Cytidine deaminase polymorphism predicts toxicity of gemcitabine-based chemotherapy.

BACKGROUND: The aim of this study was to ascertain whether single nucleotide polymorphisms of cytidine deaminase (CDA), a key enzyme in the metabolism pathway of gemcitabine, could predict clinical outcomes of cancer patients with gemcitabine-based chemotherapy. METHODS: We searched MEDLINE and EMBASE up to January 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according to the Newcastle-Ottawa Quality Assessment Scale. For each included study, the overall survival (OS), overall response rate (ORR) and toxicities were extracted and pooled using random-effects model. RESULTS: In total, data from 13 studies were included. CDA 208A>G and CDA 435C>T were not included in quantified synthesis due to limited data. CDA 79A>C polymorphism was not significantly associated with OS; however, patients carrying the variant CDA 79C allele were likely to have a poor survival, hazard ratio (HR)=1.03, 95% CI 0.957-1.27 (AC+CC vs. AA). CDA 79A>C polymorphism did not correlated with ORR, odds ratio (OR)=0.719, 95% CI 0.363-1.425 (AC+CC vs. AA). However, patients with the variant CDA 79C allele would experience more grade ≥ 3 leucopenia (OR=2.933, 95% CI 1.357-6.605) and tended to have more severe neutropenia (OR=1.313, 95% CI 0.157-10.981). CONCLUSIONS: These results suggest that CDA 79A>C polymorphisms is a potential biomarker for toxicity of gemcitabine-based chemotherapy and a CDA testing before gemcitabine administration is preferred.

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.

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.