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The Double-Edged Sword: Controversies in Anthracycline-Based Chemotherapy for Breast Cancer

  • Systemic Therapies (M Liu and T Haddad, Section Editors)
  • Published:
Current Breast Cancer Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review article seeks to summarize the existent literature regarding the use of anthracyclines (specifically doxorubicin) in the treatment of early-stage breast cancers, reviewing the clinically significant side effects of said therapy, and discussing new tools to risk stratify patients.

Recent Findings

The 2010 Early Breast Cancer Trialists’ Cooperative Group meta-analysis again found anthracycline-containing regimens to improve outcomes, while the ABC Trials have shown the superiority of regimens including doxorubicin versus regimens with docetaxel and cyclophosphamide alone in early-stage breast cancer. New risk stratification tools—such as Oncotype DX®—are helping oncologists decide which patients may be able to avoid chemotherapy.

Summary

Sequential doxorubicin/cyclophosphamide therapy, followed by treatment with docetaxel, improves outcomes in nearly all early-stage breast cancer, with the notable exception of Her2+ disease. Newer risk stratification tools allow better risk/reward calculations in which patients may be able to avoid anthracycline-based chemotherapy and its significant side effects.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. American Cancer Society. Breast Cancer Facts & Figures 2015–2016. Atlanta: American Cancer Society Inc. 2015.

  2. Cancer of the Breast (Female) - Cancer Stat Facts. NIH - National Cancer Institute. Available at https://seer.cancer.gov/statfacts/html/breast.html. Accessed 7/1/17.

  3. Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). NEJM. 1948;238(23):787–93.

    Article  CAS  PubMed  Google Scholar 

  4. Wright JC, Prigot A, Wright BP, Weintraub S, Wright LT. An evaluation of folic acid antagonists in adults with neoplastic diseases. J Natl Med Assoc. 1951;43(4):211–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Fisher B, Ravdin RG, Ausman RK, Slack NH, Moore GE, Noer RJ. Surgical adjuvant chemotherapy in cancer of the breast: results of a decade of cooperative investigation. Ann Surg. 1968;168(3):337–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Grelin A, Spella C, Di Marco A, Canevazzi G. Descrizione e classificazione di un attionamicette (Streptomyces Peucetius sp nova) produltore di un sostanza ad attivite antitumorale; La daunomicina. Giorn Microbio. 1963;11:109–18.

    Google Scholar 

  7. Dubost M, Gauter P, Maral R, et al. Un novel antibiotique a proprietes cytostatiques; la rubidomycine. CR Acad Sci Paris. 1963;257:1813–5.

    CAS  Google Scholar 

  8. Jacquillat C, Boiron M, Weil M, Tanzer J, Najean Y, Bernard J. Rubidomycin: a new agent active in the treatment of acute lymphoblastic leukaemia. Lancet. 1966;2(7453):27–8.

    Article  CAS  PubMed  Google Scholar 

  9. Lefrak EA, Pitha J, Rosenheim S, et al. A clinicopathological analysis of adriamycin cardiotoxicity. Cancer. 1973;32:302–14.

    Article  CAS  PubMed  Google Scholar 

  10. Arcamone F, Cassinelli G, Fantini G, et al. Adriamycin, 14-hydroxydaimomycin, a new antitumor antibiotic from S. Peucetius var. caesius. Biotechn Bioengin. 1969;11(6):1101–10.

    Article  CAS  Google Scholar 

  11. Arcamone F, Penco S, Vigevani A, et al. Synthesis and antitumor properties of new glycosides of daunomycinone and adriamycinone. J Med Chem. 1975;18:703–7.

    Article  CAS  PubMed  Google Scholar 

  12. French Epirubicin Study Group [no authors listed]. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. French Epirubicin Study Group. J Clin Oncol 1988;6(4):679–688.

  13. Ventura GJ. Cardiotoxicity of epirubicin versus doxorubicin: cost and clinical results. J Clin Oncol. 2005;23(12):2873–3.

  14. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976;294:405–10.

  15. Brambilla C, Valagussa P, Bonadonna G. Sequential combination chemotherapy in advanced breast cancer. Cancer Chemother Pharmacol. 1978;1(1):35–9.

    Article  CAS  PubMed  Google Scholar 

  16. Fisher B, Brown AM, Dimitrov 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(9):1483–96.

    Article  CAS  PubMed  Google Scholar 

  17. Mansour EG, Gray R, Shatila AH, Tormey DC, Cooper MR, Osborne CK, et al. Survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: ten-year analysis—an intergroup study. J Clin Oncol. 1998;16:3486–92.

    Article  CAS  PubMed  Google Scholar 

  18. Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997;89:1673–82.

    Article  CAS  PubMed  Google Scholar 

  19. Adjuvant therapy for breast cancer. NIH Consens Statement 2000; 17(4): 1–23.

  20. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet. 1998;352:930–42.

    Article  Google Scholar 

  21. Nabholtz JM, Gelmon K, Bontenbal M, et al. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 1996;14(6):1858–67.

    Article  CAS  PubMed  Google Scholar 

  22. Giordano SH, Lin YL, Kuo YF, Hortobagyi GN, Goodwin JS. Decline in the use of anthracyclines for breast cancer. J Clin Oncol. 2012;30(18):2232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984;226(4673):466–8.

    Article  CAS  PubMed  Google Scholar 

  24. Davies KJ, Doroshow JH. Redox cycling of anthracyclines by cardiac mitochondria I. Anthracycline radical formation by NADH dehydrogenase. J Biol Chem. 1986;261(7):3060–7.

    CAS  PubMed  Google Scholar 

  25. Sawyer DB, Peng X, Chen B, Pentassuglia L, Lim CC. Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis. 2010;53(2):105–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000;22(4):263–302.

