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• W2132319801 abstract "PDGFRA is mutated in 5%–10% of gastrointestinal stromal tumors (GISTs), the PDGFRA D842V mutation accounting for ∼60% of all PDGFRA mutations known in GISTs [1.Heinrich M.C. Corless C.L. Duensing A. et al.PDGFRA activating mutations in gastrointestinal stromal tumors.Science. 2003; 299: 708-710Crossref PubMed Scopus (1962) Google Scholar]. The DIMH842–845 and the IMH843–846 deletions represent ∼15% of all PDGFRA mutations. While the latter have been associated with sensitivity to imatinib, the PDGFRA D842V mutation confers primary resistance to imatinib [1.Heinrich M.C. Corless C.L. Duensing A. et al.PDGFRA activating mutations in gastrointestinal stromal tumors.Science. 2003; 299: 708-710Crossref PubMed Scopus (1962) Google Scholar, 2.Heinrich M.C. Corless C.L. Demetri G.D. et al.Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.J Clin Oncol. 2003; 21: 4342-4349Crossref PubMed Scopus (1921) Google Scholar, 3.Corless C.L. 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: 5357-5364Crossref PubMed Scopus (654) Google Scholar, 4.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; 128: 270-279Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar], sunitinib [5.Prenen H. Cools J. Mentens N. et al.Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate.Clin Cancer Res. 2006; 12: 2622-2627Crossref PubMed Scopus (245) Google Scholar], and nilotinib [6.Weisberg E. Wright R.D. Jiang J. et al.Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity.Gastroenterology. 2006; 131: 1734-1742Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. In vitro data suggested that dasatinib is a potent inhibitor of PDGFRA D842V [7.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: 5749-5758Crossref PubMed Scopus (94) Google Scholar]. Sorafenib also displayed some intermediate efficacy even if it was significantly lower than for PDGFRA ΔDIM842–844 [7.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: 5749-5758Crossref PubMed Scopus (94) Google Scholar]. Given the rarity of metastatic GIST with PDGFRA mutation, clinical data in this setting are almost nonexistent [8.Trent J.C. Wathen K. von Mehren M. et al.A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST).J Clin Oncol. 2011; 29 (Abstr 10006)Crossref PubMed Google Scholar]. We report here a series of five patients with metastatic GIST bearing a mutation of the exon 18 of PDGFRA and treated with sorafenib (400 mg twice daily). The results are presented in Table 1. Tolerance was acceptable. Treatment interruption was required in one patient with past medical history significant for congestive heart failure because of a symptomatic decrease of left ventricular ejection >10% from baseline (patient 1). Three patients (including one with D842V mutation) had partial response according to Choi criteria [9.Choi H. Charnsangavej C. Faria S.C. et al.Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.J Clin Oncol. 2007; 25: 1753-1759Crossref PubMed Scopus (1161) Google Scholar] (Figure 1).Table 1Clinical activity of sorafenib in GIST bearing PDGFRA exon 18 mutationPDGFRA mutationLine settingPrior progression on imatinibBest RECIST responseBest Choi responseTime to progressionCase 1D842VFirst lineNoSDPR>6 months stop for cardiac adverse eventsCase 2D842VThird lineYesSDSD4 monthsCase 3DIMH843–846Third lineYesSDNA3 months (died from intercurrent pneumonia)Case 4DIMH842–845Third lineYesSDPR12 monthsCase 5DIMH842–845Third lineYesPRPR>21 months (treatment ongoing)PR, partial response; SD, stable disease; NA, not available. Open table in a new tab PR, partial response; SD, stable disease; NA, not available. Sorafenib is a multi-kinase inhibitor that blocks several tyrosine kinase receptors such as KIT, vascular endothelial growth factor receptors, and platelet-derived growth factor (PDGF) receptors, as well as serine/threonine kinases in the RAS/RAF/MEK/ERK pathway [10.Wilhelm S. Chien D.S. BAY 43-9006: preclinical data.Curr Pharm Des. 2002; 8: 2255-2257Crossref PubMed Scopus (290) Google Scholar]. The antitumor effect of sorafenib in GIST may result from a direct inhibition of KIT and PDGFRA but also from an inhibition of Raf/ERK/MEK signaling and of the proangiogenic growth factor receptors Flk1 and PDGFRB [11.Huynh H. Lee J.W. Chow P.K. et al.Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor.Mol Cancer Ther. 2009; 8: 152-159Crossref PubMed Scopus (44) Google Scholar]. A phase II study recently reported in abstract form included 32 patients with imatinib- and sunitinib-resistant GIST who received 400 mg sorafenib twice daily. The results showed a clinical benefit rate of 68%, a median progression-free survival of 5.2 months, and a median overall survival of about 11.6 months [12.Kindler H.L. Campbell N.P. Wroblewski K. et al.Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): final results of a University of Chicago Phase II Consortium trial.J Clin Oncol. 2011; 29 (Abstr 10009)PubMed Google Scholar]. However, no data were provided about the efficacy of sorafenib according to the primary mutational status. Our case series represents the first clinical evidence of the potential efficacy of sorafenib in patients with exon 18 PDGFRA mutation including the D842V missense mutation and confirms the previously reported in vitro data [7.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: 5749-5758Crossref PubMed Scopus (94) Google Scholar]. Dasatinib has been also recently associated with promising clinical activity in patients with advanced GIST carrying exon 18 mutation of the PDGFRA gene (including the D842V mutation) [8.Trent J.C. Wathen K. von Mehren M. et al.A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST).J Clin Oncol. 2011; 29 (Abstr 10006)Crossref PubMed Google Scholar]. Interestingly, recent in vitro data have suggested that crenolanib, a highly selective and potent inhibitor of both PDGFRA and PDGFRB, blocks phosphorylation of D842V mutant PDGFRA at clinically achievable concentrations [13.Heinrich M.C. Griffith D. McKinley A. et al.The effect of crenolanib (CP-868596) on phosphorylation of the imatinib-resistant D842V PDGFRA activating mutation associated with advanced gastrointestinal stromal tumors.J Clin Oncol. 2011; 29 (Abstr 10012)Google Scholar]. These promising results represent the rationale for an ongoing phase II clinical study of crenolanib in patients with advanced GISTs with the D842V mutation in the PDGFRA gene (http://clinicaltrials.gov/ct2/show/NCT01243346). Further collaborative studies are still needed to define recommendations about the best management of this uncommon and heterogeneous subset of GIST. No conflicts of interest exist. Download .pdf (.26 MB) Help with pdf files Supplement Materials" @default.
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• W2132319801 title "Clinical activity of sorafenib in patients with advanced gastrointestinal stromal tumor bearing PDGFRA exon 18 mutation: a case series" @default.
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