Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

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This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.

Docetaxel is an antitubulin chemotherapeutic agent approved for the treatment of breast, lung, ovarian and non-hormonal dependent prostate cancers. However, the success of this drug is limited by adverse effects (AEs), the severity of which ranged from tolerable to life threatening. Tapering the dose or diverting to another regimen would limit the use of docetaxel. Single nucleotide polymorphisms (SNPs) of genes encoding for enzymes and proteins involved in the metabolism and transport of docetaxel can cause accumulation of the drug and consequent AEs. Hence, we embarked on a study to investigate the association between SNPs of ABCB1, SLCO1B3 and CYP3A5 genes with docetaxel AEs in Malaysian breast cancer patients. Seventy five breast cancer patients receiving docetaxel as single agent chemotherapy in the adjuvant and metastatic settings were enrolled in this study. They were recruited from University Malaya Medical Centre and Universiti Kebangsaan Malaysia Medical Centre. The doses given were 90-100 mg/m2 in adjuvant setting and 75 mg/m2 in metastatic setting. The SNPs (CYP3A5 6986AG, ABCB1 3435CT and SLCO1B3 334TG) were analyzed using PCR-RFLP technique followed by DNA sequencing of selected samples. AEs were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The SNPs were correlated with AEs using Chi-square and Fisher's exact tests. The patients aged 53.7±9.4 years consisted of three main ethnic groups (Chinese 37 (49%), Malays 32 (43%) and Indians 6 (8%). The most commonly reported AEs were fatigue (55%), nausea (40%), and mucositis (35%). There was a significant association of vomiting with race (p<0.05), where Indians significantly developed vomiting. The presence of ABCB1 3435CT (heterozygous) was significantly associated with rash (p<0.05). Simultaneous presence of SLCO1B3 334GG (mutant) and CYP3A5 6986GG (mutant) was found to have significantly protected the patients from developing mucositis. Although CYP3A5 6986AG polymorphism alone was not significantly associated with mucositis, presence of CYP3A5 6986AA (wild type) and ABCB1 3435TT (mutant) had a significant association with mucositis (p<0.05). On the contrary, patients exhibiting CYP3A5 6986AG (heterozygous) and ABCB1 3435TT (mutant) did not develop mucositis (p<0.05). In conclusion, the SNPs of CYP3A5 6986AG, ABCB1 3435CT and SLCO1B3 334TG had significant influence on the development of docetaxel AEs. Simultaneous interaction between SLCO1B3 334GG (mutant) and CYP3A5 6986GG (mutant); CYP3A5 6986AA (wild type) and ABCB1 3435TT (mutant); CYP3A5 6986AG (heterozygous) and ABCB1 3435TT (mutant) appeared to be significant factors determining whether or not specific AE develops. The SNPs-AEs association provides a great avenue for potential application of biomarkers to personalize treatment to reduce AEs of docetaxel. We would like to thank the Malaysian Ministry of Higher Education (MOHE) and University Malaya for supporting this project through FRGS (04-04-10-848FR) and HIR (UM.C/625/1/HIR) grants, respectively. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A210. Citation Format: Rafid Salim Jabir, Gwo Fuang Ho, Muhammad Azrif bin Ahmad Annuar, Johnson Stanslas. Single nucleotide polymorphisms of ABCB1, SLCO1B3, and CYP3A5: Potential biomarkers of docetaxel adverse effects in Malaysian breast cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A210.