Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib

Abstract

There is growing evidence that sunitinib plasma levels have an impact on treatment outcome in patients with metastatic renal cell carcinoma (mRCC). We studied the impact of single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics, and additionally, sunitinib pharmacodynamics on dose reductions of the tyrosine kinase inhibitor.

Methods. We retrospectively analyzed germ-line DNA retrieved from mRCC patients receiving sunitinib as first-line therapy. We genotyped 11 key SNPs, respectively, in ABCB1, NR1/2, NR1/3 and CYP3A5, involved in sunitinib pharmacokinetics as well as VEGFR1 and VEGFR3, which have been suggested as regulators of sunitinib pharmacodynamics. Association between these SNPs and time-to-dose-reduction (TTDR) was studied by Cox regression.

Results. We identified 96 patients who were treated with sunitinib and from whom germ-line DNA and data on dose reductions were available. We observed an increased TTDR in patients carrying the TT-genotype in ABCB1 rs1125803 compared to patients with CC- or CT-genotypes (19 vs. 7 cycles; p = 0.031 on univariate analysis and p = 0.012 on multivariate analysis) and an increased TTDR in patients carrying the TT/TA-variant in ABCB1 rs2032582 compared to patients with the GG- or GT/GA-variant (19 vs. 7 cycles; p = 0.046 on univariate analysis and p = 0.024 on multivariate analysis).

Conclusion. mRCC patients carrying the rs1128503 TT-variant or the TT/TA-variant in rs2032582 in ABCB1, which encodes for an efflux pump, do require less dose reductions due to adverse events compared to patients with the wild type or heterozygote variants in these genes.

Acknowledgments

This project is a common project of two kidney tumor banks: the CIT-rein tumor bank (Paris, France) and the University Hospitals Leuven kidney tumor bank (Leuven, Belgium). The CIT-rein project is headed by Professor Stéphane Oudard and Professor Jean-Jacques Patard. We want to thank sincerely for their collaboration the urologists, medical oncologists and pathologists of the following centers, whose biological material was used in the analysis: Angers: Centre Oncologique Paul Papin: Abdel Azzouzi, Rémy Delva, Stéphane Triau, Pierre Bigot; Créteil: Hôpital Henri Mondor: Alexandre de la Taille, Bernard Paule, Yves Allory; Suresnes: Hôpital Foch: Thierry Lebret, Christine Théodore, Yves Denoux; Leuven: University Hospitals Leuven: Hendrik Van Poppel, Evelyne Lerut, Joost Berkers, Pascal Wolter, Patrick Schöffski, Robert Paridaens; Limoges: Hôpital Dupuytren: Aurélien Descazeaud, Julien Berger; Lyon: Centre Léon Bérard: Marc Colombel, Sylvie Négrier, Florence Mege-Lechevallier; Marseille: Institut Paoli-Calmettes: Franck Bladou, Gwénaelle Gravis, Myriam Marcy; Nantes: ICO Gauducheau: Olivier Bouchot, Frédéric Rolland, Karine Reanudin; Paris: Hôpital Necker: Arnaud Méjean, Virginie Verkarre, Vincent Molinié; Poitiers: Jacques Irani, Jean Marc Tourani, Pierre Marie Le Villain; Rennes: Brigitte Laguerre, Jean-Jacques Patard, Nathalie Rioux-Leclercq; Strasbourg: CHRU Strasbourg: Didier Jacqmin, Brigitte Duclos, Véronique Lindler. The tissue collection was coordinated by the Plateforme de Ressources Biologiques de l’Hôpital Européen Georges Pompidou in Paris. We are grateful to Corine Takouchop Teghom, Claudia De Toma and Reza Elaidi for the coordination of the tissue and clinical data collection. Benoit Beuselinck received a grant from the Fondation Martine Midy (Paris, France) (2009–2010). His work is also funded by the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (Belgium) (2011–2013). Alexandra Karadimou received a grant from the Hellenic Society of Medical Oncology (Athens, Greece) (2010–2011). Diether Lambrechts is supported by the Stichting Tegen Kanker. Evelyne Lerut received fundings from Fonds voor Wetenschappelijk Onderzoek Vlaanderen (Belgium) and Stichting tegen Kanker. Stéphane Oudard received honorarium from Novartis, Pfizer, Roche and Bayer. Patrick Schöffski received research funding and honoriaria for consultant, advisory and educational functions from Pfizer and GSK. Benoit Beuselinck and Pascal Wolter are investigators of the EudraCT: 2011-006085-40/MetaSun trial financed by Pfizer. Benoit Beuselinck received honorarium from Bayer for educational activities. Pierre Bigot received honorarium from Novartis. Jean Jacques Patard is a consultant and principal investigator in Pfizer trials. The other authors have no conflicts of interest to declare.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.