title: The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients.
abstract: OBJECTIVE
  Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.
  
  
  METHODS
  The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan-Meier analysis.
  
  
  RESULTS
  The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.
  
  
  CONCLUSIONS
  Discrepancies between preclinical success and clinical failure may be due to the patients' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.
authors.affiliation: Institute of Pharmacogenetics, University of Duisburg-Essen, Essen.
authors.forename: Hagen Sjard
authors.initials: HS
authors.lastname: Bachmann
authors.affiliation: Department of Gynecology and Obstetrics, Evangelisches Krankenhaus Duesseldorf, Dusseldorf.
authors.forename: Werner
authors.initials: W
authors.lastname: Meier
authors.affiliation: Department of Gynecology and Gynecologic Oncology, Klinikum Essen Mitte, Essen.
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.affiliation: Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.affiliation: Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen.|Department of Gynecology and Obstetrics Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg.
authors.forename: Jan Dominik
authors.initials: JD
authors.lastname: Kuhlmann
authors.affiliation: Institute of Pharmacogenetics, University of Duisburg-Essen, Essen.
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.affiliation: Department of Gynecology, Charité Medical University of Berlin, Berlin.
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: Department of Gynecology and Obstetrics, University of Magdeburg, Magdeburg.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wollschlaeger
authors.affiliation: Department of Gynecology and Obstetrics, University of Ulm, Ulm.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.affiliation: Department of Gynecology and Obstetrics, Medical University of Hannover, Hannover.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillemanns
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum Großhadern, Munich.
authors.forename: Alexander
authors.initials: A
authors.lastname: Burges
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Munich.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmalfeldt
authors.affiliation: Coordinating Centre for Clinical Trials (KKS), Philipps University of Marburg, Marburg, Germany.
authors.forename: Behnaz
authors.initials: B
authors.lastname: Aminossadati
authors.affiliation: Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen.|Department of Gynecology and Obstetrics Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg.
authors.forename: Pauline
authors.initials: P
authors.lastname: Wimberger
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D017239:Paclitaxel / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult; D003986:Dibenzocycloheptenes
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D051231:Farnesyltranstransferase; D005819:Genetic Markers; D017239:Paclitaxel; D010880:Piperidines; D021122:Protein Subunits; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes
keywords: farnesyltransferase inhibitor; lonafarnib; ovarian cancer; rs11623866; single nucleotide polymorphism