Article date: November 2015
By: Hagen Sjard Bachmann, Werner Meier, Andreas Bois, Rainer Kimmig, Jan Dominik Kuhlmann, Winfried Siffert, Jalid Sehouli, Kerstin Wollschlaeger, Jens Huober, Peter Hillemanns, Alexander Burges, Barbara Schmalfeldt, Behnaz Aminossadati, Pauline Wimberger, in Volume 80, Issue 5, pages 1139-1148
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.
DOI: 10.1111/bcp.12688
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