title: Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients.
abstract: BACKGROUND
  Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2, CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen.
  
  
  METHODS
  Patients were monitored for adverse reactions throughout the treatment, then divided into "none or mild" (80 %) or "severe" (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 10(9)/L anytime during the treatment. DNA was extracted from patients' peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis.
  
  
  RESULTS
  Logistic regression revealed that rs776746 or CYP3A5*3 strongly associated with grade 4 neutropenia (OR = 2.56, P = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 10(9)/L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia (P = 0.004).
  
  
  CONCLUSIONS
  Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene-environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters.
authors.affiliation: Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China. nelsontang@cuhk.edu.hk
authors.forename: Nelson L S
authors.initials: NL
authors.lastname: Tang
authors.forename: Chen Di
authors.initials: CD
authors.lastname: Liao
authors.forename: Xingyan
authors.initials: X
authors.lastname: Wang
authors.forename: Frankie K F
authors.initials: FK
authors.lastname: Mo
authors.forename: Vicky T C
authors.initials: VT
authors.lastname: Chan
authors.forename: Rita
authors.initials: R
authors.lastname: Ng
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pang
authors.forename: Joyce J S
authors.initials: JJ
authors.lastname: Suen
authors.forename: Jean
authors.initials: J
authors.lastname: Woo
authors.forename: Winnie
authors.initials: W
authors.lastname: Yeo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects*; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D010597:Pharmacogenetics; D055815:Young Adult
chemical_list: C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A