    Article  CAS  PubMed  Google Scholar 

  27. Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7(4):214–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710–7.

  29. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin. Cancer. 2003;97(11):2869–79.

    Article  CAS  PubMed  Google Scholar 

  30. Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104:1293–305.

  31. Alexander J, Dainiak N, Berger HJ, et al. Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med. 1979;300(6):278–83.

    Article  CAS  PubMed  Google Scholar 

  32. Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol. 2007;25:3808–15.

    Article  CAS  PubMed  Google Scholar 

  33. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342(15):1077–84.

  34. Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2017;35(8):893–911.

    Article  PubMed  Google Scholar 

  35. Foss AA, Andersen A, Nome O, et al. Long-term risk of second malignancy after treatment of Hodgkin’s disease: the influence of treatment, age and follow-up time. Ann Oncol. 2002;13(11):1786–91.

    Article  Google Scholar 

  36. Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin Oncol. 2008;35(4):418–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smith RE, Bryant J, DeCillis A, Anderson S. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol. 2003;21:1195–204.

    Article  CAS  PubMed  Google Scholar 

  38. Praga C, Bergh J, Bliss J, et al. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol. 2005;23:4179–91.

    Article  CAS  PubMed  Google Scholar 

  39. Kantarjian HM, Keating MJ, Walters RS, Smith TL, Cork A, McCredie KB, et al. Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features. J Clin Oncol. 1986;4:1748–57.

  40. Klimek VM. Recent advances in the management of therapy-related myelodysplastic syndromes and acute myeloid leukemia. Curr Opin Hematol. 2013;20(2):137–43.

    Article  CAS  PubMed  Google Scholar 

  41. Le Deley MC, Suzan F, Cutuli B, et al. Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol. 2007;25:292–300.

    Article  PubMed  Google Scholar 

  42. AJCC (American Joint Committee on Cancer). Cancer staging manual, 7th edition, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer-Verlag, New York 2010.

  43. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003;100(14):8418–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Vulsteke C, Pfeil AM, Maggen C, Schwenkglenks M, Pettengell R, Szucs TD, et al. Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients. Breast Cancer Res Treat. 2015;152(1):67–76.

    Article  CAS  PubMed  Google Scholar 

  47. Lotrionte M, Biondi-Zoccai G, Abbate A, Lanzetta G, D’Ascenzo F, Malavasi V, et al. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol. 2013;112(12):1980–4.

  48. Migrino RQ, Aggarwal D, Konorev E, Brahmbhatt T, Bright M, Kalyanaraman B. Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography. Ultrasound Med Biol. 2008;34(2):208–14.

    Article  PubMed  Google Scholar 

  49. Kang Y, Xu X, Cheng L, et al. Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. Eur J Heart Fail. 2014;16(3):300–8.

    Article  CAS  PubMed  Google Scholar 

  50. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817–26.

    Article  CAS  PubMed  Google Scholar 

  51. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726–34.

    Article  CAS  PubMed  Google Scholar 

  52. • Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005–14. Prospective validation of using Oncotype DX to decide in which women to withhold chemo

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sestak I, Dowsett M, Zabaglo L, et al. Factors predicting late recurrence for estrogen receptor-positive breast cancer. J Natl Cancer Inst. 2013;105(19):1504–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(10):1134–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Drukker CA, Bueno-de-Mesquita JM, Retèl VP, et al. A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study. Int J Cancer. 2013;133(4):929–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Krop I, Ismaila N, Andre F, Bast RC, Barlow W, Collyar DE, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline focused update. J Clin Oncol. 2017;35(24):2838–47.

    Article  PubMed  Google Scholar 

  57. AJCC (American Joint Committee on Cancer). In: Amin MB, Edge SB, Greene FL, et al., editors. Cancer staging manual. 8th ed. Chicago: Springer; 2017.

    Google Scholar 

  58. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717.

    Article  Google Scholar 

  59. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet. 2012;379(9814):432–44.

    Article  Google Scholar 

  60. LN Shulman CT, Cirrincione DA, Berry BHP, Perez EA, O’Regan R, et al. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to 4 cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012;30(33):4071–6.

    Article  Google Scholar 

  61. Jones S, Holmes FA, O’Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol. 2009;27(8):1177–83.

    Article  CAS  PubMed  Google Scholar 

  62. •• Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, et al. Anthracyclines in early breast cancer: the ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017:JCO2016714147. Compared TAC (various administration regimens) vs TC. Found superiority in regimens w/A.

  63. • Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martin M, Chan A. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016;27(6):1041–7. Review of the study comparing concurrent TAC to sequential AC-T in Her2(-), lymph-node positive therapy. Stated no difference between the two regimens in terms of outcomes, though the actual amount of docetaxel differed in the two arms

    Article  CAS  PubMed  Google Scholar 

  64. Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, et al. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst. 2008;100(2):121–33.

    Article  CAS  PubMed  Google Scholar 

  65. Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010;362(22):2053–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Slamon DJ, Eiermann W, Robert NJ, et al: Ten-year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2-positive early breast cancer patients. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 11, 2015.

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  1. Division of Geriatrics, University of Pittsburgh Medical Center Presbyterian, Pittsburgh, PA, USA

    Karthik J Kota

  2. Division of Hematology-Oncology, University of Pittsburgh Medical Center Magee, Pittsburgh, PA, USA

    Adam M Brufsky

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Kota, K.J., Brufsky, A.M. The Double-Edged Sword: Controversies in Anthracycline-Based Chemotherapy for Breast Cancer. Curr Breast Cancer Rep 9, 210–216 (2017). https://doi.org/10.1007/s12609-017-0254-7

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