BACKGROUND/AIM: Gemcitabine/carboplatin is efficacious in breast cancer but results in significant hematologic toxicities. We employed a multi-gene approach to identify variants to predict its toxicities. PATIENTS AND METHODS: Twenty-six gemcitabine and platinum-based DNA repair pathway polymorphisms were correlated with gemcitabine pharmacokinetics, hematologic toxicities, response and survival in 41 Asian breast cancer patients receiving gemcitabine/carboplatin. RESULTS: The combined effects of solute carrier family (SLC)28A1+1528C>T and thymidylate synthetase (TYMS)+1494del6 significantly influenced hematologic toxicities: 89% of patients who possessed either SLC28A1+1528TT or TYMS+1494ins6/ins6 (n=9) developed grade 4 thrombocytopenia, versus 14% with neither genotype (n=29; p<0.001). In concordance, all patients who possessed either genotype developed grade 3/4 neutropenia, compared to 38% with neither genotype (p=0.001). None of the other genetic variants analyzed correlated with drug pharmacokinetics and pharmacodynamics. CONCLUSION: Approximately one-quarter of our Asian cohort carried SLC28A1+1528TT or TYMS+1494ins6/ins6, which are associated with increased myelotoxicity from gemcitabine/carboplatin. This has potential utility in treatment selection and genotype-based dosing strategies.
BACKGROUND/AIM: Gemcitabine/carboplatin is efficacious in breast cancer but results in significant hematologic toxicities. We employed a multi-gene approach to identify variants to predict its toxicities. PATIENTS AND METHODS: Twenty-six gemcitabine and platinum-based DNA repair pathway polymorphisms were correlated with gemcitabine pharmacokinetics, hematologic toxicities, response and survival in 41 Asian breast cancerpatients receiving gemcitabine/carboplatin. RESULTS: The combined effects of solute carrier family (SLC)28A1+1528C>T and thymidylate synthetase (TYMS)+1494del6 significantly influenced hematologic toxicities: 89% of patients who possessed either SLC28A1+1528TT or TYMS+1494ins6/ins6 (n=9) developed grade 4 thrombocytopenia, versus 14% with neither genotype (n=29; p<0.001). In concordance, all patients who possessed either genotype developed grade 3/4 neutropenia, compared to 38% with neither genotype (p=0.001). None of the other genetic variants analyzed correlated with drug pharmacokinetics and pharmacodynamics. CONCLUSION: Approximately one-quarter of our Asian cohort carried SLC28A1+1528TT or TYMS+1494ins6/ins6, which are associated with increased myelotoxicity from gemcitabine/carboplatin. This has potential utility in treatment selection and genotype-based dosing strategies.
Authors: Nelson L S Tang; Chen Di Liao; Xingyan Wang; Frankie K F Mo; Vicky T C Chan; Rita Ng; Elizabeth Pang; Joyce J S Suen; Jean Woo; Winnie Yeo Journal: J Cancer Res Clin Oncol Date: 2012-11-10 Impact factor: 4.553
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