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Predictive Factors of Efficacy of Sunitinib Therapy in Gastrointestinal Stromal Tumours

Published Online: May 15th 2012 European Oncology & Haematology, 2012;8(3):167-172 DOI: https://doi.org/10.17925/EOH.2012.08.3.167
Authors: Piotr Rutkowski, Monika Jurkowska
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Abstract
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Abstract:
Overview

Until the introduction of tyrosine kinase inhibitors, only limited treatment options were available for advanced/inoperable gastrointestinal stromal tumours (GISTs), the most common mesenchymal tumours of the gastrointestinal tract. Initially, it was imatinib mesylate that revolutionised patient outcomes in advanced cases, followed by sunitinib malate when the activity of imatinib turned out to be time-limited. There is substantial heterogeneity between GISTs in terms of response to targeted therapy. As was the case for imatinib, the efficacy of sunitinib depends on the primary tumour’s KIT/PDGFRA (platelet-derived growth factor receptor-alpha) genotype and on secondary mutations emerging during treatment. Interestingly, sunitinib-related adverse effects, such as arterial hypertension, may serve as biomarkers of the antitumour efficacy of the drug. Here we discuss possible mechanisms underlying these phenomena as well as data from our recently published study – the first to investigate the clinicopathologic and genetic characteristics associated with the results of sunitinib therapy in a large group of patients treated in routine clinical practice.

Keywords

Sunitinib, genotype, gastrointestinal stromal tumour, prognosis, predictive factors, arterial hypertension

Article:

Gastrointestinal stromal tumours (GISTs) are rare mesenchymal tumours that may develop anywhere along the gastrointestinal tract. Approximately 95 % of cases share the expression of the CD117 surface antigen, also known as KIT or stem cell factor receptor. The management of localised GISTs relies on the complete surgical excision of the tumour. Until the introduction of tyrosine kinase inhibitors (TKIs), limited treatment options were available for patients once the tumour had spread or if it was inoperable.1

Unprecedented improvement in the management of advanced GIST has been achieved through the relatively recent recognition of the important biological role of activating mutations in the KIT and PDGFRA (platelet-derived growth factor receptor-alpha) genes. These observations led to the introduction into therapy of imatinib mesylate, a small-molecule selective TKI targeting stem-cell factor receptor (KIT, CD117), breakpoint cluster region/C-abl oncogene 1, non-receptor tyrosine kinase (BCR/ABL) and platelet-derived growth factor receptors (PDGFRs) A and B. Imatinib revolutionised the treatment of patients with advanced CD117-positive GISTs and is currently approved as first-line treatment in metastatic and/or inoperable disease.2–6 However, approximately 10–15 % of GIST patients are initially insensitive to imatinib, around 5 % are intolerant to it, and the spectacular response of the remaining patients is time-limited. As shown by median progression-free survival (PFS), approximately 50 % of patients treated with imatinib ultimately develop secondary resistance and experience disease progression within two years of treatment initiation.2,3,5 The management of GIST resistant to first-line treatment represents a clinical challenge.5 Insights into resistance mechanisms have allowed the development of several alternative strategies for patients who experience disease progression following imatinib treatment, which are currently being tested. In the case of generalised disease progression (or intolerance to imatinib), monotherapy with an alternative multitargeted TKI – i.e., sunitinib – represents the main option. Sunitinib remains the only approved second-line drug for the treatment of advanced GIST after failure of imatinib therapy.7

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Disclosure

Piotr Rutkowski has received honoraria and travel grants from Novartis and Pfizer, and has served on advisory boards for Novartis. Monika Jurkowska has benefited from research support from Novartis.

Correspondence

Piotr Rutkowski, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland. E: rutkowskip@coi.waw.pl

Received

2012-05-27T00:00:00

References

  1. Bamboat ZM, Dematteo RP, Updates on the management of gastrointestinal stromal tumors, Surg Oncol Clin N Am, 2012;21:301–16.
  2. Demetri GD, von Mehren M, Blanke CD, et al., Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, New Engl J Med, 2002;347:472–80.
  3. Verweij J, Casali PG, Zalcberg J, et al., Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial, Lancet, 2004;364:1127–34.
  4. Joensuu H, Gastrointestinal stromal tumor (GIST), Ann Oncol, 2006;10(Suppl.):x280–6.
  5. Rutkowski P, Debiec-Rychter M, Ruka W, Gastrointestinal stromal tumors: key to diagnosis and choice of therapy, Mol Diagn Ther, 2008;12:131–43.
  6. 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 Ca Res Clin Oncol, 2007;133:589–97.
  7. Blay JY, Pharmacological management of gastrointestinal stromal tumours: an update on the role of sunitinib, Ann Oncol, 2010;21:208–15.
  8. Abrams TJ, Lee LB, Murray LJ, et al., SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer, Mol Cancer Ther, 2003;2:471–8.
  9. O’Farrell AM, Abrams TJ, Yuen HA, et al., SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo, Blood, 2003;101:3597–605.
  10. Murray LJ, Abrams TJ, Long KR, et al., SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model, Clin Exp Metastasis, 2003;20:757–66.

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