High-Level Expression of HSP90 Is an Independent Prognostic Factor Predicting Recurrence in Intermediate and High-Risk Gastrointestinal Stromal Tumor
GH Kang, DY Kang, KM Kim, CK Park. Samsung Medical Center, Seoul, Korea; Chung Nam National University, Daejeon, Korea
Background: Despite the therapeutic success of imatinib in gastrointestinal stromal tumor (GIST), patients often develop resistances to the kinase inhibitor, generally resulted from secondary mutations. It is, therefore, important to identify alternative signaling targets for therapies and relevant prognostic factors. The mutant kinase proteins can be targeted using heat shock protein 90 (HSP90) inhibitor, which result in degradation of activated KIT and/or PDGFRA, or using KIT transcriptional repressors.
Design: To evaluate HSP90 expression as a prognostic marker and therapeutic target in GISTs, intermediate- and high-risk of aggressive behavior GISTs in a single institute between 1998 and 2005 were analyzed immunohistochemically. Clinicopathologic features and mutation results of KIT and PDFGRA genes were compared with clinical outcome in 57 patients followed up after complete surgical resection of GIST.
Results: HSP90 was expressed in 100% of cases and the intensity was strong in 9, moderate in 27, and weak in 21 cases. Forty eight (84.2%) GISTs had KIT mutations; 43 with exon 11 mutations (25 deletion, 5 duplication and 13 missense) and 5 with exon 9 duplication mutations. After a median follow-up of 64.1 months, 24 cases (42.1%) showed recurrence of disease and the recurrence-free survival rate was 87%, 58% and 51% at 1, 3 and 5 years, respectively. On univariate analysis, histologic subtype, risk grade, mitotic rate, intensity of HSP90 expression and specific KIT mutation types had prognostic importance (p<0.05). Patients with exon 11 deletion mutations or deletions affecting codon 557 or 558 had higher rates of recurrence. In multivariate analysis by Cox proportional hazards model, high risk (p=0.02, hazard ratio 7.087) and strong HSP90 immunoreactivity (p=0.02, hazard ratio 8.8) have been identified as independent prognostic variables for recurrence-free survival.
Conclusions: These findings highlight that HSP90 is an independent prognostic factor predicting recurrence and moreover, warrants clinical evaluation as potential therapeutic targets in patients with intermediate or high-risk GIST.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 98, Monday Morning