Progress in the clinical diagnosis has led to an increased recognition of this disease as a distinct clinical entity. Treatment of metastatic GIST with imatinib has led to unprecedented improvements in progression-free and overall survival. The use of imatinib in the preoperative and postoperative treatment of GISTs is an area of intense investigation.

EGFR, PDGFR-alpha, PDGFR-beta, Bcl-2, and Bax are frequently expressed in human RMS tissue and may represent new therapeutic targets. Absence of PDGFR-alpha and the presence of Bax are associated with a longer median OS in patients with RMS. Targeting these molecules may be a successful therapeutic strategy.

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...

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BACKGROUNDThe natural history of gastrointestinal stromal tumor (GIST) has been revolutionized by imatinib mesylate (imatinib) therapy. Before imatinib, Bcl‐2 expression in GIST was associated with a worse prognosis or added no additional prognostic value. To the authors' knowledge, the current study is the first to evaluate Bcl‐2 expression in pre‐imatinib GIST tissue samples as a prognostic marker of progression‐free survival (PFS) time in patients treated with imatinib.METHODSThe cases of 81 patients with GIST who were evaluated between December 15, 2000 and September 1, 2001 were retrospectively reviewed. Clinicopathologic variables were reviewed. GIST cell morphology and patterns of Bcl‐2 expression were described. The methods of Kaplan–Meier and the Cox proportional hazards regression model were used for statistical analysis.RESULTSSixty‐one (75%) patients had tumors that expressed Bcl‐2, and 20 (25%) patients had tumors that were negative for Bcl‐2. All epithelioid tumors (n = 12) expressed Bcl‐2 and tumors with mixed morphology exhibited Bcl‐2 expression in the epithelioid component. A trend toward longer PFS for patients whose tumors expressed Bcl‐2 at a greater immunohistochemical intensity was observed (20.6 mos for no Bcl‐2 expression; 28.3 mos for 1++Bcl‐2 expression; 31.9 mos for 1.5++Bcl‐2 expression; 40.8 mos for 2++Bcl‐2 expresssion; and 35.9 mos for 3++Bcl‐2 expression).CONCLUSIONSIn contrast to studies performed in the preimatinib era, in which Bcl‐2 was found to be a negative prognostic indicator, the current study suggests a trend toward better PFS with increasing Bcl‐2 expression level in GISTs from patients subsequently treated with imatinib. Larger studies may help elucidate the influence of Bcl‐2 expression on PFS after therapy with imatinib. Cancer 2006. © 2006 American Cancer Society.