Abstract 5029: Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial

Abstract

Abstract Introduction The treatment of locally advanced or metastatic soft tissue sarcoma remains a significant clinical challenge, with overall survival rates of approximately 12 months observed with current first line palliative chemotherapy. A recently completed randomised phase III clinical trial entitled GeDDiS (ISRCTN07742377), was designed to compare first line treatment with gemcitabine in combination with docetaxel (GemDoc) versus current standard treatment with doxorubicin. A pharmacogenetic sub-study was incorporated into the trial to assess potential impact of single nucleotide polymorphisms (SNPs) in genes associated with the pharmacology of the three drugs. Methods A total of 240 patients were recruited to the sub-study with 119 on the doxorubicin arm and 121 on the GemDoc arm. A 4 ml blood sample was taken from each participant and genomic DNA extracted. Individual candidate SNPs were assessed by Taqman PCR in 7 genes associated with doxorubicin pharmacology, 7 genes associated with gemcitabine and 5 genes associated with the pharmacology of docetaxel. Association between the SNPs and efficacy and toxicity was assessed. Results SNPs within the solute transporter SLC22A16, associated with the intracellular influx of doxorubicin, were associated with worse PFS (HR = 1.72, p=0.04) and decreased frequency of grade 3/4 adverse events (71% vs 48%, p=0.04) in the doxorubicin arm of the study but not in the GemDoc arm. Conclusions The association of genetic variants of SLC22A16 with decreased efficacy and decreased incidence of toxicity is consistent with a loss of function in the transporter and previous observation of increased AUC in pharmacokinetic studies assuming that distribution of the drug into target and collateral tissues is restricted. Citation Format: David Jamieson, Beatrice Seddon, Katja Kuever, Hakim-Moulay Dehbi, Sandra Strauss, Sandy Beare, Gareth Veal. Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5029. doi:10.1158/1538-7445.AM2017-5029