Evaluation of SSTR2 Expression in SI-NETs and Relation to Overall Survival after PRRT

Abstract

Simple SummarySmall intestinal neuroendocrine tumors (SI-NETs) are slow growing tumors expressing somatostatin receptors (SSTR), which are targeted in diagnostic and therapeutic methods. A fairly new treatment that targets SSTR2 is peptide receptor radionuclide therapy (PRRT), which prolongs survival for patients with metastasized NETs. However, the treatment is costly, and the effect is variable. Therefore, finding predictors for treatment response is warranted. The aim of this retrospective study was to immunohistochemically analyze the SSTR2 expression in SI-NETs, using a previously constructed tissue microarray, and to investigate if a high SSTR2 expression was correlated to overall survival (OS). Among 42 patients that had received PRRT, 10 had at least one tumor with low SSTR2 expression. The patients were grouped according to the SSTR2 expression (“High SSTR2” and “Low SSTR2”) in previously resected tumors. In contrast to the hypothesis of the study, patients with low SSTR2 expression had significantly longer OS after PRRT, compared with patients with high SSTR2 expression. Hence, the study suggests that low SSTR2 expression in resected tumors should not exclude SI-NET patients from receiving PRRT.(1) Purpose: Small intestinal neuroendocrine tumors (SI-NETs) often present with distant metastases at diagnosis. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a systemic treatment that increases overall survival (OS) in SI-NET patients with stage IV disease. However, the treatment response after PRRT, which targets somatostatin receptor 2 (SSTR2), is variable and predictive factors have not been established. This exploratory study aims to evaluate if SSTR2 expression in SI-NETs could be used to predict OS after PRRT treatment. (2) Methods: Using a previously constructed Tissue Micro Array (TMA) we identified tissue samples from 42 patients that had received PRRT treatment during 2006–2017 at Sahlgrenska University hospital. Immunohistochemical expression of SSTR2, Ki-67 and neuroendocrine markers synaptophysin and Chromogranin A (CgA) were assessed. A retrospective estimation of 177Lu-DOTATATE uptake in 33 patients was performed. Data regarding OS and non-surgical treatment after PRRT were collected. Another subgroup of 34 patients with paired samples from 3 tumor sites (primary tumor, lymph node and liver metastases) was identified in the TMA. The SSTR2 expression was assessed in corresponding tissue samples (n = 102). (3) Results: The patients were grouped into Low SSTR2 or High SSTR2 groups based upon on levels of SSTR2 expression. There was no significant difference in 177Lu-DOTATATE uptake between the groups. The patients in the Low SSTR2 group had significantly longer OS after PRRT than the patients in the High SSTR2 group (p = 0.049). PRRT treated patients with low SSTR2 expression received less additional treatment compared with patients with high SSTR2 expression. SSTR2 expression did not vary between tumor sites but correlated within patients. (4) Conclusion: The results from the present study suggest that retrospective evaluation of SSTR2 expression in resected tumors cannot be used to predict OS after PRRT.