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The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients

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The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients. / Bachmann, Hagen Sjard; Meier, Werner; du Bois, Andreas; Kimmig, Rainer; Kuhlmann, Jan Dominik; Siffert, Winfried; Sehouli, Jalid; Wollschlaeger, Kerstin; Huober, Jens; Hillemanns, Peter; Burges, Alexander; Schmalfeldt, Barbara; Aminossadati, Behnaz; Wimberger, Pauline.

In: BRIT J CLIN PHARMACO, Vol. 80, No. 5, 11.2015, p. 1139-48.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Bachmann, HS, Meier, W, du Bois, A, Kimmig, R, Kuhlmann, JD, Siffert, W, Sehouli, J, Wollschlaeger, K, Huober, J, Hillemanns, P, Burges, A, Schmalfeldt, B, Aminossadati, B & Wimberger, P 2015, 'The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients', BRIT J CLIN PHARMACO, vol. 80, no. 5, pp. 1139-48. https://doi.org/10.1111/bcp.12688

APA

Bachmann, H. S., Meier, W., du Bois, A., Kimmig, R., Kuhlmann, J. D., Siffert, W., Sehouli, J., Wollschlaeger, K., Huober, J., Hillemanns, P., Burges, A., Schmalfeldt, B., Aminossadati, B., & Wimberger, P. (2015). The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients. BRIT J CLIN PHARMACO, 80(5), 1139-48. https://doi.org/10.1111/bcp.12688

Vancouver

Bachmann HS, Meier W, du Bois A, Kimmig R, Kuhlmann JD, Siffert W et al. The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients. BRIT J CLIN PHARMACO. 2015 Nov;80(5):1139-48. https://doi.org/10.1111/bcp.12688

Bibtex

@article{0e3f604e084d47c9a6b25e7ac2dac370,
title = "The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients",
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.",
author = "Bachmann, {Hagen Sjard} and Werner Meier and {du Bois}, Andreas and Rainer Kimmig and Kuhlmann, {Jan Dominik} and Winfried Siffert and Jalid Sehouli and Kerstin Wollschlaeger and Jens Huober and Peter Hillemanns and Alexander Burges and Barbara Schmalfeldt and Behnaz Aminossadati and Pauline Wimberger",
note = "{\textcopyright} 2015 The British Pharmacological Society.",
year = "2015",
month = nov,
doi = "10.1111/bcp.12688",
language = "English",
volume = "80",
pages = "1139--48",
journal = "BRIT J CLIN PHARMACO",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "5",

}

RIS

TY - JOUR

T1 - The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients

AU - Bachmann, Hagen Sjard

AU - Meier, Werner

AU - du Bois, Andreas

AU - Kimmig, Rainer

AU - Kuhlmann, Jan Dominik

AU - Siffert, Winfried

AU - Sehouli, Jalid

AU - Wollschlaeger, Kerstin

AU - Huober, Jens

AU - Hillemanns, Peter

AU - Burges, Alexander

AU - Schmalfeldt, Barbara

AU - Aminossadati, Behnaz

AU - Wimberger, Pauline

N1 - © 2015 The British Pharmacological Society.

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

U2 - 10.1111/bcp.12688

DO - 10.1111/bcp.12688

M3 - SCORING: Journal article

C2 - 26033044

VL - 80

SP - 1139

EP - 1148

JO - BRIT J CLIN PHARMACO

JF - BRIT J CLIN PHARMACO

SN - 0306-5251

IS - 5

ER -