Purpose: Heat shock protein 90 (HSP90) is a chaperone mediating the folding and stabilization of many oncoproteins. Considerable attention has been focused on the role of the HSP90 in the therapeutic strategy of molecular targeting HSP90. Recently it has reported that Trastuzumab, a recombinant monoclonal antibody against HER2, plus chemotherapy improved survival in HER2-positive gastric cancer patients. This study was designed to delineate the clinical implications of Hsp90 and HER2 immunoexpression in advanced gastric cancer.

Material and Methods: The study group comprised 47 patients who underwent gastrectomy at Shikoku Cancer Center Hospital excluding patients with stage I. According to the TNM classification, 18 tumors were identified as being stage II, 25 stage III, 4 stage IV. Using immunohistochemical techniques, we analyzed the expressions of HSP90 and HER2 on formalin-fixed paraffin-embedded specimens of surgically removed primary tumors. Immunostaining was graded as follows: low-HSP90 (defined as weaker staining compared with adjacent normal gastric mucosa), moderate-HSP90 (defined as equal), high-HSP90 (defined as stronger). HER2 expression was graded using a 4-point scale according to the criteria of HER2 membranous staining, which have been widely accepted. Chi-square test, Kaplan-Meier and Cox regression analysis were used for statistical analysis.

Results: Low-HSP90 expression was found in 13 tumors (28%) and HER2 high-expression (moderate to strong membrane staining in > 10% of tumor cells) in 13 tumors (28%). Low-HSP90 was significantly detected in diffuse type (p = 0.0047) and was associated with clinicopathological parameters involved with tumor progression, including the depth of tumor invasion (p = 0.049) and advanced stage tumor (p = 0.029). Of note, High-HSP90 and HER2 overexpression (3+) were mutually exclusive (P=0.031). Kaplan-Meier survival analysis determined that tumors with low-HSP90 expression were statistically associated with worse disease-free survival (p = 0.036), and tended to detect poor postoperative survival (p = 0.084). Multivariate survival analysis showed that HSP90-negative expression [hazard ratio (HR) 3.05, 95% confidence interval (95% CI) 1.02-9.18; p = 0.046] and lymph node metastasis (HR 5.55; 95% CI 1.68-18.2; p = 0.005) were significant predictors of poor postoperative survival.

Conclusions: Our results indicate that low-HSP90 expression correlated with more aggressive disease and poor prognosis, and that HSP90 and HER2 overexpression might separately be molecular targets in gastric cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2691.