title: Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.
abstract: BACKGROUND
  The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities.
  
  
  METHODS
  93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded.
  
  
  RESULTS
  GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity.
  
  
  CONCLUSIONS
  These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhou
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Qingkun
authors.initials: Q
authors.lastname: Song
authors.forename: Huabing
authors.initials: H
authors.lastname: Yang
authors.forename: Xishan
authors.initials: X
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.forename: Guohong
authors.initials: G
authors.lastname: Song
authors.forename: Lijun
authors.initials: L
authors.lastname: Di
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Hong
authors.initials: H
authors.lastname: Shao
authors.forename: Herbert Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016009:Chi-Square Distribution; D002681:China; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D016017:Odds Ratio; D018579:Patient Selection; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012307:Risk Factors; D016879:Salvage Therapy; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013852:Thiotepa / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D013721:Triethylenephosphoramide / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D013852:Thiotepa; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D013721:Triethylenephosphoramide