title: Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897.
abstract: OBJECTIVE
  Myeloperoxidase (MPO) generates reactive oxygen species and also activates xenobiotics. In a rigorous clinical trial (Southwest Oncology Group SWOG-8897), we examined relationships between genotypes and disease-free survival (DFS) among women treated for breast cancer, as well as those who did not receive adjuvant chemotherapy.
  
  
  METHODS
  Patients were assigned to risk groups according to standard prognostic features; the low-risk group (n = 753 genotyped) received follow-up only, and the high-risk group (n = 401 genotyped) was randomly assigned to adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or cyclophosphamide, doxorubicin, and fluorouracil (CAF), with or without tamoxifen. DNA from archived normal lymph node tissue was genotyped, and Cox proportional hazard models were used to calculate DFS associated with MPO genotypes.
  
  
  RESULTS
  Among women in the treatment arm, those with MPO G alleles had more than a two-fold reduction in hazard of recurrence (adjusted hazard ratio [HR] for GA genotypes, 0.51; 95% CI, 0.21 to 0.99; HR for GG genotypes, 0.41; 95% CI, 0.21 to 0.77). Effects were greatest among women who were further randomly assigned to tamoxifen (HR for GA genotypes, 0.28; 95% CI, 0.12 to 0.69; HR for GG genotypes, 0.19; 95% CI, 0.08 to 0.45). There were no significant associations between genotypes and DFS among women in the untreated arm, and relationships between genotypes and DFS did not differ by CAF or CMF.
  
  
  CONCLUSIONS
  These results, observed in two independent study populations, indicate that high-activity MPO genotypes are associated with better survival among women receiving cyclophosphamide-containing therapy, particularly when followed by tamoxifen therapy. MPO can be inhibited and/or upregulated by commonly used drugs; thus, our findings merit further investigation for optimization of therapeutics for breast cancer.
authors.affiliation: Roswell Park Cancer Institute, Department of Cancer Prevention and Control, Buffalo, NY 14263, USA. Christine.ambrosone@roswellpark.org
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: William E
authors.initials: WE
authors.lastname: Barlow
authors.forename: Wanda
authors.initials: W
authors.lastname: Reynolds
authors.forename: Robert B
authors.initials: RB
authors.lastname: Livingston
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Ji-Yeob
authors.initials: JY
authors.lastname: Choi
authors.forename: Warren
authors.initials: W
authors.lastname: Davis
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Laura R
authors.initials: LR
authors.lastname: Hutchins
authors.forename: Peter M
authors.initials: PM
authors.lastname: Ravdin
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Alan P
authors.initials: AP
authors.lastname: Lyss
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009195:Peroxidase / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D013629:Tamoxifen; D004317:Doxorubicin; D003520:Cyclophosphamide; D009195:Peroxidase; D005472:Fluorouracil; D008727:Methotrexate