title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Awada
authors.forename: Syed
authors.initials: S
authors.lastname: Haider
authors.forename: Arafat
authors.initials: A
authors.lastname: Tfayli
authors.forename: Ali
authors.initials: A
authors.lastname: Bazarbachi
authors.forename: Nagi S
authors.initials: NS
authors.lastname: El-Saghir
authors.forename: Ziad
authors.initials: Z
authors.lastname: Salem
authors.forename: Ali
authors.initials: A
authors.lastname: Shamseddine
authors.forename: Ali
authors.initials: A
authors.lastname: Taher
authors.forename: Nathalie Khoueiry
authors.initials: NK
authors.lastname: Zgheib
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D000077143:Docetaxel; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014943:Global Health; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D007861:Lebanon; D008875:Middle Aged; D010597:Pharmacogenetics / Q000191:economics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011203:Poverty; D043823:Taxoids / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D043823:Taxoids; D000077143:Docetaxel; D000068878:Trastuzumab