SSRI use and clinical outcomes in epithelial ovarian cancer

// Desire K. Christensen 1 , Guillermo N. Armaiz-Pena 2 , Edgardo Ramirez 1 , Koji Matsuo 3 , Bridget Zimmerman 4 , Behrouz Zand 5, 6 , Eileen Shinn 7 , Michael J. Goodheart 8, 9 , David Bender 8 , Premal H. Thaker 10 , Amina Ahmed 11 , Frank J. Penedo 12 , Koen DeGeest 13 , Luis Mendez 14 , Frederick Domann 15 , Anil K. Sood 5, 6 , Susan K. Lutgendorf 1, 8, 9, 16 1 Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa, USA 2 Department of Pharmacology, Ponce Health Sciences University, Ponce, Puerto Rico 3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA 4 Department of Biostatistics, University of Iowa, Iowa City, Iowa, USA 5 Department of Gynecologic Oncology and Reproductive Medicine, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA 6 Department of Cancer Biology, and Center for RNA Interference and Noncoding RNA, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA 7 Department of Behavioral Science, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA 8 Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, USA 9 Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA 10 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University, St. Louis, Missouri, USA 11 Department of Obstetrics and Gynecology, Lutheran General Hospital, Park Ridge, Illinois, USA 12 Department of Medical Social Sciences, Northwestern University, Chicago, Illinois, USA 13 Division of Gynecologic Oncology, Oregon Health and Sciences University, Portland, Oregon, USA 14 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Florida International University School of Medicine, Miami, Florida, USA 15 Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA 16 Department of Urology, University of Iowa, Iowa City, Iowa, USA Correspondence to: Susan K. Lutgendorf, e-mail: susan-lutgendorf@uiowa.edu Keywords: selective serotonin reuptake inhibitors, epithelial ovarian cancer, serotonin, progression, cell proliferation Received: November 09, 2015     Accepted: April 02, 2016     Published: April 21, 2016 ABSTRACT Selective serotonin reuptake inhibitor (SSRI) use is common among ovarian cancer patients. We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. Cox proportional hazards models were used for multivariate analysis. SSRI use was associated with decreased time to disease recurrence (HR 1.3, CI 1.0-1.6, p =0.03), but not overall survival (HR 1.1, CI 0.9-1.3, p =0.56). Compared to normal ovarian cells, most OCCs had elevated 5-HT2A receptor mRNA expression (up to 1600 fold greater expression). Clonogenic survival increased in cells treated with 10 uM (1.6 fold, p <0.001) and 20uM (1.9 fold, p =0.018) 5-HT. Mice receiving 5-HT injections had increases in tumor weight ( p =0.07) and nodules ( p =0.08) with increased Ki67 expression. Injections with sertraline doubled mean tumor weight in mice ( p =0.16). 5-HT and sertraline both increased Ki67 expression in mouse tumors ( p < 0.001). Patients using SSRIs had significantly decreased time to disease progression. It is possible that SSRIs alter serotonin levels in the tumor microenvironment, resulting in activation of proliferation pathways. Further characterization of serotonergic pathways in ovarian cancer is recommended to demonstrate safety of these medications.