Originally published as JCO Early Release 10.1200/JCO.2009.21.8669 on September 14 2009

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Myeloperoxidase Genotypes and Enhanced Efficacy of Chemotherapy for Early-Stage Breast Cancer in SWOG-8897

From the Roswell Park Cancer Institute, Department of Cancer Prevention and Control, Buffalo, NY; Southwest Oncology Group Statistical Center, Seattle, WA; The Sidney Kimmel Cancer Center, San Diego; The Angeles Clinic and Research Institute, Santa Monica, CA; University of Arizona Cancer Center, Tucson, AZ; University of Texas Health Science Center at San Antonio, San Antonio; Baylor College of Medicine, Houston, TX; University of Michigan Medical Center, Ann Arbor, MI; University of Arkansas for Medical Sciences, Little Rock, AR; Heartland Cancer Research Community Clinical Oncology Program, Missouri Baptist Medical Center, St. Louis, MO; Loyola University Stritch School of Medicine, Maywood, IL.

Corresponding author: Christine B. Ambrosone, PhD, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263; e-mail: Christine.ambrosone{at}roswellpark.org.

Purpose 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.

Patients and 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.

Conclusion 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.

Supported in part by the Department of Health and Human Services, National Cancer Institute R01 and Public Health Service Cooperative Agreement Grants No. CA095222, CA32102, CA38926, CA02599, CA13612, CA22433, CA27057, CA37981, CA46282, CA20319, CA35431, CA76447, CA45560, CA12644, CA14028, CA58416, CA04919, CA35090, CA35176, CA58686, CA58861, CA46113, CA58882, CA35128, CA74647, CA46136, CA45450, CA35261, CA35192, CA12213, CA16385, CA58658, CA46441, CA58723, CA45377, CA35119, CA42777, CA73590, CA114558-02, CA35178, and CA35262. C.B.A., J.M.R., and D.F.H. are recipients of funding from the Breast Cancer Research Foundation.

Presented in part at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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