title: Gemcitabine and platinum pathway pharmacogenetics in Asian breast cancer patients.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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: Department of Hematology-Oncology, National University Cancer Institute of Singapore.
authors: Andrea Li-Ann
authors: AL
authors: Wong
authors: Hui-Ling
authors: HL
authors: Yap
authors: Wee-Lee
authors: WL
authors: Yeo
authors: Richie
authors: R
authors: Soong
authors: Swee-Siang
authors: SS
authors: Ng
authors: Ling-Zhi
authors: LZ
authors: Wang
authors: Maricel Tiemsim
authors: MT
authors: Cordero
authors: Wei-Peng
authors: WP
authors: Yong
authors: Boon-Cher
authors: BC
authors: Goh
authors: Soo-Chin
authors: SC
authors: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D044466:Asian People; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D016190:Carboplatin; D000093542:Gemcitabine