Association of intratumoral vascular endothelial growth factor expression and clinical outcome for patients with gastrointestinal stromal tumors treated with imatinib mesylate.

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 GIST cell 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 GIST with a regimen targeting both Kit and VEGFR based on the presence of tumor VEGF levels.

Expression of receptor tyrosine kinases and apoptotic molecules in rhabdomyosarcoma: correlation with overall survival in 105 patients.

BACKGROUND: Rhabdomyosarcoma (RMS) is a rare mesenchymal tumor with few treatment options after the failure of first-line therapy. Understanding the expression of kinases and apoptotic molecules in RMS tumors may lead to elucidation of mechanisms of resistance to chemotherapy and development of new therapies. METHODS: Paraffin-embedded tissue samples were collected from 105 RMS patients treated at the M. D. Anderson Cancer Center and examined for the immunohistochemical expression of kinases and apoptotic molecules deemed potential therapeutic targets. Clinicopathologic information was collected on all patients and analyzed for correlation with overall survival (OS). RESULTS: Of the 105 patients, 44 (42%) were female and 89 (85%) were older than 10 years of age. The 5-year OS for this cohort was 24.7%, with inferior median OS in patients with genitourinary primary tumors and those with invasion through the deep fascial plane. Immunohistochemistry revealed Kit and c-erb-b2 to be present on < 10% of tumors but EGFR, PDGFR-alpha, PDGFR-beta, Bcl-2, and Bax were present in > 40% of tumors. Patients whose tumors expressed PDGFR-alpha were found to have a shorter median OS by multivariate analysis (26 vs 266 months, P = .076). Conversely, patients whose tumors expressed Bax were found to have a longer OS (31 vs 19 months, P = .047). CONCLUSIONS: 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.

Correlation of immunophenotype with progression-free survival in patients with gastrointestinal stromal tumors treated with imatinib mesylate.

BACKGROUND: The therapy for gastrointestinal stromal tumor (GIST) has been revolutionized by imatinib mesylate (IM). It is unknown whether the levels of KIT expression or the presence of CD34, smooth muscle actin (SMA), desmin, or S-100 protein predicts patient outcome from IM therapy. In the current study, the prognostic effects for KIT and other proteins (CD34, SMA, desmin, S-100) were analyzed in a series of GISTs in which protein expression was evaluated by immunohistochemical analysis (IHC). METHODS: The cases of 106 patients with GIST who were uniformly treated with IM at the study institution between December 15, 2000, and January 13, 2002 were evaluated retrospectively. The association between KIT intensity, CD34, desmin, SMA, S-100 protein, and progression-free survival (PFS) was studied. Kaplan-Meier analysis and the Cox proportional hazards regression model were used for statistical analysis. RESULTS: The majority of tumors arose from the stomach (37%), small intestine (35%), and colorectum (14%). KIT expression as determined by IHC was categorized as weak (10%), intermediate (32%), or strong (58%). Patient tumors expressed CD34 (75%), SMA (56%), desmin (1%), and S-100 protein (32%). Patients whose GIST had weak, intermediate, or strong KIT expression were found to have an 18-month PFS rate of 80%, 84%, and 69%, respectively (P = .30). The presence or absence of CD34, SMA, desmin, or S-100 protein did not appear to correlate with PFS after IM. CONCLUSIONS: Patients with the appropriate clinical presentation and KIT-positive GIST tumors appear to benefit from IM independent of the level of KIT or the expression of CD34, SMA, desmin, or S-100 protein by IHC.

Expression of Bcl-2 in gastrointestinal stromal tumors: correlation with progression-free survival in 81 patients treated with imatinib mesylate.

BACKGROUND: The 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. METHODS: The 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. RESULTS: Sixty-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). CONCLUSIONS: In 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.

Recent studies in novel therapy for metastatic sarcomas.

Many new chemotherapeutic agents and targeted therapies are being studied in the treatment of metastatic soft tissue sarcomas (STSs). This article reviews results of recent clinical studies of gemcitabine, docetaxel, paclitaxel, ecteinascidin, 9-nitrocamptothecin, and pegylated liposomal doxorubicin, in patients who have STSs. The use of targeted therapy in STSs is an exciting, constantly changing field. The activity of imatinib mesylate, SU11248, everolimus, and bortezomib are summarized.

Imatinib mesylate in the treatment of gastrointestinal stromal tumour.

Imatinib mesylate is a selective and potent small-molecule inhibitor of tyrosine kinases, including Kit, platelet-derived growth factor receptor, and the BCR-Abl fusion protein. Kit plays an important role in gastrointestinal stromal tumours (GISTs) and is one of the most exciting therapeutic targets discovered so far. Clinical trials have consistently shown the dramatic efficacy of imatinib mesylate in patients with GIST. This article will review the development and pharmacology of this small-molecule inhibitor and summarise the clinical trials of imatinib mesylate for the treatment of GIST. Although imatinib mesylate has significantly improved the outcomes of most patients with advanced GIST, unanswered questions remain: what is the role of imatinib mesylate in the pre- and postoperative settings? What is the mechanism of the antitumour activity of imatinib? How do you manage patients whose tumours are refractory to imatinib mesylate?

Update on the biology and therapy of gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are an example of a disease with an effective, molecularly targeted therapy. METHODS: Published articles and author experience were used to comprehensively define the clinical features, biology, and state-of-the-art therapy of GISTs. RESULTS: GISTs are thought to originate from the neoplastic transformation of the interstitial cells of Cajal, the intestinal pacemaker cells. GISTs commonly have mutations in the kit gene, resulting in a gain-of-function mutation and ligand-independent constitutive activation of the KIT receptor tyrosine kinase. Successful tyrosine kinase inhibitors target the aberrant pathways that are critical for tumor cell viability. The development of imatinib mesylate (formerly STI 571) in the treatment of metastatic GISTs represents a therapeutic breakthrough. CONCLUSIONS: 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.

Molecular targets in therapy for human soft-tissue and bone sarcomas.

Sarcomas represent a heterogeneous group of tumors with different natural histories and therapeutic approaches. Recent discoveries have identified molecular alterations in the pathogenesis of these tumors that lead to distinct effects on sarcoma cell biology. These tumor cell characteristics include independence from growth factors, evasion of apoptosis, and maintenance of genomic integrity. Inhibition of these molecular alterations represents a therapeutic opportunity to reverse the biologic basis of tumor formation in soft-tissue sarcomas and bone tumors.