Abstract A55: Influence of ABCB1 polymorphisms on paclitaxel pharmacokinetics in ovarian cancer patients
Authors: Gao Bo , Nieuweboer Annemieke J.M. , Xu Hongmei , Beesley Jonathan , Moghaddam-Helmantel Inge M. Ghobadi , Graan Anne-Joy M. de , Bruijn Peter de , Gurney Howard , Johnatty Sharon E. , Beale Philip , Chenevix-Trench Georgia , Balleine Rosemary L. , Mathijssen Ron H.J. Ron H.J. , Harnett Paul R. 
Published: August 2014

Abstract
Introduction: Epithelial ovarian cancer is generally treated by cytoreductive surgery followed by paclitaxel and carboplatin combination chemotherapy. Despite the high initial response rate, most patients with advanced disease will relapse and eventually succumb to illness due to intrinsic or acquired chemotherapy resistance. ABCB1 (ATP–binding cassette, sub-family B, member 1) mediates cellular elimination of many chemotherapeutic drugs, including paclitaxel. We previously reported a significant association between ABCB1 SNPs (single nucleotide polymorphisms) and PFS (progression-free survival) in ovarian cancer patients (Johnatty et al Clin Cancer Res 2008; 14: 5594-601). In patients with ≥1 cm residual disease, PFS was significantly shorter in homozygote GG carriers compared with patients who carried the minor T/A alleles at the G2677T/A locus (median PFS, 18 months compared with 32 months; p = 0.002). We hypothesized that variability in paclitaxel clearance (CL) resulting from genotypic differences in ABCB1 may underlie the impact of ABCB1 SNPs on clinical outcome.
Methods: Pharmacokinetic sampling was performed during the first cycle of paclitaxel (175 mg/m2) and carboplatin (AUC5 or 6) combination chemotherapy treatment in two independent patient cohorts. These included 39 patients in a hospital based series in the Netherlands and 55 patients recruited prospectively in Australia. Paclitaxel levels were measured using liquid chromatography - tandem mass spectrometry (LC-MS/MS). The individual posterior Bayesian estimates of paclitaxel CL and model-based estimate of AUC (area-under-curve) were determined by using population pharmacokinetics with the NONMEM software. Common ABCB1 SNPs in exon 12 (C1236T), 21 (G2677T/A) and 26 (C3435T) were examined by iPLEX genotyping on Sequenom's MassARRAY platform. Nonparametric Jonckheere-Terpstra tests were used to compare the distribution of paclitaxel CL and AUC between patients of different genotypes.
Results: In the Netherlands cohort, there were statistically significant associations observed between ABCB1 SNPs at exon 12 (C1236T), 21 (G2677T/A) and 26 (C3435T) and paclitaxel CL and AUC. Homozygote GG carriers at the G2677T/A locus had higher paclitaxel CL and lower AUC compared with minor T/A allele carriers. Similar findings were found for C1236T and C3435T. These findings were consistent with our previous clinical observations that patients with homozygote GG at exon 21 (G2677T/A), or homozygote CC at exon 12 (C1236T) or 26 (C3435T), had shorter PFS. The paclitaxel pharmacokinetic modeling results in the Australian cohort will be available for analysis shortly.
Conclusion: The results to date suggest that common ABCB1 SNPs may contribute to chemotherapy resistance in women with ovarian cancer through their effects on paclitaxel drug disposition.
Citation Format: Bo Gao, Annemieke J.M. Nieuweboer, Hongmei Xu, Jonathan Beesley, Inge M. Ghobadi Moghaddam-Helmantel, Anne-Joy M. de Graan, Peter de Bruijn, Howard Gurney, Sharon E. Johnatty, Philip Beale, Georgia Chenevix-Trench, Rosemary L. Balleine, Ron H.J. Ron H.J. Mathijssen, Paul R. Harnett. Influence of ABCB1 polymorphisms on paclitaxel pharmacokinetics in ovarian cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A55.