Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897

Christine B. Ambrosone, William E. Barlow, Wanda Reynolds, Robert B Livingston, I. Tien Yeh, Ji Yeob Choi, Warren Davis, James M. Rae, Li Tang, Laura R. Hutchins, Peter M. Ravdin, Silvana Martino, C. Kent Osborne, Alan P. Lyss, Daniel F. Hayes, Kathy S. Albain

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4973-4979
Number of pages7
JournalJournal of Clinical Oncology
Volume27
Issue number30
DOIs
StatePublished - Oct 20 2009
Externally publishedYes

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Peroxidase
Genotype
Breast Neoplasms
Drug Therapy
Cyclophosphamide
Fluorouracil
Disease-Free Survival
Tamoxifen
Methotrexate
Doxorubicin
Xenobiotics
Therapeutics
Adjuvant Chemotherapy
Proportional Hazards Models
Reactive Oxygen Species
Lymph Nodes
Alleles
Clinical Trials
Recurrence
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897. / Ambrosone, Christine B.; Barlow, William E.; Reynolds, Wanda; Livingston, Robert B; Yeh, I. Tien; Choi, Ji Yeob; Davis, Warren; Rae, James M.; Tang, Li; Hutchins, Laura R.; Ravdin, Peter M.; Martino, Silvana; Osborne, C. Kent; Lyss, Alan P.; Hayes, Daniel F.; Albain, Kathy S.

In: Journal of Clinical Oncology, Vol. 27, No. 30, 20.10.2009, p. 4973-4979.

Research output: Contribution to journalArticle

Ambrosone, CB, Barlow, WE, Reynolds, W, Livingston, RB, Yeh, IT, Choi, JY, Davis, W, Rae, JM, Tang, L, Hutchins, LR, Ravdin, PM, Martino, S, Osborne, CK, Lyss, AP, Hayes, DF & Albain, KS 2009, 'Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897', Journal of Clinical Oncology, vol. 27, no. 30, pp. 4973-4979. https://doi.org/10.1200/JCO.2009.21.8669
Ambrosone, Christine B. ; Barlow, William E. ; Reynolds, Wanda ; Livingston, Robert B ; Yeh, I. Tien ; Choi, Ji Yeob ; Davis, Warren ; Rae, James M. ; Tang, Li ; Hutchins, Laura R. ; Ravdin, Peter M. ; Martino, Silvana ; Osborne, C. Kent ; Lyss, Alan P. ; Hayes, Daniel F. ; Albain, Kathy S. / Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 30. pp. 4973-4979.
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abstract = "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.",
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T1 - Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897

AU - Ambrosone, Christine B.

AU - Barlow, William E.

AU - Reynolds, Wanda

AU - Livingston, Robert B

AU - Yeh, I. Tien

AU - Choi, Ji Yeob

AU - Davis, Warren

AU - Rae, James M.

AU - Tang, Li

AU - Hutchins, Laura R.

AU - Ravdin, Peter M.

AU - Martino, Silvana

AU - Osborne, C. Kent

AU - Lyss, Alan P.

AU - Hayes, Daniel F.

AU - Albain, Kathy S.

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