Current Breast Cancer Reports

, Volume 1, Issue 1, pp 5–11

The role of adjuvant anthracyclines for breast cancer treatment: Can we use molecular predictors?

  • Chau Dang
  • Clifford Hudis


Anthracyclines have been widely used in the adjuvant treatment of breast cancer and are part of most adjuvant regimens for the treatment of high-risk disease. The 2000 Early Breast Cancer Trialists Collaborative Group overview of polychemotherapy in breast cancer demonstrated that anthracycline-based regimens are superior to non-anthracycline-based therapies in terms of disease-free and overall survival. However, recently, there has been controversy related to anthracycline based on retrospective analyses which showed that only patients with human epidermal growth factor receptor 2 (HER2)-amplified tumors benefited from anthracyclines. However, caution must be used in basing treatments on retrospective data. HER2 should not be the only target used when considering an anthracycline because there may be other suspected molecular predictors of response, such as topoisomerase II alpha (TOPO II α) gene aberrations (amplifications and deletions), TOPO II α protein overexpression, and DNA repair dysfunction, as well as others as yet undiscovered. Further, TOPO II α gene amplifications and gene deletions have been seen in HER2-negative tumors. This review argues against the use of HER2 as the sole target for predicting response to anthracyclines.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Fisher B, Foster R, Gardner B, et al.: Relation of positive axillary nodes to the prognosis of patients with primary breast cancer. Cancer 1983, 52:1551–1557.PubMedCrossRefGoogle Scholar
  2. 2.
    National Institutes of Health Consensus Development Panel: National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1, 2000. J Natl Cancer Inst Monogr 2001, 93:979–989.Google Scholar
  3. 3.
    Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet 2005, 365:1687–1717.Google Scholar
  4. 4.
    Fisher B, Brown AM, Dimittrov NV, et al.: 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, 8:1483–1496.PubMedGoogle Scholar
  5. 5.
    Henderson IC, Berry DA, Demetri GD, et al.: 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, 21:976–983.PubMedCrossRefGoogle Scholar
  6. 6.
    Mamounas EP, Bryant J, Lembersky BC, et al.: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP-B 28. J Clin Oncol 2005, 23:3686–3696.PubMedCrossRefGoogle Scholar
  7. 7.
    Citron ML, Berry DA, Cirrincione C, et al.: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003, 21:1431–1439.PubMedCrossRefGoogle Scholar
  8. 8.
    Hudis C, Citron M, Berry D, et al.: Five year follow-up of INT C9741: dose-dense chemotherapy is safe and effective [abstract 49]. Breast Cancer Res Treat 2005, 94:S20.Google Scholar
  9. 9.
    Sparano JA, Wang M, Martino S, et al.: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008, 358:1663–1671.PubMedCrossRefGoogle Scholar
  10. 10.
    Martin M, Pienkowski T, Mackey J, et al.: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005, 352:2302–2313.PubMedCrossRefGoogle Scholar
  11. 11.
    Jones SE, Savin MA, Holmes FA, et al.: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006, 24:5381–5387.PubMedCrossRefGoogle Scholar
  12. 12.
    Bonneterre J, Roche H, Kerbrat P, et al.: Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2005, 23:2686–2693.PubMedCrossRefGoogle Scholar
  13. 13.
    Levine MN, Pritchard KI, Bramwell VH, et al.: 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 Trial MA5. J Clin Oncol 2005, 23:5166–5170.PubMedCrossRefGoogle Scholar
  14. 14.
    Roche H, Fumoleau P, Spielmann M, et al.: Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol 2006, 24:5664–5671.PubMedCrossRefGoogle Scholar
  15. 15.
    Martin M, Rodriguez-Lescure A, Ruiz A, et al.: Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst 2008, 100:805–814.PubMedCrossRefGoogle Scholar
  16. 16.
    Di Leo A, Claudino W, Biganzoli L: Why is anthracycline use controversial? Presented at the 2007 Breast Cancer Symposium. San Francisco, CA; September 7–8, 2007.Google Scholar
  17. 17.
    Yamauchi H, Stearns V, Hayes DF: When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol 2001, 19:2334–2356.PubMedGoogle Scholar
  18. 18.
    Pritchard KI, Sheperd LE, O’Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006, 354:2103–2111.PubMedCrossRefGoogle Scholar
  19. 19.
