Gemcitabine and Platinum Pathway Pharmacogenetics in Asian Breast Cancer Patients

Cancer Genomics - Proteomics

Maricel Tiemsim Cordero³  Swee-Siang Ng¹  Wee-Lee Yeo³  Soo-Chin Lee²  Hui-Ling Yap¹  Wei-Peng Yong³  Boon-Cher Goh²  Ling-Zhi Wang¹  Richie Soong¹  Andrea Li-Ann Wong³ 

[1] Cancer Science Institute, Singapore, SingaporeCancer Science Institute, Singapore, SingaporeCancer Science Institute, Singapore, Singapore;Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, SingaporeCancer Science Institute, Singapore, SingaporeDepartment of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, SingaporeDepartment of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, SingaporeCancer Science Institute, Singapore, SingaporeCancer Science Institute, Singapore, SingaporeDepartment of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, SingaporeCancer Science Institute, Singapore, Singapore;Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, SingaporeDepartment of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, SingaporeDepartment of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore

关键词: Gemcitabine;    carboplatin;    pharmacogenetics;    genetic polymorphisms;    breast cancer;   

DOI  :  

来源: Delinasios GJ CO

【 摘 要 】

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.

【 授权许可】

Unknown