Association of Intratumoral Vascular Endothelial Growth Factor Expression and Clinical Outcome for Patients with Gastrointestinal Stromal Tumors Treated with Imatinib Mesylate

Abstract

Purpose: Imatinib mesylate (imatinib) has revolutionized clinical outcomes of patients with advanced gastrointestinal stromal tumor (GIST). However, the degree of individual benefit varies, and little is known about prognostic factors for these patients. Importantly, selected patients may be treated with an approach to target both Kit and vascular endothelial growth factor receptor (VEGFR) expression. Experimental Design: Using tissue microarray technology, we analyzed 53 imatinib-naive GISTs for vascular endothelial growth factor (VEGF) expression from patients who then received imatinib. In multivariate analyses, we evaluated overall survival (OS) and progression-free survival (PFS) of these patients based on putative prognostic factors, including VEGF expression. In a separate study, 12 matched pre-imatinib and post-imatinib GIST patient specimens and two human GISTcell lines were assessed for VEGF production in response to imatinib. Results: Independent of kit genotype, patients with GIST expressing high VEGF had inferior median PFS (7.1 months versus 29 months, P = 0.42) and median OS (20 months versus not reached at >50 months; P = 0.02) compared with weak or nonexpressers of VEGF. Non^exon 11 kit mutation predicted inferior PFS but not OS. High mitotic rate was marginally predictive of improved OS. Imatinib resulted in decreased production of VEGF in only a subset of GIST patients (2 of 12) and both cell lines. Conclusions: We present a study to address the prognostic factors for patients with GIST in the imatinib era.We present a rationale to consider exploration of a front-line therapy of GISTwith a regimen targeting both Kit andVEGFR based on the presence of tumor VEGF levels.Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy in the gastrointestinal tract. GISTs may arise anywhere in the alimentary tract and rarely in extraintestinal sites (1). GISTs are distinct from smooth muscle tumors and share features with the interstitial cells of Cajal, the putative progenitor cell of GIST (2).Immunostaining of most GISTs shows expression of the receptor tyrosine kinase Kit for which the majority of GISTs encode activating mutations (2, 3). Most mutations in GIST are deletions or insertions residing in exon 11 of the kit gene. Less frequently, mutations can be found in exons 9, 13, or 17 (4). Alternatively, a minority of GISTs encode activating mutations in exons 12 or 18 of the platelet-derived growth factor receptora (PDGFR-a) gene (5).Before the utilization of imatinib mesylate (imatinib, Gleevec; STI571; Novartis) for the treatment of GIST, patients with advanced disease had limited therapeutic options. GISTs are notoriously chemoresistant and radioresistant, with overall responses of <10% to these modalities (6). Likewise, in the era before imatinib, tumor size (z10 cm), mitotic count (z10 of 50 high power field), small bowel disease, mixed morphology, metastases, BCL-2 expression, exon 11 mutation, and vascular endothelial growth factor (VEGF) expression predicted agg...

Natural Killer Cell IFN-γ Levels Predict Long-term Survival with Imatinib Mesylate Therapy in Gastrointestinal Stromal Tumor–Bearing Patients

“…Moreover, vaccination against cancer-specific antigens can sensitize the tumor against subsequent chemotherapeutic treatment (38-43). Our data bring up the first evidence of (a) a host-derived factor in dictating GIST outcome during IM therapy (3,44,45), of (b) a prognostic effect of NK cell functions in solid tumors, and of (c) an immunologic ''off-target'' effect on NK cells of a tyrosine kinase inhibitor. A larger patient series will be needed to validate the prognostic value of an augmented NK cell IFN-g production at 2 months of IM therapy and to establish the added value of this immunologic parameter over that of the c-kit mutation status or ultrasonography (46).…”

A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib

“…In a small study by Wang et al, serum vascular endothelial growth factor (VEGF) levels were higher in the high-risk GIST patients [10]. Another study showed a positive correlation between high VEGF expression and poor survival independent by KIT genotype [11]. All of our patients enrolled, previously received the antiangiogenesis agent, SU.…”

Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors

“…There was a trend toward better outcomes for patients with wild-type KIT or exon 11 mutation compared with exon 9 mutation, although this was not statistically significant. In addition to tumor genotype, other molecular markers such as vascular endothelial growth factor [25] or Bcl-2 [26] expression have been suggested to correlate with survival in GIST patients treated with imatinib. The role of these biomarkers in Korean patients compared with those from western populations also needs to be explored further.…”