Nitric Oxide Synthase Variants and Disease-Free Survival among Treated and Untreated Breast Cancer Patients in a Southwest Oncology Group Clinical Trial
Year: 2009
Type: article
Abstract: PURPOSE: 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). EXPERIMENTAL DESIGN: 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. CONCLUSION: 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.
Source: Clinical Cancer Research
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: bronze
Awards: G1033243903, G117886320, G1202672505, G1216887118, G1235982543, SOUTHWEST ONCOLOGY GROUP, G1343089328, G1375689152, Columbus Community Clinical Oncology Program (Columbus CCOP), G1545560008, G1646027999, COOPERATIVE STUDY OF CANCER CHEMOTHERAPY, G1790576020, G1911575068, G1958973285, G1985252453, G2043432835, G2064543036, Scott & White Community Clinical Oncology Program, G215985982, G2160369479, G2276667821, G2405064429, G2419449687, G2435896781, G2485941414, G2562936776, G2646278872, G268786457, G2734683319, G2750730928, Ozark Health Ventures, LLC dba Cancer Research for the Ozarks, GRAND RAPIDS CLINICAL ONCOLOGY PROGRAM, G3041257426, SOUTHWEST ONCOLOGY GROUP STATISTICAL CENTER, G3103693091, G3126600779, G313314762, G3239274266, G3242537740, G3295642875, G3334379738, G345775953, G3484997517, G3521018462, G36541222, G3737421695, G379387698, G4110529384, G413878341, G425646771, Southwest Oncology Group, G4292856267, G444114835, G4499432180, G4525186751, G4527800867, SOUTHWEST ONCOLOGY GROUP, CANCER AND LEUKEMIA GROUP B: RPMI/SUNYAB, G4935167430, G5264753430, G5566132837, G5660033547, G591690631, SOUTHWEST ONCOLOGY GROUP, SOUTHWEST ONCOLOGY GROUP, G6211207823, G6290519354, G6358381031, G6452040166, G6723594983, SOUTHWEST ONCOLOGY GROUP, G6782300252, G7061256793, G7103307427, G712978930, G7222907299, G7520596819, G758084519, Virginia Mason Community Clinical Oncology Program, G763325562, G7926913928, G8006406963, G8036334546, G8432681756, G8523218764, G8593264226, G860872252, SOUTHWEST ONCOLOGY GROUP, G8740717309, G8777682367, PARTICIPATE AS MEMBER OF SOUTHWEST ONCOLOGY GROUP, G8937348795, Roswell Park Cancer Center Support Grant, G933283670, G971274320
OpenAlex ID: W2127003087