search in Google Scholar
  • 50 ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 Feb 29. Identifier NCT02260505, Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST) (ImadGist) 2014. [access in 2023 December 20]. Available from https://clinicaltrials.gov/study/NCT02260505
    Search in Google Scholar
  • 51 Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H. et al. Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor. J Clin Oncol 2023; Nov 41 (31) 4829-36
    Search in Google Scholar
  • 52 Ishikawa T, Kanda T, Kameyama H, Wakai T. Neoadjuvant therapy for gastrointestinal stromal tumor. Transl Gastroenterol Hepatol 2018; Jan 3: 3
    Search in Google Scholar
  • 53 von Mehren M, Joensuu H. Gastrointestinal Stromal Tumors. J Clin Oncol 2018; Jan 36 (02) 136-43
    Search in Google Scholar
  • 54 Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA. et al. Long-term results from a randomized phase II trial of standardversus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; Feb 26 (04) 620-5
    Search in Google Scholar
  • 55 Tirumani SH, Shinagare AB, Jagannathan JP, Krajewski KM, Ramaiya NH, Raut CP. Radiologic assessment of earliest, best, and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to successful surgical resection. Eur J Surg Oncol 2014; Apr 40 (04) 420-8
    Search in Google Scholar
  • 56 von Mehren Margaret. et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) - Gastrointestinal Stromal Tumors. 2023 Mar 13;(Version 1.2023). Available from https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf
    Search in Google Scholar
  • 57 Van den Abbeele AD, Gatsonis C, de Vries DJ, Melenevsky Y, Szot-Barnes A, Yap JT. et al. ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression. J Nucl Med 2012; Apr 53 (04) 567-74
    Search in Google Scholar
  • 58 Farag S, IJzerman NS, Houdijk MPM, Reyners AKL, Arens AI, Grünhagen DJ. et al. Early response evaluation using 18F-FDG-PET/CT does not influence management of patients with metastatic gastrointestinal stromal tumors (GIST) treated with palliative intent. Nuklearmedizin 2021; Dec 60 (06) 411-6
    Search in Google Scholar
  • 59 Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; Aug 347 (07) 472-80
    Search in Google Scholar
  • 60 von Mehren M, Heinrich MC, Joensuu H, Blanke CD, Wehrle E, Demetri GD. Follow-up results after 9 years (yrs) of the ongoing, phase II B2222 trial of imatinib mesylate (IM) in patients (pts) with metastatic or unresectable KIT+ gastrointestinal stromal tumors (GIST). J Clin Oncol 2011; May 29 15_Suppl 10016
    Search in Google Scholar
  • 61 Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS. et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008; Feb 26 (04) 626-32
    Search in Google Scholar
  • 62 Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY. et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364 (9440) 1127-34
    Search in Google Scholar
  • 63 Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY. et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 2005; Aug 41 (12) 1751-7
    Search in Google Scholar
  • 64 Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH. et al. Ten-Year Progression-Free and Overall Survival in Patients With Unresectable or Metastatic GI Stromal Tumors: Long-Term Analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels. J Clin Oncol 2017; May 35 (15) 1713-20
    Search in Google Scholar
  • 65 Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT. et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; May 42 (08) 1093-103
    Search in Google Scholar
  • 66 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; Mar 28 (07) 1247-53
    Search in Google Scholar
  • 67 Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD. 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; Nov 26 (33) 5360-7
    Search in Google Scholar
  • 68 Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ. et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006; Oct 24 (29) 4764-74
    Search in Google Scholar
