Pancreas
Original Articles
Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors
Qian, Zhi Rong MD, PhD; Li, Tingting MD, PhD; Ter-Minassian, Monica ScD; Yang, Juhong MD, PhD; Chan, Jennifer A. MD, MPH; Brais, Lauren K. MPH; Masugi, Yohei MD, PhD; Thiaglingam, Arunthathi PhD; Brooks, Nichole BS; Nishihara, Reiko PhD; Bonnemarie, Mireille MD; Masuda, Atsuhiro MD, PhD; Inamura, Kentaro MD, PhD; Kim, Sun A. MD, PhD; Mima, Kosuke MD, PhD; Sukawa, Yasutaka MD, PhD; Dou, Ruoxu MD; Lin, Xihong PhD; Christiani, David C. MD, MPH; Schmidlin, Fabien PhD; Fuchs, Charles S. MD, MPH; Mahmood, Umar MD, PhD; Ogino, Shuji MD, PhD, MS; Kulke, Matthew H. MD, MMsc
From the *Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; †Department of Geriatric Gastroenterology, Chinese PLA General Hospital, Beijing, China; ‡Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; §Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China; ∥IPSEN Bioscience Inc, Global Drug Discovery Department, Cambridge, MA; ¶IPSEN Innovation, Global Drug Discovery Department, Les Ulis, France; Departments of #Biostatistics, and **Epidemiology, Harvard T.H. Chan School of Public Health, ††Massachusetts General Hospital, ‡‡Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, §§Department of Radiology, Massachusetts General Hospital, and ∥∥Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Received for publication October 21, 2015; accepted April 29, 2016.
Address correspondence to: Zhi Rong Qian, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Room MA420, Boston, MA 02115 (e-mail: [email protected]).
This study was funded in part from a grant from Ipsen Pharmaceuticals. This work was also supported by US National Institutes of Health grants P50 CA127003 to C.S.F., R01 CA151532 to M.H.K., R01 CA151993 to S.O., R35 CA197735 to S.O., R01 CA166582 to U.M., and K07 CA190673 to R.N.
Zhi Rong Qian and Tingting Li contributed equally.
Contributors: Study concept and design: Z.R.Q., T.L., M.H.K. Acquisition of data: all coauthors. Analysis and interpretation of data: Z.R.Q., T.L., J.M.F., M.T.-M., J.A.C., C.S.F., M.M., S.O., M.H.K. Manuscript writing: Z.R.Q., M.H.K. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Z.R.Q., T.L. Final approval of manuscript: all authors. Obtain funding: M.H.K. Study supervision: S.O., M.H.K.
Declaration of interest: Partial funding for this project was provided by Ipsen Pharmaceuticals. Authors A.T., M.B., and F.S. are employees of Ipsen. No other conflict of interest exists.
Use of standardized official symbols: We use HUGO (Human Genome Organisation)-approved official symbols for genes and gene products, including MKI67, SST, SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, all of which are described at www.genenames.org. Gene names are italicized, and gene product names are nonitalicized.
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.