Gene polymorphisms in cyclophosphamide metabolism pathway,treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer.

Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Song Yao, William E Barlow, Kathy S Albain, Ji-Yeob Choi, Hua Zhao, Robert B Livingston, Warren Davis, James M Rae, I-Tien Yeh, Laura F Hutchins, Peter M Ravdin, Silvana Martino, Alan P Lyss, C Kent Osborne, Martin Abeloff, Gabriel N Hortobagyi, Daniel F Hayes, Christine B Ambrosone
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 24 Pg. 6169-76 (Dec 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 21169260 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2010 AACR

Chemical References

• Antineoplastic Agents, Alkylating
• Cyclophosphamide
• Aryl Hydrocarbon Hydroxylases
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Oxidoreductases, N-Demethylating
• GSTA1 protein, human
• GSTP1 protein, human
• Glutathione S-Transferase pi
• Glutathione Transferase

Topics

• Adult
• Aged
• Aged, 80 and over
• Algorithms
• Antineoplastic Agents, Alkylating (adverse effects, metabolism, pharmacokinetics, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Aryl Hydrocarbon Hydroxylases (genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Carcinoma (drug therapy, genetics, metabolism)
• Cyclophosphamide (adverse effects, metabolism, pharmacokinetics, therapeutic use)
• Cytochrome P-450 CYP2B6
• Cytochrome P-450 CYP3A (genetics)
• Disease-Free Survival
• Female
• Glutathione S-Transferase pi (genetics)
• Glutathione Transferase (genetics)
• Humans
• Inactivation, Metabolic (genetics)
• Metabolic Networks and Pathways (genetics)
• Middle Aged
• North America
• Oxidoreductases, N-Demethylating (genetics)
• Polymorphism, Genetic (physiology)