em Data acquisition /em : PR, EB, AK, T?, SF, JK, I?, WM, CO, AW, UG, ZIN. SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH em vs /em . 22% (median 17 weeks) in patients without AH. Patients with main tumors transporting mutations in em KIT /em exon 9 or wild-type experienced substantially better 1-12 months PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with em KIT /em exon 11 or em PDGFRA /em mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We recognized two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: main tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of em VEGFA /em were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively). Conclusions We confirmed that many advanced GIST patients benefit from SU therapy with OS 1.5 year. Main tumor em KIT/PDGFRA /em genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two Mouse Monoclonal to 14-3-3 impartial factors influencing both PFS and OS. Note The preliminary data of this study were offered during Annual Getting together with of American Society of Clinical Oncology, 4-8 June 2011 and Connective Tissue Oncology Society Getting together with, 26-28 October 2011 in Chicago, IL. strong class=”kwd-title” Keywords: Sunitinib, Genotype, GIST, Prognosis, Predictive factors, Arterial hypertension Background Unprecedented improvement in advanced gastrointestinal stromal tumors (GIST management has been achieved due to recent recognition of the important biological role of activating ESI-09 mutations in em KIT /em and em PDGFRA /em (platelet-derived growth factor receptor- alpha) genes. Those observations led to the introduction of imatinib mesylate, a small-molecule selective inhibitor of the receptor tyrosine kinases such as stem-cell factor receptor (KIT, CD117), BCR-ABL and platelet-derived growth factor receptors (PDGFRs)-A and -B. Imatinib revolutionized the outcome of patients with advanced CD117-positive GISTs and is currently approved as the ESI-09 first-line treatment in advanced (metastatic and/or inoperable) GISTs [1-5]. However, the spectacular response to imatinib therapy is usually time-limited and secondary resistance to imatinib therapy (after initial stabilization or response) evolves in majority of patients [4]. Currently, the only approved second-line drug is usually sunitinib malate – a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET) [6-11]. Sunitinib possesses both antiangiogenic and cytostatic properties and by competing with ATP binding prevents multiple receptor tyrosine kinases phosphorylation em in vitro /em and em in vivo /em . Two phase II, one phase III and one “treatment-use” trials have investigated the activity of sunitinib in GIST patients after the failure of prior imatinib treatment, and all these trials have shown the significant activity of sunitinib in this populace of patients [11-14]. The objective clinical benefit was achieved in approximately 60% of GIST patients who received sunitinib after failure of prior imatinib treatment [11-14]. Median progression -free survival time on sunitinib is usually 6-8 months. The adverse events reported during this therapy are frequent. The most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, nausea, mucositis, arterial hypertension, hand and foot syndrome (palmar-plantar erythrodysesthesia), impairment of left ventricular ejection fraction and hypothyroidism [12,14]. Moreover, arterial hypertension was not only the common adverse event during sunitinib therapy, but it was reported as.18%; median 77 em vs /em . The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH em vs /em . 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in em KIT /em exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with em KIT /em exon 11 or em PDGFRA /em mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events ESI-09 during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of em VEGFA /em were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively). Conclusions We confirmed that many advanced GIST patients benefit from SU therapy with OS 1.5 year. Primary tumor em KIT/PDGFRA /em genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS. Note The preliminary data of this study were presented during Annual Meeting of American Society of Clinical Oncology, 4-8 June 2011 and Connective Tissue Oncology Society Meeting, 26-28 October 2011 in Chicago, IL. strong class=”kwd-title” Keywords: Sunitinib, Genotype, GIST, Prognosis, Predictive factors, Arterial hypertension Background Unprecedented improvement in advanced gastrointestinal stromal tumors (GIST management has been achieved due to recent recognition of the important biological role of activating mutations in em KIT /em and em PDGFRA /em (platelet-derived growth factor receptor- alpha) genes. Those observations led to the introduction of imatinib mesylate, a small-molecule selective inhibitor of the receptor tyrosine kinases such as stem-cell factor receptor (KIT, CD117), BCR-ABL and platelet-derived growth factor receptors (PDGFRs)-A and -B. Imatinib revolutionized the outcome of patients with advanced CD117-positive GISTs and is currently approved as the first-line treatment in advanced (metastatic and/or inoperable) GISTs [1-5]. However, the spectacular response to imatinib therapy is time-limited and secondary resistance to imatinib therapy (after initial stabilization or response) develops in majority of patients [4]. Currently, the only approved second-line drug is sunitinib malate – a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET) [6-11]. Sunitinib possesses both antiangiogenic and cytostatic properties and by competing with ATP binding prevents multiple receptor tyrosine kinases phosphorylation em in vitro /em and em in vivo /em . Two phase II, one phase III and one “treatment-use” trials ESI-09 have investigated the activity of sunitinib in GIST patients after the failure of prior imatinib treatment, and all these trials have shown the significant activity of sunitinib in this population of patients [11-14]. The objective clinical benefit was achieved in approximately 60% of GIST patients who received sunitinib after failure of prior imatinib treatment [11-14]. Median progression -free survival time on sunitinib is 6-8 months. The adverse events reported during this therapy are frequent. The most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, nausea, mucositis, arterial hypertension, hand and foot syndrome (palmar-plantar erythrodysesthesia), impairment of left ventricular ejection fraction and hypothyroidism [12,14]. Moreover, arterial hypertension was not only the common adverse event during sunitinib therapy, but it was reported as predictive factor for results of renal-cell carcinoma (RCC) patients [15,16]. This phenomenon has not been yet analyzed in GIST patients. There is a lack of studies analyzing the outcome of sunitinib in advanced GISTs after imatinib.