Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors

Demetri, George D.; Mehren, Margaret von; Blanke, Charles D.; Abbeele, Annick D. Van den; Eisenberg, Burton L.; Roberts, Peter; Heinrich, Michael C.; Tuveson, David A.; Singer, Samuel; Janicek, Mike F.; Fletcher, Jonathan A.; Silverman, Stuart G.; Silberman, Sandra; Capdeville, Renaud; Kiese, Beate; Peng, Bin; Dimitrijević, Saša; Druker, Brian J.; Corless, Christopher L.; Fletcher, Christopher D.�M.; Joensuu, Heikki

doi:10.1056/nejmoa020461

Cited by 3,876 publications

(2,679 citation statements)

References 19 publications

(26 reference statements)

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“…22,23 Conjunctival hemorrhage was noted in 14 (11%) patients in the absence of marrow suppression or systemic bleeding tendency, which is consistent with the result in a cohort of 87 GIST patients. 24 In our study, we found, for the first time, that the ocular side effects of Imatinib are independent of plasma concentration and KIT or PDGFRA mutation status, but significantly correlated with the SNPs of EGFR, SLC22A1, SLC22A5 and ABCB1, indicating that these variants might be markers for predicting the ocular toxicity in patients treated with Imatinib.…”

Section: Discussionsupporting

confidence: 87%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

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Imatinib-induced ophthalmological side-effects, including conjunctiva hemorrhage and periorbital oedema, although very common and still remain relatively little understood. The present study investigated the effects of genetic polymorphisms of drug targets and membrane transporters on these side effects. We found that the minor allele of EGFR rs10258429 and SLC22A1 rs683369 were significant risk determinants of conjunctival hemorrhage with OR of 7.061 (95%CI = 1.791-27.837, P = 0.005 for EGFR rs10258429 CT +TT vs CC), and 4.809 (95%CI = 1.267-18.431, P = 0.021 for SLC22A1 rs683369 GG+CG vs CC). The minor allele of SLC22A5 rs274558 and ABCB1 rs2235040 were protective factors to periorbital oedema with OR of 0.313 (95%CI = 0.149-0.656, P = 0.002 for SLC22A5 rs274558 AA+AG vs GG), and 0.253 (95%CI = 0.079-0.805, P = 0.020 for ABCB1 rs2235040 CT vs CC). These results indicated that variants in EGFR, SLC22A1, SLC22A5 and ABCB1 influenced the incidence of Imatinib-induced ophthalmological toxicities, and polymorphism analyses in associated genes might be beneficial to optimize Imatinib treatment.

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Section: Discussionsupporting

confidence: 87%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

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“…As such, these tumors are often effectively treated with the small molecule tyrosine kinase inhibitors imatinib and sunitinib. 3,4 In contrast, approximately 15% of GISTs in adults and 490% of GISTs in children are categorized as 'wild-type' GISTs because they lack KIT and PDGFRA mutations. [5][6][7] In recent years, a defined set of genetic changes in these so-called wild-type GISTs have begun to be characterized, including activating mutations in BRAF, [8][9][10] loss of function mutations in NF1, 11 and mutations leading to loss of function of the succinate dehydrogenase (SDH) enzyme complex.…”

mentioning

confidence: 99%

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

Mason

Hornick

2013

Modern Pathology

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“…20 Another tumor that commonly expresses KIT is gastrointestinal stromal tumor (GIST). 21 Successful treatment of metastatic and unresectable GIST with the ATP-competitive protein kinase inhibitor, imatinib mesylate (Gleevec), 22,23 has prompted a search for activating mutations in KIT and related receptor tyrosine kinases in Merkel cell carcinoma. In vitro studies have shown a decrease in proliferation of Merkel cell carcinoma by addition of Gleevec.…”

mentioning

confidence: 99%

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

Modern Pathology

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Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

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Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors

Cited by 3,876 publications

References 19 publications

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

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