Hagen Sjard Bachmann1, Werner Meier2, Andreas du Bois3, Rainer Kimmig4, Jan Dominik Kuhlmann4,5,6, Winfried Siffert1, Jalid Sehouli7, Kerstin Wollschlaeger8, Jens Huober9, Peter Hillemanns10, Alexander Burges11, Barbara Schmalfeldt12, Behnaz Aminossadati13, Pauline Wimberger4,5,6. 1. Institute of Pharmacogenetics, University of Duisburg-Essen, Essen. 2. Department of Gynecology and Obstetrics, Evangelisches Krankenhaus Duesseldorf, Dusseldorf. 3. Department of Gynecology and Gynecologic Oncology, Klinikum Essen Mitte, Essen. 4. Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen. 5. Department of Gynecology and Obstetrics Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden. 6. German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg. 7. Department of Gynecology, Charité Medical University of Berlin, Berlin. 8. Department of Gynecology and Obstetrics, University of Magdeburg, Magdeburg. 9. Department of Gynecology and Obstetrics, University of Ulm, Ulm. 10. Department of Gynecology and Obstetrics, Medical University of Hannover, Hannover. 11. Department of Gynecology and Obstetrics, Klinikum Großhadern, Munich. 12. Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Munich. 13. Coordinating Centre for Clinical Trials (KKS), Philipps University of Marburg, Marburg, Germany.
Abstract
AIM: 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.
AIM: 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.
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