    Gennari A, Sormani MP, Pronzato P, et al.: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008, 100:14–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Burden DA, Osheroff N: Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim Biophys Acta 1998, 1400:139–154.PubMedGoogle Scholar
  21. 21.
    Bartlett JMS, Munro A, Cameron DA, et al.: CType I receptor tyrosine kinase profiles indentify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol 2008, 26:5027–5035.PubMedCrossRefGoogle Scholar
  22. 22.
    Jarvinen TA, Tanner M, Barlund M, et al.: Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Genes Chromosomes Cancer 1999, 26:142–150.PubMedCrossRefGoogle Scholar
  23. 23.
    Jarvinen TA, Tanner M, Rantanen V, et al.: Amplification and deletion of topoisomerase II alpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol 2000, 156:839–847.PubMedGoogle Scholar
  24. 24.
    Di Leo A, Gancberg D, Larsimont D, et al.: HER2 amplification and topoisomerase II alpha 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, 8:1107–1116.PubMedGoogle Scholar
  25. 25.
    Knoop AS, Knudsen H, Balslev E, et al.: 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, 23:7483–7490.PubMedCrossRefGoogle Scholar
  26. 26.
    O’Malley FP, Chia S, Tu D, et al.: Prognostic and predictive value of topoisomerase II alpha in randomized trial comparing CMF to CEF in premenopausal women with node-positive breast cancer (NCIC CTG MA.5). Proc Am Soc Clin Oncol 2006, 24:11s.Google Scholar
  27. 27.
    Slamon D, Eiermann W, Robert N, et al.: BCIRG 006: 2nd interim analysis of phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2 neu positive early breast cancer patients. Breast Cancer Res Treat 2006, 100 (LBA #52).Google Scholar
  28. 28.
    Isaacs RJ, Davies SL, Sandri MI, et al.: Physiological regulation of eukaryotic topoisomerase II. Biochim Biophys Acta 1998, 1400:121–137.PubMedGoogle Scholar
  29. 29.
    Stacey DW, Hitomi M, Chen G: Influence of cell cycle and oncogene activity upon topoisomerase II alpha expression and drug toxicity. Mol Cell Biol 2000, 20:9127–9137.PubMedCrossRefGoogle Scholar
  30. 30.
    Adachi N, Nomoto M, Kohno K, et al.: Cell-cycle regulation of the DNA topoisomerase II alpha promoter is mediated by proximal CCAAT boxes: possible involvement of acetylation. Gene 2000, 245:49–57.PubMedCrossRefGoogle Scholar
  31. 31.
    Goswami PC, Sheren J, Albee LD, et al.: Cell cycle-coupled variation in topoisomerase II alpha mRNA is regulated by the 3′-untranslated region. Possible role of redox-sensitive protein binding in mRNA accumulation. J Biol Chem 2000, 75:38384–38392.CrossRefGoogle Scholar
  32. 32.
    Durbecq V, Desmed C, Paesmans M, et al.: Correlation between topoisomerase-II alpha gene amplification and protein expression in HER2 amplified breast cancer. Int J Oncol 2004, 25:1473–1479.PubMedGoogle Scholar
  33. 33.
    Mueller RE, Parkes RK, Andrulis I, et al.: Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples. Genes Chromosomes Cancer 2004, 39:288–297.PubMedCrossRefGoogle Scholar
  34. 34.
    Jarvinen TA, Kononen J, Pelto-Huikko M, et al.: Expression of topoisomerase II alpha is associated with rapid cell proliferation, aneuploidy, and c-ErbB2 overexpression in breast cancer. Am J Pathol 1996, 148:2073–2082.PubMedGoogle Scholar
  35. 35.
    Nakopoulou L, Lazaris AC, Kavantzas N, et al.: DNA topoisomerase II-alpha immunoreactivity as a marker of tumor aggressiveness in invasive breast cancer. Pathobiology 2000, 68:137–143.PubMedCrossRefGoogle Scholar
  36. 36.
    Di Leo A, Larsimont D, Gancberg D, et al.: HER-2 and topo-isomerase II-alpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Ann Oncol 2001, 12:1081–1089.PubMedCrossRefGoogle Scholar
  37. 37.
    Durbecq V, Paesmans M, Cardoso F, et al.: Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther 2004, 3:1207–1214.PubMedGoogle Scholar
  38. 38.
    Fedier A, Steiner RA, Schwarz VA, et al.: The effect of loss of BRCA1 on the sensitivity of anticancer agents in P53- deficient cells. Int J Oncol 2003, 22:1169–1173.PubMedGoogle Scholar
  39. 39.
    Chappuis PO, Goffin J, Wong N, et al.: A significant response to neoadjuvant chemotherapy in BRCA1/2 related breast cancer. J Med Genet 2002, 39:608–610.PubMedCrossRefGoogle Scholar
  40. 40.
    Rakha EA, Reis-Filho JS, Ellis IO: Basal-like breast cancer: a critical review. J Clin Oncol 2008, 26:2568–2581.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Chau Dang
    • 1
  • Clifford Hudis
  1. 1.Department of Medicine, Memorial Sloan-Kettering Cancer CenterBreast Cancer Medicine ServiceNew YorkUSA

Personalised recommendations