  • 69 Nishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T. et al. Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib‐resistant gastrointestinal stromal tumor. Cancer Sci 2008; Apr 99 (04) 799-804
    Search in Google Scholar
  • 70 Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J. et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; Oct 368 (9544) 1329-38
    Search in Google Scholar
  • 71 Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H. et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; Jan 381 (9863) 295-302
    Search in Google Scholar
  • 72 Wozniak A, Rutkowski P, Piskorz A, Ciwoniuk M, Osuch C, Bylina E. et al. Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience. Ann Oncol 2012; Feb 23 (02) 353-60
    Search in Google Scholar
  • 73 Kang G, Lee J, Jang KT, Beadling C, Corless CL, Heinrich MC. et al. Multiplex mutation screening by mass spectrometry in gastrointestinal stromal tumours. Pathology 2012; Aug 44 (05) 460-4
    Search in Google Scholar
  • 74 Ko TK, Lee E, Ng CCY, Yang VS, Farid M, Teh BT. et al. Circulating Tumor DNA Mutations in Progressive Gastrointestinal Stromal Tumors Identify Biomarkers of Treatment Resistance and Uncover Potential Therapeutic Strategies. Front Oncol 2022; Feb 22 12: 840843
    Search in Google Scholar
  • 75 Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D. et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 2008; Nov 26 (33) 5352-9
    Search in Google Scholar
  • 76 Lee JH, Kim Y, Choi JW, Kim YS. Correlation of imatinib resistance with the mutational status of KIT and PDGFRA genes in gastrointestinal stromal tumors: a meta-analysis. J Gastrointestin Liver Dis 2013; Dec 22 (04) 413-8
    Search in Google Scholar
  • 77 Huss S, Pasternack H, Ihle MA, Merkelbach-Bruse S, Heitkötter B, Hartmann W. et al. Clinicopathological and molecular features of a large cohort of gastrointestinal stromal tumors (GISTs) and review of the literature: BRAF mutations in KIT/PDGFRA wild-type GISTs are rare events. Hum Pathol 2017; Apr 62: 206-214
    Search in Google Scholar
  • 78 My Cancer Genome®. Gastrointestinal Stromal Tumor [Data set]. Vanderbilt University, Vanderbilt-Ingram Cancer Center; Nashville(TN): 2015. [access in 2023 August 02]. Available from https://www.mycancergenome.org/content/disease/gist/
    Search in Google Scholar
  • 79 Astolfi A, Pantaleo MA, Indio V, Urbini M, Nannini M. The Emerging Role of the FGF/FGFR Pathway in Gastrointestinal Stromal Tumor. Int J Mol Sci 2020; May 21 (09) 3313
    Search in Google Scholar
  • 80 Gasparotto D, Rossi S, Polano M, Tamborini E, Lorenzetto E, Sbaraglia M. et al. Quadruple-Negative GIST Is a Sentinel for Unrecognized Neurofibromatosis Type 1 Syndrome. Clin Cancer Res 2017; Jan 23 (01) 273-82
    Search in Google Scholar
  • 81 Joensuu H, Blay JY, Comandone A, Martin-Broto J, Fumagalli E, Grignani G. et al. Dovitinib in patients with gastrointestinal stromal tumour refractory and/or intolerant to imatinib. Br J Cancer 2017; Oct 117 (09) 1278-85
    Search in Google Scholar
  • 82 Soria JC, Massard C, Magné N, Bader T, Mansfield CD, Blay JY. et al. Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers. Eur J Cancer 2009; Sep 45 (13) 2333-41
    Search in Google Scholar
  • 83 Prenen H, Cools J, Mentens N, Folens C, Sciot R, Schöffski P. et al. Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 2006; Apr 12 (08) 2622-7
    Search in Google Scholar
  • 84 Jeffers M, Kappeler C, Kuss I, Beckmann G, Mehnert DH, Fredebohm J. et al. Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial. Gastric Cancer 2022; May 25 (03) 598-608
    Search in Google Scholar
  • 85 Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H. et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebocontrolled, phase 3 trial. Lancet Oncol 2020; Jul 21 (07) 923-34
    Search in Google Scholar
  • 86 Bauer S, Jones RL, Blay JY, Gelderblom H, George S, Schöffski P. et al. Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial. J Clin Oncol 2022; Dec 40 (34) 3918-28
    Search in Google Scholar
  • 87 Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E. et al. Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol 2016; May 17 (05) 632-41
