Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897.
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.
Ambrosone
Christine B
CB
Roswell Park Cancer Institute, Department of Cancer Prevention and Control, Buffalo, NY 14263, USA. Christine.ambrosone@roswellpark.org
Barlow
William E
WE
Reynolds
Wanda
W
Livingston
Robert B
RB
Yeh
I-Tien
IT
Choi
Ji-Yeob
JY
Davis
Warren
W
Rae
James M
JM
Tang
Li
L
Hutchins
Laura R
LR
Ravdin
Peter M
PM
Martino
Silvana
S
Osborne
C Kent
CK
Lyss
Alan P
AP
Hayes
Daniel F
DF
Albain
Kathy S
KS
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
D013629:Tamoxifen; D004317:Doxorubicin; D003520:Cyclophosphamide; D009195:Peroxidase; D005472:Fluorouracil; D008727:Methotrexate