Abstract 1883: Pharmacogenetic analysis of the weekly paclitaxel/IP carboplatin combination therapy for ovarian and peritoneal cancers

Abstract

Abstract Background: Suboptimal ovarian and peritoneal cancer patients with stage II-IV are regularly received TC chemotherapy using 180 mg/m2 paclitaxel (TXL) and AUC 5-6 of iv carboplatin (CBDCA) tri-weekly. The response rate of the TC is ∼60% and thus a further improvement is urgently required. So far, two modified TC regimens, i.e., 1) IP administration of CBDCA, and 2) application of dose-dense weekly 80 mg/m2 TXL have resulted in favorable prognostics as compared with the authentic one. We then commenced phase II clinical trials of weekly TXL/ IP CBDCA for these patients since 2009 under approval of each IRB. Since weekly administration of TXL has been reported to show higher rate of adverse effects such as hematotoxicity, establishment of tailored-therapy is needed for the regimen based on the individuals’ genetic background and cancer characteristics. Methods: Plasma TXL concentrations at 0, 2, 8, and 24 hrs after the administration were measured at a single laboratory, SRL (Tokyo). Forty-seven Japanese patients who were eligible for the TXL concentrations as of June 2011 were included for the analysis. Genotypes of ABCB1 (rs3213619, rs1128503, rs2032582, rs1045642), ABCC1 (rs60782127, rs4148356), ABCC2 (rs3740066), CYP1B1 (rs1056836), CYP2C8 (rs10509681, rs11572080, rs1058930, rs11572093), CYP3A4 (rs12721627, rs4646438, rs55951658, rs55901263, rs55785340), CYP3A5 (rs776746, rs10264272) and GSTP1 (rs1695) were determined using TaqMan® SNP genotyping assay (Applied Biosystems). Deletion polymorphisms of GSTT1 and GSTM1 were analyzed using PCR amplification and agarose gel electrophoresis. Results: Among the tested polymorphisms, only absence of GSTM1 was associated with the higher levels of TXL AUC (P=0.016) in the univariate analysis. When stratified by the GSTM1 status, other SNPs also showed some associations: In the presence of GSTM1, a combination of CYP2C8 rs11572093, CYP3A4 rs12721627 and CYP3A5 rs776746 enabled classification of patients with altered levels of AUC and CL of TXL (P=0.0037 and 0.0003, respectively); combined genotypes using ABCB1 rs11278503 and ABCC1 rs4148356 were useful for identifying patients with higher AUC and Cmax (P=0.036, 0.0031, respectively) in the absence of GSTM1. Conclusion: Stratification of patients with GSTM1 status and combinations with certain SNPs of cytochrome P450s and drug pumps were useful for identifying patients with altered pharmacokinetics parameters for TXL. This finding suggested a possible involvement of GSTM1 enzyme in the metabolism of TXL, though no conjugate of TXL has been reported thus far. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1883. doi:1538-7445.AM2012-1883