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PMID: 21189395 Published · ppublish English Clinical Trial, Phase III Comparative Study 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.

Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology ·Vol. 29 ·No. 7 ·2011-03-01 ·Pages 859-67

Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, Santiago A, Villalobos IE, Eiermann W, Pienkowski T, Martin M, Robert N, Crown J, Bee V, Taupin H, Flom KJ, Tabah-Fisch I, Pauletti G, Lindsay MA, Riva A, Slamon DJ

Abstract

Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers. A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined. Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P = .0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P = .004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification. In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought.

MeSH Terms
Adult Aged Anthracyclines/administration & dosage Antigens, Neoplasm/drug effects,genetics Antineoplastic Combined Chemotherapy Protocols/administration & dosage Breast Neoplasms/drug therapy,genetics,mortality DNA Topoisomerases, Type II/drug effects,genetics DNA-Binding Proteins/drug effects,genetics Disease-Free Survival Female Gene Amplification/drug effects Gene Expression Regulation, Neoplastic Genes, erbB-2/drug effects Genetic Predisposition to Disease Humans In Situ Hybridization, Fluorescence Middle Aged Poly-ADP-Ribose Binding Proteins Prognosis Proportional Hazards Models Risk Assessment Statistics, Nonparametric Survival Analysis Treatment Outcome
Chemicals
Anthracyclines Antigens, Neoplasm DNA-Binding Proteins Poly-ADP-Ribose Binding Proteins DNA Topoisomerases, Type II TOP2A protein, human
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Press Michael F
Norris Comprehensive Cancer Center, University of Southern California, CA, USA. [email protected]
Sauter Guido
Buyse Marc
Bernstein Leslie
Guzman Roberta
Santiago Angela
Villalobos Ivonne E
Eiermann Wolfgang
Pienkowski Tadeusz
Martin Miguel
Robert Nicholas
Crown John
Bee Valerie
Taupin Henry
Flom Kerry J
Tabah-Fisch Isabelle
Pauletti Giovanni
Lindsay Mary-Ann
Riva Alessandro
Slamon Dennis J
References (63)
63 references, click to expand
  1. Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601).
    Lancet Oncol. 2010 Mar;11(3):266-74 PMID: 20079691
  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. HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15.
    J Natl Cancer Inst. 2000 Dec 20;92(24):1991-8 PMID: 11121461
  4. Trastuzumab cardiac side effects: only time will tell.
    J Clin Oncol. 2005 Nov 1;23(31):7775-6 PMID: 16258081
  5. HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients.
    J Clin Oncol. 2010 Feb 20;28(6):984-90 PMID: 20038724
  6. Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients.
    J Clin Oncol. 2005 Jul 1;23(19):4287-97 PMID: 15994142
  7. Topoisomerase IIalpha gene (TOP2A) amplification and deletion in cancer--more common than anticipated.
    Cytopathology. 2003 Dec;14(6):309-13 PMID: 14632727
  8. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer.
    J Natl Cancer Inst. 1998 Sep 16;90(18):1361-70 PMID: 9747867
  9. HER-2/neu and topoisomerase IIalpha in breast cancer.
    Breast Cancer Res Treat. 2003 Apr;78(3):299-311 PMID: 12755489
  10. HER2 overexpression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: long-term results.
    Clin Breast Cancer. 2005 Aug;6(3):253-9 PMID: 16137437
  11. HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer.
    J Clin Oncol. 2003 Feb 1;21(3):458-62 PMID: 12560435
  12. Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens.
    J Clin Oncol. 2002 Jul 15;20(14):3095-105 PMID: 12118023
  13. Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy.
    J Natl Cancer Inst. 2007 Feb 7;99(3):196-205 PMID: 17284714
  14. Comparison of topoisomerase-IIalpha gene status between primary breast cancer and corresponding distant metastatic sites.
    Breast Cancer Res Treat. 2003 Feb;77(3):199-204 PMID: 12602919
  15. 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
  16. Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene.
    Mol Cell Biol. 1987 May;7(5):2019-23 PMID: 3299059
  17. Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials.
    Clin Cancer Res. 2005 Sep 15;11(18):6598-607 PMID: 16166438
  18. 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
  19. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31.
    J Clin Oncol. 2005 Nov 1;23(31):7811-9 PMID: 16258083
  20. CMF vs alternating CMF/EV in the adjuvant treatment of operable breast cancer. A single centre randomised clinical trial (Naples GUN-3 study).
    Br J Cancer. 1995 Jun;71(6):1283-7 PMID: 7779724
  21. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials.
    J Natl Cancer Inst. 2008 Jan 2;100(1):14-20 PMID: 18159072
  22. HER-2 and topoisomerase II as predictors of response to chemotherapy.
    J Clin Oncol. 2008 Feb 10;26(5):736-44 PMID: 18258981
  23. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design.
    Br J Cancer. 1976 Dec;34(6):585-612 PMID: 795448
  24. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.
    J Clin Oncol. 1998 Aug;16(8):2651-8 PMID: 9704715
  25. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17.
    Genomics. 1995 Aug 10;28(3):367-76 PMID: 7490069
  26. Herceptin and the heart--a molecular modifier of cardiac failure.
    N Engl J Med. 2006 Feb 23;354(8):789-90 PMID: 16495390
  27. Are HER2 and TOP2A useful as prognostic or predictive biomarkers for anthracycline-based adjuvant chemotherapy for breast cancer?
