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

John C Mcauliffe,A Kevin Raymond,Jonathan C Trent,Wei Qiao,Peter F Thall,Alexander J.F Lazar,Dan Yang,Dejka M Steinert,Robert S Benjamin

doi:10.1158/1078-0432.ccr-07-0895

Abstract

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. 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 GIST cell lines were assessed for VEGF production in response to imatinib. 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. 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 GIST with a regimen targeting both Kit and VEGFR based on the presence of tumor VEGF levels.

Highlights

N 11 kit mutation predicted inferior progression-free survival (PFS) but not overall survival (OS)
We present a study to address the prognostic factors for patients with Gastrointestinal stromal tumor (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 vascular endothelial growth factor (VEGF) levels
The 53 GIST patients whose tumors were analyzed by tissue microarray (TMA) were treated at M.D

Summary

Introduction

N 11 kit mutation predicted inferior PFS but not OS. High mitotic rate was marginally predictive of improved OS. 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. 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 aggressive disease and poor outcome (4, 7 – 10). Imatinib is a small molecule inhibitor whose target in GIST is the protein product of the mutated kit or PDGFR-a gene [11]. Other than limited data on the site of mutation within the kit gene, prognostic features of GIST in the imatinib era remain largely undefined. The effects of imatinib on the tumor, including vascular cytokines, are not fully understood

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