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PMID: 19620488 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology ·Vol. 27 ·No. 24 ·2009-08-20 ·Pages 3881-6

Tubbs R, Barlow WE, Budd GT, Swain E, Porter P, Gown A, Yeh IT, Sledge G, Shapiro C, Ingle J, Haskell C, Albain KS, Livingston R, Hayes DF

Abstract

Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C). TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533). An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio > or = 4.0). Survival was not associated with low-level HER2 amplification (ratio > or = 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio > or = 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size. In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.

MeSH Terms
Antigens, Neoplasm/analysis,genetics Breast Neoplasms/chemistry,drug therapy,genetics Chemotherapy, Adjuvant Chromosomes, Human, Pair 17 DNA Topoisomerases, Type II/analysis,genetics DNA-Binding Proteins/analysis,genetics Doxorubicin/therapeutic use Female Gene Amplification Gene Dosage Humans Immunohistochemistry In Situ Hybridization, Fluorescence Neoplasm Staging Poly-ADP-Ribose Binding Proteins Receptor, ErbB-2/analysis,genetics Tissue Array Analysis Treatment Outcome
Chemicals
Antigens, Neoplasm DNA-Binding Proteins Poly-ADP-Ribose Binding Proteins Doxorubicin ERBB2 protein, human Receptor, ErbB-2 DNA Topoisomerases, Type II TOP2A protein, human
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Tubbs Raymond
Department of Molecular Pathology, Cleveland Clinic, Cleveland, OH 44195, USA. [email protected]
Barlow William E
Budd G Thomas
Swain Eric
Porter Peggy
Gown Allen
Yeh I-Ten
Sledge George
Shapiro Charles
Ingle James
Haskell Charles
Albain Kathy S
Livingston Robert
Hayes Daniel F
References (32)
32 references, click to expand
  1. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22.
    J Clin Oncol. 1997 May;15(5):1858-69 PMID: 9164196
  2. retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group.
    J Clin Oncol. 2005 Oct 20;23(30):7483-90 PMID: 16234514
  3. HER-2 and topoisomerase II as predictors of response to chemotherapy.
    J Clin Oncol. 2008 Feb 10;26(5):736-44 PMID: 18258981
  4. Simultaneous amplification of HER-2 (ERBB2) and topoisomerase IIalpha (TOP2A) genes--molecular basis for combination chemotherapy in cancer.
    Curr Cancer Drug Targets. 2006 Nov;6(7):579-602 PMID: 17100565
  5. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
    Lancet. 2005 May 14-20;365(9472):1687-717 PMID: 15894097
  6. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy.
    J Clin Oncol. 2011 Mar 1;29(7):859-67 PMID: 21189395
  7. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas.
    J Clin Oncol. 1997 Aug;15(8):2894-904 PMID: 9256133
  8. The 17q12-q21 amplicon: Her2 and topoisomerase-IIalpha and their importance to the biology of solid tumours.
    Cancer Treat Rev. 2007 Feb;33(1):64-77 PMID: 17113234
  9. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5.
    J Clin Oncol. 2005 Aug 1;23(22):5166-70 PMID: 16051958
  10. Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313).
    J Clin Oncol. 2007 Feb 20;25(6):656-61 PMID: 17308269
  11. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.
    J Clin Oncol. 2007 Jan 1;25(1):118-45 PMID: 17159189
  12. Breast cancer and aneusomy 17: implications for carcinogenesis and therapeutic response.
    Lancet Oncol. 2009 Mar;10(3):267-77 PMID: 19261255
  13. HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil.
    Clin Cancer Res. 2002 May;8(5):1107-16 PMID: 12006526
  14. HER-2 and topo-isomerase IIalpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide.
    Ann Oncol. 2001 Aug;12(8):1081-9 PMID: 11583189
  15. p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy.
    J Natl Cancer Inst. 2006 Dec 6;98(23):1723-31 PMID: 17148774
