Pharmacogenomics Variation in Drug Metabolizing Enzymes and Transporters in Relation to Docetaxel Toxicity in Lebanese Breast Cancer Patients: Paving the Way for OMICs in Low and Middle Income Countries

Abstract

We investigated the association of genetic polymorphisms in drug metabolizing enzymes (DMEs) and transporters in patients with docetaxel-induced febrile neutropenia, by a new high-throughput DMEs and transporters (DMETPlus) microarray platform, characterizing 1936 single nucleotide polymorphisms (SNPs) in 225 genes. We recruited 100 Lebanese breast cancer patients from a consecutive cohort of 277 patients who received docetaxel either alone, or in combination with trastuzumab. Out of 100 patients, 18 had developed febrile neutropenia (cases). They were age- and treatment- matched with 18 patients who did not develop febrile neutropenia on docetaxel (controls). We found that 12 SNPs in seven genes (ABCC6, ABCG1, ABCG2, CYP1A2, CYP2D6, FMO2, and FMO3) were significantly associated with febrile neutropenia after docetaxel treatment. Many of these SNPs have not been previously reported to be associated with toxicity due to docetaxel treatment. Interestingly, one SNP in the FMO3 gene (rs909530) was significantly associated with three clinical endpoints: febrile neutropenia, reduced absolute neutrophil count, and hemoglobin reduction. To the best of our knowledge, this is the first study that evaluated the effect of a large array of nearly 2000 polymorphisms in DMEs and transporters on docetaxel toxicity in breast cancer patients, and in a previously understudied population. Additionally, it attests to the feasibility of genomics research in low- and middle-income countries (LMICs). In light of the current global epidemic of noncommunicable diseases (NCDs) such as breast cancer impacting LMICs, we suggest pharmacogenomics is considered as an integral part of the global health research agenda for NCDs and personalized therapeutics.

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

“…FMO3 rs2266782 gene in our optimal model was found to be associated with risk of myelotoxicity and leukopenia. Several SNPs in FMO3 have been included in the genetic model for predicting neutropenia in docetaxel or paclitaxel treated patients in earlier studies . Rs2266782 is a common G to A variant, which leads to a shift of amino acid from Glu to Lys.…”

“…FMO3 catalyses oxygenations of a variety of exogenous chemicals such as nitrogen‐ and sulphur‐containing medicines. Although how FMO3 is involved in docetaxel metabolism remains unclear, it has been reported that FMO3 was associated with blood drug concentration of docetaxel . Therefore, FMO3 rs2266782 might increase the risk of myelosuppression by reducing FMO3 in the liver, leading to the accumulation of docetaxel in cellar and inducing docetaxel toxicity.…”

“…Except the genes that are directly involved in docetaxel pathways, genes related to other metabolism pathways were also found to be associated with docetaxel hematotoxicity, such as CYP2D6 ( Cytochrome P450 Family 2 Subfamily D Member 6 ), NAT2 ( N‐acetyltransferase 2 ) and ABCG1 ( ATP‐binding Cassette Subfamily G Member 1 ) . ERCC2 ( ERCC Excision Repair 2 ), a gene involved in repair of DNA damage, was demonstrated to be associated with docetaxel‐induced neutropenia .…”

Effects of Single-Nucleotide Polymorphisms of FMO3 and FMO6 Genes on Pharmacokinetic Characteristics of Sulindac Sulfide in Premature Labor

“…This was attributable to the decreased FMO3 activity in patients with mutant alleles. Recent study also showed that rs909530 among studied polymorphisms was significantly associated with clinical endpoints such as febrile neutropenia, reduced absolute neutrophil count, and hemoglobin reduction in patients on docetaxel (Awada et al, 2013). It is a synonymous SNP, which is not expected to change the catalytic activity of sulindac sulfide.…”

The pharmacogenetics of drug metabolizing enzymes in the Lebanese population

“…In addition, one SNP in the FMO3 gene (rs909530) was significantly associated with three clinical endpoints: reduced absolute neutrophil count, febrile neutropenia, and hemoglobin reduction. Interestingly, most of these SNPs were not previously reported to be associated with toxicity after docetaxel treatment, since most previous reports assessed a small number of functional variants in candidate genes previously known to be responsible for either clearance or toxicity of docetaxel [65]. This study, although limited by a small sample size, underscores the importance of advanced OMICS technologies in PGx research and potential clinical applications, especially when the discovery of new candidate genes is followed by functional studies that evaluate the potential role of the aberrant proteins in drug kinetics and dynamics.…”