Abstract 5563: Docetaxel-induced mucositis in breast cancer patients: Association with plasma alpha-1-acid glycoprotein level and SLCO1B3 genotype

Abstract

Abstract Mucositis is one of the major non-hematological adverse effects (AEs) of docetaxel, besides fatigue, nausea, vomiting, diarrhea and rash which limit its use in cancer patients. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel demonstrates extensive binding to plasma proteins (>98%) including AAG, lipoproteins and albumin. However, there is a remarkable inter-individual variation of AAG level among cancer patients. Low plasma AAG levels will result in excessive free drug in the circulation, which in turn causes more AEs. Consequently, either the dose is reduced or treatment modality is diverted. In addition, single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in the transport of docetaxel (SLCO1B3) could lead to reduced clearance and accumulation in the circulation and subsequent AEs. Hence, we investigated 91 Malaysian breast cancer patients receiving docetaxel as a single agent chemotherapy at 90-100 mg/m2 and 75 mg/m2 in the adjuvant and metastatic settings respectively, to determine the association between the SNP (SLCO1B3 334TG), plasma AAG level and docetaxel AEs. The plasma AAG level was determined using Enzyme Linked Immunosorbent assay (ELISA) technique, while the SNPs were analyzed using PCR-RFLP technique followed by DNA sequencing of selected samples. The patients consisted of 49 Chinese (54%), 34 Malays (37%) and 8 Indians (9%). We found a significant difference in plasma AAG level between patients with mucositis and those without (178±74 mg/dl vs 225±97 mg/dl,P<0.05). Moreover, patients with mutant SLCO1B3 334GG who developed diarrhea also had mucositis (p<0.05). In conclusion, patients with lower plasma AAG level are more susceptible to develop mucositis. In addition, patients carrying mutant SLCO1B3 334GG who have diarrhea tend to develop mucositis concurrently. Plasma AAG level and SNPs could serve as potential predictive biomarkers of docetaxel-induced mucositis.We would like to thank Malaysian Ministry of Higher Education (MOHE) and University Malaya for funding this project through FRGS (04-04-10-848FR) and HIR (UM.C/625/1/HIR) grants. Citation Format: Rafid S. Jabir, Gwo F. HO, Muhammad Azrif A. Anuar, Johnson Stanslas. Docetaxel-induced mucositis in breast cancer patients: Association with plasma alpha-1-acid glycoprotein level and SLCO1B3 genotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5563. doi:10.1158/1538-7445.AM2014-5563