Gene Polymorphisms in Cyclophosphamide Metabolism Pathway, Treatment-Related Toxicity, and Disease-Free Survival in SWOG 8897 Clinical Trial for Breast Cancer

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...

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Published in:Clinical cancer research 2010-12, Vol.16 (24), p.6169-6176
Main Authors: SONG YAO, BARLOW, William E, RAVDIN, Peter M, MARTINO, Silvana, LYSS, Alan P, OSBORNE, C. Kent, ABELOFF, Martin, HORTOBAGYI, Gabriel N, HAYES, Daniel F, AMBROSONE, Christine B, ALBAIN, Kathy S, CHOI, Ji-Yeob, HUA ZHAO, LIVINGSTON, Robert B, DAVIS, Warren, RAE, James M, YEH, I-Tien, HUTCHINS, Laura F
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Algorithms
Antineoplastic agents
Antineoplastic Agents, Alkylating - adverse effects
Antineoplastic Agents, Alkylating - metabolism
Antineoplastic Agents, Alkylating - pharmacokinetics
Antineoplastic Agents, Alkylating - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Aryl Hydrocarbon Hydroxylases - genetics
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Carcinoma - drug therapy
Carcinoma - genetics
Carcinoma - metabolism
Cyclophosphamide - adverse effects
Cyclophosphamide - metabolism
Cyclophosphamide - pharmacokinetics
Cyclophosphamide - therapeutic use
Cytochrome P-450 CYP2B6
Cytochrome P-450 CYP3A - genetics
Disease-Free Survival
Female
Glutathione S-Transferase pi - genetics
Glutathione Transferase - genetics
Gynecology. Andrology. Obstetrics
Humans
Inactivation, Metabolic - genetics
Mammary gland diseases
Medical sciences
Metabolic Networks and Pathways - genetics
Middle Aged
North America
Oxidoreductases, N-Demethylating - genetics
Pharmacology. Drug treatments
Polymorphism, Genetic - physiology
Tumors
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Summary: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). 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. 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. 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-10-0281