Nitric oxide synthase variants and disease-free survival among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial.
OBJECTIVE
Numerous chemotherapeutic agents are cytotoxic through generation of reactive species, and variability in genes related to oxidative stress may influence disease-free survival (DFS). We examined relationships between DFS and variants in NOS3, as well as NQO1, NQO2, and CBR3, among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial (S8897).


METHODS
In the parent trial, women were assigned according to prognostic features; the high-risk group was randomized to cyclophosphamide, i.v. methotrexate, and 5-fluorouracil or to cyclophosphamide, i.v. doxorubicin, and 5-fluorouracil +/- tamoxifen, and the low-risk group did not receive adjuvant therapy. We extracted DNA from normal lymph node tissue and examined functional polymorphisms in NOS3, NQO1, NQO2, and CBR3, in relation to DFS, using Cox proportional hazard model.


RESULTS
There were significant interactions between DFS, adjuvant therapy, and NOS3 Glu298Asp and -786 polymorphisms, alone and in combination (P for interaction = 0.008). When NOS3 genotypes were combined, women with genotypes encoding for lower nitric oxide who received chemotherapy had a >2-fold increase in hazard of progression (hazard ratio, 2.32; 95% confidence interval, 1.26-4.25), whereas there was reduced risk for those who did not receive adjuvant therapy (hazard ratio, 0.42; 95% confidence interval, 0.19-0.95). There were no associations between the other genotypes and DFS in either group.


CONCLUSIONS
Variants encoding lower activity of NOS3 may affect outcomes in breast cancer patients, with the direction of risk differing depending on chemotherapy status. These results may mirror the known dual functions of nitric oxide and nitric oxide synthase, depending on oxidative environment.
Choi
Ji-Yeob
JY
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Barlow
William E
WE
Albain
Kathy S
KS
Hong
Chi-Chen
CC
Blanco
Javier G
JG
Livingston
Robert B
RB
Davis
Warren
W
Rae
James M
JM
Yeh
I-Tien
IT
Hutchins
Laura F
LF
Ravdin
Peter M
PM
Martino
Silvana
S
Lyss
Alan P
AP
Osborne
C Kent
CK
Abeloff
Martin D
MD
Hayes
Daniel F
DF
Ambrosone
Christine B
CB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D002945:Cisplatin / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D008495:Medical Oncology / Q000379:methods; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology; D011379:Prognosis; D015206:Southwestern United States
D004317:Doxorubicin; D003520:Cyclophosphamide; D052250:Nitric Oxide Synthase Type III; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate