Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors

Zhi Rong Qian, Tingting Li, Monica Ter-Minassian, Juhong Yang, Jennifer A Chan, Lauren K Brais, Yohei Masugi, Arunthathi Thiaglingam, Nichole Brooks, Reiko Nishihara, Mireille Bonnemarie, Atsuhiro Masuda, Kentaro Inamura, Sun A Kim, Kosuke Mima, Yasutaka Sukawa, Ruoxu Dou, Xihong Lin, David C Christiani, Fabien Schmidlin, Charles S Fuchs, Umar Mahmood, Shuji Ogino, Matthew H Kulke, Zhi Rong Qian, Tingting Li, Monica Ter-Minassian, Juhong Yang, Jennifer A Chan, Lauren K Brais, Yohei Masugi, Arunthathi Thiaglingam, Nichole Brooks, Reiko Nishihara, Mireille Bonnemarie, Atsuhiro Masuda, Kentaro Inamura, Sun A Kim, Kosuke Mima, Yasutaka Sukawa, Ruoxu Dou, Xihong Lin, David C Christiani, Fabien Schmidlin, Charles S Fuchs, Umar Mahmood, Shuji Ogino, Matthew H Kulke

Abstract

Objective: Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET.

Methods: Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders.

Results: High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs.

Conclusions: Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival.

Conflict of interest statement

Declaration of interest: Partial funding for this project was provided by Ipsen Pharmaceuticals. Authors AT, MB and FS are employees of Ipsen. No other conflict of interest exists.

Figures

Figure 1. Expression of SSTRs in small…
Figure 1. Expression of SSTRs in small intestine NET
A. Representative expression of SSTR2 and SSTR5 in small intestinal NET. Strong staining (a and f), weak staining (b and g), negative staining in (c and h) are shown, respectively. Positive staining in normal pancreatic islet cells in (d and i), and negative staining after using blocking peptides are shown in (e and j), respectively. B. Representative expression of SSTR1 and SSTR3 in small intestinal NET. Strong staining is shown in a and d, respectively. Positive staining in normal pancreatic islet cells is shown in b and e, with negative staining after omitting the primary antibodies shown in c and f. C. Representative expression of SSTR4 in small intestinal NET. Strong staining is shown in (a). Positive staining is additionally shown in an SSTR4-expressing CHO cell line (b), and in normal pancreatic islet cells (c). Negative staining is shown after omitting the primary antibody (d).
Figure 1. Expression of SSTRs in small…
Figure 1. Expression of SSTRs in small intestine NET
A. Representative expression of SSTR2 and SSTR5 in small intestinal NET. Strong staining (a and f), weak staining (b and g), negative staining in (c and h) are shown, respectively. Positive staining in normal pancreatic islet cells in (d and i), and negative staining after using blocking peptides are shown in (e and j), respectively. B. Representative expression of SSTR1 and SSTR3 in small intestinal NET. Strong staining is shown in a and d, respectively. Positive staining in normal pancreatic islet cells is shown in b and e, with negative staining after omitting the primary antibodies shown in c and f. C. Representative expression of SSTR4 in small intestinal NET. Strong staining is shown in (a). Positive staining is additionally shown in an SSTR4-expressing CHO cell line (b), and in normal pancreatic islet cells (c). Negative staining is shown after omitting the primary antibody (d).
Figure 1. Expression of SSTRs in small…
Figure 1. Expression of SSTRs in small intestine NET
A. Representative expression of SSTR2 and SSTR5 in small intestinal NET. Strong staining (a and f), weak staining (b and g), negative staining in (c and h) are shown, respectively. Positive staining in normal pancreatic islet cells in (d and i), and negative staining after using blocking peptides are shown in (e and j), respectively. B. Representative expression of SSTR1 and SSTR3 in small intestinal NET. Strong staining is shown in a and d, respectively. Positive staining in normal pancreatic islet cells is shown in b and e, with negative staining after omitting the primary antibodies shown in c and f. C. Representative expression of SSTR4 in small intestinal NET. Strong staining is shown in (a). Positive staining is additionally shown in an SSTR4-expressing CHO cell line (b), and in normal pancreatic islet cells (c). Negative staining is shown after omitting the primary antibody (d).
Figure 2
Figure 2
A. Frequency of expression (at any level) of SSTR1-5 is shown according to tumor primary sites (small intestinal NETs, pancreatic NETs and other NETs). B. Frequency of high expression of SSTR1-5 is shown according to tumor primary site.
Figure 3
Figure 3
Progression-free survival (A) and overall survival (B) according to expression of SSTR2 in patients with small intestine NET receiving treatment with an SSA.

Source: PubMed

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