  16. The value of TOP2A gene copy number variation as a biomarker in breast cancer: Update of DBCG trial 89D.
    Acta Oncol. 2008;47(4):725-34 PMID: 18465341
  17. Topoisomerase II alpha as a marker predicting the efficacy of anthracyclines in breast cancer: are we at the end of the beginning?
    Clin Breast Cancer. 2003 Aug;4(3):179-86 PMID: 14499010
  18. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer.
    J Clin Oncol. 2003 Mar 15;21(6):976-83 PMID: 12637460
  19. An approach to the validation of novel molecular markers of breast cancer via TMA-based FISH scanning.
    J Mol Histol. 2007 May;38(2):141-50 PMID: 17211577
  20. Reporting recommendations for tumor marker prognostic studies (REMARK).
    J Natl Cancer Inst. 2005 Aug 17;97(16):1180-4 PMID: 16106022
  21. Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial.
    J Clin Oncol. 2008 Nov 1;26(31):5027-35 PMID: 18768436
  22. Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.
    J Clin Oncol. 1999 Nov;17(11):3374-88 PMID: 10550131
  23. HER2 and responsiveness of breast cancer to adjuvant chemotherapy.
    N Engl J Med. 2006 May 18;354(20):2103-11 PMID: 16707747
  24. High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system.
    Mod Pathol. 2008 Oct;21(10):1271-7 PMID: 18487992
  25. Fluorescence in situ hybridization (FISH) as primary methodology for the assessment of HER2 Status in adenocarcinoma of the breast: a single institution experience.
    Diagn Mol Pathol. 2007 Dec;16(4):207-10 PMID: 18043283
  26. Changes of topoisomerase IIalpha expression in breast tumors after neoadjuvant chemotherapy predicts relapse-free survival.
    Clin Cancer Res. 2006 Mar 1;12(5):1501-6 PMID: 16533774
  27. Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401.
    J Clin Oncol. 2006 Jun 1;24(16):2428-36 PMID: 16682728
  28. Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer.
    Int J Oncol. 2004 Jan;24(1):201-9 PMID: 14654958
  29. Topoisomerase IIalpha gene amplification and response to anthracycline-containing adjuvant chemotherapy in breast cancer.
    J Clin Oncol. 2006 Jun 1;24(16):2409-11 PMID: 16682721
  30. Topoisomerase II-alpha (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy.
    Eur J Cancer. 2003 Mar;39(5):631-4 PMID: 12628842
  31. An evaluation of cytotoxicity of the taxane and platinum agents combination treatment in a panel of human ovarian carcinoma cell lines.
    Gynecol Oncol. 2005 Jul;98(1):141-5 PMID: 15963813
  32. The incidence of topoisomerase II-alpha genomic alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 gene amplification: a fluorescence in situ hybridization study.
    Hum Pathol. 2005 Apr;36(4):348-56 PMID: 15891995
Article Info
Journal
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Abbr.
J Clin Oncol
ISSN
1527-7755
DOI
10.1200/JCO.2008.20.1566
Email
[email protected]
Published
2009-08-20
Epub
2009-00-20
Pages
3881-6
Language
English
Region
United States
NLM ID
8309333
PMCID
PMC2734394
Subset
IM
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NCI NIH HHS · CA22433 · United States
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NCI NIH HHS · N01 CA027057 · United States
NCI NIH HHS · U10 CA046441 · United States
NCI NIH HHS · U10 CA045377 · United States
NCI NIH HHS · CA35192 · United States
NCI NIH HHS · CA74647 · United States
NCI NIH HHS · U10 CA020319 · United States
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NCI NIH HHS · U10 CA038926 · United States
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NCI NIH HHS · U10 CA035431 · United States
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Corrections
CommentIn
PMID: 19620479
External Links
PubMed source DOI: 10.1200/JCO.2008.20.1566 PMC Full Text View journal details
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