HSP90 expression and early recurrence in gastroenteropancreatic neuroendocrine tumors: Potential for novel therapeutic targets.

Abstract

235 Background: Heat shock protein (HSP) 90 promotes tumor growth and is overexpressed in many malignancies. HSP90 expression profile and its potential as a therapeutic target in primary and metastatic neuroendocrine tumors (NETs) are not known. Methods: HSP90 cytoplasmic expression and Ki-67 index were re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables using tissue microarray (TMA) blocks created in triplicate for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution from 2000-2013. Primary outcome was recurrence-free survival (RFS). Results: Of 278 tumors reviewed, 194 (68%) were primary GEP NETs, and 31 (11%) were NET liver metastases. Of the primary GEP NETs, mean age was 56yrs, 42% were male; 103 (53%) were pancreas and 44 (23%) were small bowel. HSP90 expression was high in 66 (34%) and low in 128 (66%). Compared to low expression, high HSP90 was associated with lymphovascular invasion (70vs42%; p = 0.049) and advanced T-stage (T3/T4: 48vs27%; p = 0.01). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 147), high HSP90 was associated with decreased 1-, 3-, and 5-yr RFS (80%, 72%, 62%) compared to low (89%, 86%, 83%; p = 0.03), which persisted on multivariable analysis (HR 5.2, 95%CI 1.7-16.0; p = 0.004), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67 index. When assessing NET liver metastases, high HSP90 expression was seen in 4 (13%) patients and low in 27 (87%). Similar to primary GEP NETs, patients with liver metastases that exhibited high HSP90 expression had decreased 1-, 3-, and 5-yr progression-free survival (25%, 25%, 0%) compared to those with low HSP90 (69%, 49%, 33%; p = 0.052). Conclusions: Heat shock protein 90 exhibits differential expression in resected GEP NETs and liver metastases. High cytoplasmic expression is associated with early recurrence of disease, even after accounting for other adverse pathologic factors, including Ki-67 index. HSP90 inhibition is a potential target for novel therapeutic strategies for neuroendocrine tumors.