    J Clin Oncol. 2009 Aug 20;27(24):3875-6 PMID: 19620479
  28. HER2 and responsiveness of breast cancer to adjuvant chemotherapy.
    N Engl J Med. 2006 May 18;354(20):2103-11 PMID: 16707747
  29. 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
  30. Selection of a subpopulation with fewer DNA topoisomerase II alpha gene copies in a doxorubicin-resistant cell line panel.
    Br J Cancer. 1996 Aug;74(4):502-7 PMID: 8761362
  31. Topoisomerase II alpha co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity.
    Oncogene. 1993 Apr;8(4):933-8 PMID: 8096076
  32. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial.
    J Clin Oncol. 2011 Oct 10;29(29):3877-84 PMID: 21911726
  33. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer.
    J Natl Cancer Inst. 1998 Sep 16;90(18):1346-60 PMID: 9747866
  34. Adenovirus-mediated human topoisomerase IIalpha gene transfer increases the sensitivity of etoposide-resistant human breast cancer cells.
    Cancer Res. 1999 Sep 15;59(18):4618-24 PMID: 10493516
  35. Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab.
    Clin Breast Cancer. 2005 Aug;6(3):240-6 PMID: 16137435
  36. Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study.
    J Clin Oncol. 2005 Dec 1;23(34):8597-605 PMID: 16314622
  37. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells.
    Oncogene. 1997 Jul 31;15(5):537-47 PMID: 9247307
  38. Amplification and overexpression of topoisomerase IIalpha predict response to anthracycline-based therapy in locally advanced breast cancer.
    Clin Cancer Res. 2002 Apr;8(4):1061-7 PMID: 11948114
  39. Topoisomerase II{alpha} amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in HER2-amplified early breast cancer: results of CALGB 8541/150013.
    J Clin Oncol. 2009 Jul 20;27(21):3430-6 PMID: 19470942
  40. Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience.
    J Clin Oncol. 1989 May;7(5):572-82 PMID: 2651576
  41. Two distinct amplified regions at 17q11-q21 involved in human primary breast cancer.
    Cancer Res. 1996 Sep 1;56(17):3886-90 PMID: 8752152
  42. Co-amplification of erbB2, topoisomerase II alpha and retinoic acid receptor alpha genes in breast cancer and allelic loss at topoisomerase I on chromosome 20.
    Eur J Cancer. 1993;29A(10):1469-75 PMID: 8104440
  43. Human DNA topoisomerase II: biochemistry and role in chemotherapy resistance (review).
    Anticancer Res. 1996 Jul-Aug;16(4A):1867-80 PMID: 8712715
  44. Anthracyclines and the tailoring of treatment for early breast cancer.
    N Engl J Med. 2006 May 18;354(20):2177-9 PMID: 16707755
  45. TOP2A and HER-2 gene amplification in fine needle aspirates from breast carcinomas.
    Cytopathology. 2003 Dec;14(6):314-9 PMID: 14632728
  46. Amplification of HER2 and TOP2A and deletion of TOP2A genes in breast cancer investigated by new FISH probes.
    Acta Oncol. 2004;43(1):35-42 PMID: 15068318
  47. Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations.
    J Clin Oncol. 2009 Mar 10;27(8):1323-33 PMID: 19204209
  48. Identification of genetic changes associated with drug resistance by reverse in situ hybridization.
    Br J Cancer. 1997;75(2):275-82 PMID: 9010038
  49. 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
  50. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
    N Engl J Med. 2001 Mar 15;344(11):783-92 PMID: 11248153
  51. Interphase cytogenetic analysis of erbB2 and topoII alpha co-amplification in invasive breast cancer and polysomy of chromosome 17 in ductal carcinoma in situ.
    Int J Cancer. 1995 Feb 20;64(1):18-26 PMID: 7665243
  52. Amplification and deletion of topoisomerase IIalpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer.
    Am J Pathol. 2000 Mar;156(3):839-47 PMID: 10702400
  53. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15.
    J Clin Oncol. 1990 Sep;8(9):1483-96 PMID: 2202791
  54. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy.
    J Natl Cancer Inst. 2009 May 6;101(9):644-50 PMID: 19401546
  55. Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study.
    Eur J Cancer. 2002 Nov;38(17):2279-88 PMID: 12441265
  56. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer.
    N Engl J Med. 1994 May 5;330(18):1260-6 PMID: 7908410
  57. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer.
    J Clin Oncol. 2007 Sep 1;25(25):3808-15 PMID: 17664460
  58. 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
  59. Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA.
    Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3231-5 PMID: 8386368
  60. Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer.
    Genes Chromosomes Cancer. 1999 Oct;26(2):142-50 PMID: 10469452
  61. 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
  62. Adjuvant trastuzumab in HER2-positive breast cancer.
    N Engl J Med. 2011 Oct 6;365(14):1273-83 PMID: 21991949
  63. Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status.
    J Clin Oncol. 2009 Aug 20;27(24):3881-6 PMID: 19620488
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.2009.27.5644
Email
[email protected]
Published
2011-03-01
Epub
2010-00-28
Pages
859-67
Language
English
Region
United States
NLM ID
8309333
PMCID
PMC3068060
Subset
IM
Grants
NCI NIH HHS · R01 CA048780 · United States
NCI NIH HHS · R01 CA077398 · United States
NCI NIH HHS · CA48780 · United States
NCI NIH HHS · CA77398 · United States
Corrections
CommentIn
PMID: 21670460
External Links
PubMed source DOI: 10.1200/JCO.2009.27.5644 PMC Full Text View journal details
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