    Search in Google Scholar
  • 88 Eriksson M, Reichardt P, Joensuu H, Krarup-Hansen A, Hagberg O, Hohenberger P. et al. Benefit of pazopanib in advanced gastrointestinal stromal tumours: results from a phase II trial (SSG XXI, PAGIST). ESMO Open 2021; Aug 6 (04) 100217
    Search in Google Scholar
  • 89 Schöffski P, Mir O, Kasper B, Papai Z, Blay JY, Italiano A. et al. Activity and safety of the multitarget tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 ‘CaboGIST’. Eur J Cancer 2020; Jul 134: 62-74
    Search in Google Scholar
  • 90 Park SH, Ryu MH, Ryoo BY, Im SA, Kwon HC, Lee SS. et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs 2012; Dec 30 (06) 2377-83
    Search in Google Scholar
  • 91 Montemurro M, Gelderblom H, Bitz U, Schütte J, Blay JY, Joensuu H. et al. Sorafenib as third- or fourthline treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis. Eur J Cancer 2013; Mar 49 (05) 1027-31
    Search in Google Scholar
  • 92 Heinrich MC, Marino-Enriquez A, Presnell A, Donsky RS, Griffith DJ, McKinley A. et al. Sorafenib inhibits many kinase mutations associated with drugresistant gastrointestinal stromal tumors. Mol Cancer Ther 2012; Aug 11 (08) 1770-80
    Search in Google Scholar
  • 93 Franck C, Rosania R, Franke S, Haybaeck J, Canbay A, Venerito M. The BRAF Status May Predict Response to Sorafenib in Gastrointestinal Stromal Tumors Resistant to Imatinib, Sunitinib, and Regorafenib: Case Series and Review of the Literature. Digestion 2019; 99 (02) 179-84
    Search in Google Scholar
  • 94 Reichardt P, Blay JY, Gelderblom H, Schlemmer M, Demetri GD, Bui-Nguyen B. et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 2012; Jul 23 (07) 1680-7
    Search in Google Scholar
  • 95 Hsueh YS, Lin CL, Chiang NJ, Yen CC, Li CF, Shan YS. et al. Selecting tyrosine kinase inhibitors for gastrointestinal stromal tumor with secondary KIT activation-loop domain mutations. Sabapathy K. editor PLoS One 2013; Jun 8 (06) e65762
    Search in Google Scholar
  • 96 Spitaleri G, Biffi R, Barberis M, Fumagalli C, Toffalorio F, Catania C. et al. Inactivity of imatinib in gastrointestinal stromal tumors (GISTs) harboring a KIT activation-loop domain mutation (exon 17 mutation pN822K). Onco Targets Ther 2015; Aug 8: 1997-2003
    Search in Google Scholar
  • 97 Blay JY, Shen L, Kang YK, Rutkowski P, Qin S, Nosov D. et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; May 16 (05) 550-60
    Search in Google Scholar
  • 98 Heinrich MC, Rankin C, Blanke CD, Demetri GD, Borden EC, Ryan CW. et al. Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol 2017; Jul 3 (07) 944-52
    Search in Google Scholar
  • 99 Janeway KA, Kim SY, Lodish M, Nosé V, Rustin P, Gaal J. et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 2011; Jan 108 (01) 314-8
    Search in Google Scholar
  • 100 von Mehren M, George S, Heinrich MC, Schuetze SM, Yap JT, Yu JQ. et al. Linsitinib (OSI-906) for the Treatment of Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors, a SARC Phase II Study. Clin Cancer Res 2020; Apr 26 (08) 1837-45
    Search in Google Scholar
  • 101 Jilg S, Rassner M, Maier J, Waldeck S, Kehl V, Follo M. et al. Circulating cKIT and PDGFRA DNA indicates disease activity in Gastrointestinal Stromal Tumor (GIST). Int J Cancer 2019; Oct 145 (08) 2292-303
    Search in Google Scholar
  • 102 Mandelker D, Marra A, Mehta N, Selenica P, Yelskaya Z, Yang C. et al. Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations. NPJ Precis Oncol 2023; Jan 7 (01) 1
    Search in Google Scholar
  • 103 Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; Dec 15 (12) 731-47
    Search in Google Scholar
  • 104 Serrano C, Wang Y, Mariño-Enríquez A, Lee JC, Ravegnini G, Morgan JA. et al. KRAS and KIT Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation. J Clin Oncol J Clin Oncol 2015; Aug 33 (22) e93-6
    Search in Google Scholar
  • 105 Urbini M, Astolfi A, Indio V, Nannini M, Schipani A, Bacalini MG. et al. Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST. Sci Rep 2020; Nov 10 (01) 19829
    Search in Google Scholar