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

Abstract

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 for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution (2000-2013). Primary outcome was recurrence-free survival (RFS).

RESULTS:

Of 263 tumors reviewed, 73% (n = 191) were primary GEP NETs, and 12% (n = 31) were NET liver metastases. Of the primary GEP-NETs, mean age was 56 years, 42% were male; 53% (n = 103) were pancreatic and 23% (n = 44) were small bowel. HSP90 expression was high in 34% (n = 64) and low in 66% (n = 127). Compared to low expression, high HSP90 was associated with advanced T-stage (T3/T4) (47 vs 27%; p = 0.02). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 145), high HSP90 was independently associated with worse RFS (HR 5.09, 95% CI 1.65-15.74; p = 0.005), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67. When assessing NET liver metastases, 13% (n = 4) had high HSP90 expression and 87% (n = 26) had low expression. Patients with liver metastases with high HSP90 tended to have worse 1- and 3-year progression-free survival (25%, 25%) compared to those with low HSP90 (69%, 49%; p = 0.059).

CONCLUSION:

HSP90 exhibits differential expression in resected GEP-NETs and liver metastases. High cytoplasmic expression is associated with early disease recurrence, even after accounting for other adverse pathologic factors. HSP90 inhibition may be a potential therapeutic target for neuroendocrine tumors.

• Authors: Adriana C Gamboa, Cecilia G Ethun, Lauren M Postlewait, Alexandra G Lopez-Aguiar, Kristen Zhelnin, Alyssa Krasinskas, Bassel F El-Rayes, Maria C Russell, David A Kooby, Charles A Staley, Kenneth Cardona, Shishir K Maithel
• Journal: Surgical oncology (Surg Oncol) Vol. 35 Pg. 460-465 (Dec 2020) ISSN: 1879-3320 [Electronic] Netherlands
• PMID: 33080545 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Biomarkers, Tumor
• HSP90 Heat-Shock Proteins

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Chick Embryo
• Female
• Follow-Up Studies
• HSP90 Heat-Shock Proteins (metabolism)
• Humans
• Intestinal Neoplasms (metabolism, pathology, surgery)
• Liver Neoplasms (metabolism, secondary, surgery)
• Male
• Middle Aged
• Neoplasm Recurrence, Local (metabolism, pathology, surgery)
• Neoplasms (pathology, surgery)
• Neuroendocrine Tumors (metabolism, pathology, surgery)
• Pancreatic Neoplasms (metabolism, pathology, surgery)
• Prognosis
• Retrospective Studies
• Stomach Neoplasms (metabolism, pathology, surgery)
• Survival Rate