title: Gene polymorphisms in cyclophosphamide metabolism pathway,treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer.
abstract: OBJECTIVE
  There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS).
  
  
  METHODS
  Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6CYP3A4GSTA1 and GSTP1 were estimated by logistic regression and Cox proportional hazard regression.
  
  
  RESULTS
  Compared with women with AA genotypes, those with at least 1 GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia [odds ratios (OR) = 0.63, 95% CI = 0.41-0.97] and leucopenia (OR = 0.59, 95% CI = 0.39-0.89). No other associations between single nucleotide polymorphisms and toxicity or survival were found in the treated or untreated group.
  
  
  CONCLUSIONS
  Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high-grade hematologic toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematologic toxicities with CP-containing therapies.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. Song.Yao@roswellpark.org
authors.forename: Song
authors.initials: S
authors.lastname: Yao
authors.forename: William E
authors.initials: WE
authors.lastname: Barlow
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: Ji-Yeob
authors.initials: JY
authors.lastname: Choi
authors.forename: Hua
authors.initials: H
authors.lastname: Zhao
authors.forename: Robert B
authors.initials: RB
authors.lastname: Livingston
authors.forename: Warren
authors.initials: W
authors.lastname: Davis
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Laura F
authors.initials: LF
authors.lastname: Hutchins
authors.forename: Peter M
authors.initials: PM
authors.lastname: Ravdin
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: Alan P
authors.initials: AP
authors.lastname: Lyss
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Martin
authors.initials: M
authors.lastname: Abeloff
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D009656:North America; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D011110:Polymorphism, Genetic / Q000502:physiology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; C484555:GSTA1 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase