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Adjuvant Therapy for HER-2-Positive Early Breast Cancer

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Breast Disease
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Abstract

The discovery of human epidermal growth factor receptor 2 (HER-2/neu) and its role in the biology of breast cancer is one of the most important success stories in the history of breast cancer. The development of HER-2-targeted therapies has changed the natural history of HER-2-positive breast cancer dramatically in the past two decades. Success in the metastatic setting has been subsequently translated into improved clinical outcomes for women with HER-2-positive early-stage breast cancer. Multiple phase III clinical trials including Herceptin Adjuvant (HERA), Finland Herceptin (FinHer), Breast Cancer International Research Group (BCIRG) 006, and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, have demonstrated that trastuzumab in combination with or subsequent to chemotherapy was associated with significant improvements in disease-free and overall survival in patients with HER-2-positive early breast cancer. Thus, the monoclonal antibody trastuzumab has been approved as the first and only molecularly targeted agent for the adjuvant treatment of HER-2-positive breast cancer. Despite tremendous progress in the treatment of HER-2-positive breast cancer, many questions regarding the optimal tailoring of anti-HER-2 therapy remain. Current adjuvant anti-HER-2 therapies need to be refined for different patient subsets with HER-2-positive tumors to provide personalized, effective, and minimally toxic treatment. Additional molecular biomarkers beyond HER-2 are necessary for the identification of low-risk patients who could benefit from less intensive or even no chemotherapy in combination with trastuzumab as well as for the identification of patients with resistance to anti-HER-2 therapy.

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References

  1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–82.

    Article  CAS  Google Scholar 

  2. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14(4):320–68.

    Article  CAS  Google Scholar 

  3. Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312:513–6.

    Article  CAS  Google Scholar 

  4. Verma S, Joy AA, Rayson D, McLeod D, Brezden-Masley C, Boileau JF, et al. HER story: the next chapter in HER-2-directed therapy for advanced breast cancer. Oncologist. 2013;18(11):1153–66.

    Article  CAS  Google Scholar 

  5. Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  Google Scholar 

  6. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659.

    Article  CAS  Google Scholar 

  7. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;(4):CD006243.

    Google Scholar 

  10. Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S. Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist. 2008;13(6):620–30.

    Article  CAS  Google Scholar 

  11. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trails. BMC Cancer. 2007;7:153.

    Article  Google Scholar 

  12. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. 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;25:118–45.

    Article  CAS  Google Scholar 

  13. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.

    Article  Google Scholar 

  14. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER-2 positive breast cancer: a randomized controlled trial. Lancet. 2007;369:29–36.

    Article  CAS  Google Scholar 

  15. Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011;12:236.

    Article  CAS  Google Scholar 

  16. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021–8.

    Article  CAS  Google Scholar 

  17. Perez EA, Romond EH, Suman VJ, Jeong J, Davidson NE, Geyer CE, et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2- positive breast cancer. J Clin Oncol. 2007;25(18S, June 20 Suppl):512.

    Google Scholar 

  18. Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, et al. Four-year follow- up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011;29:3366–73.

    Article  CAS  Google Scholar 

  19. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744–52.

    Article  CAS  Google Scholar 

  20. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354(8):809–20.

    Article  CAS  Google Scholar 

  21. Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009;27:5685–92.

    Article  CAS  Google Scholar 

  22. Pivot X, Romieu G, Bonnefoi H, Pierga J-Y, Kerbrat P, Guastalla J-P, et al. Phare trial results of subset analysis comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. Cancer Res. 2012;72:S5.

    Google Scholar 

  23. Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14:741–8.

    Article  CAS  Google Scholar 

  24. Spielmann M, Roché H, Delozier T, Canon JL, Romieu G, Bourgeois H, et al. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009;27:6129–34.

    Article  CAS  Google Scholar 

  25. Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Herceptin Adjuvant (HERA) Trial Study Team, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195–205.

    Article  CAS  Google Scholar 

  26. Olson EM, Abdel-Rasoul M, Maly J, Wu CS, Lin NU, Shapiro CL. Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann Oncol. 2013;24(6):1526–33.

    Article  CAS  Google Scholar 

  27. Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, Ewer MS, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30:3792–9.

    Article  CAS  Google Scholar 

  28. Russell SD, Blackwell KL, Lawrence J, Pippen JE Jr, Roe MT, Wood F, et al. Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol. 2010;28:3416–21.

    Article  CAS  Google Scholar 

  29. Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P. NCCTG N9831: May 2005 update. Best of ASCO 2005 San Francisco. www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Virtual+Meeting.

  30. Perez EA, Suman VJ, Davidson NE, Gralow J, Kaufman PA, Ingle JN, Dakhil SR, et al. Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer trial. LBA 80, Program and abstracts of the 32nd Annual San Antonio Breast Cancer Symposium; December 2009; San Antonio, Texas. p. 69–80.

    Google Scholar 

  31. Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011;29:4491–7.

    Article  CAS  Google Scholar 

  32. Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M, Jasiowka M, 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.

    Google Scholar 

  33. Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, Santiago A, et al. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol. 2011;29:859–67.

    Article  CAS  Google Scholar 

  34. Burstein HJ, Piccart-Gebhart MJ, Perez EA, Hortobagyi GN, Wolmark N, Albain KS, et al. Choosing the best trastuzumab-based adjuvant chemotherapy regimen: should we abandon anthracyclines? J Clin Oncol. 2012;30(18):2179–82.

    Article  CAS  Google Scholar 

  35. Gianni L, Norton L, Wolmark N, Suter TM, Bonadonna G, Hortobagyi GN. Role of anthracyclines in the treatment of early breast cancer. J Clin Oncol. 2009;27:4798–808.

    Article  Google Scholar 

  36. Pietras RJ, Poen JC, Gallardo D, Wongvipat PN, Lee HJ, Slamon DJ. Monoclonal antibody to HER-2/neu receptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res. 1999;59(6):1347–55.

    CAS  PubMed  Google Scholar 

  37. Halyard MY, Pisansky TM, Dueck AC, Suman V, Pierce L, Solin L, et al. Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. J Clin Oncol. 2009;27(16):2638–44.

    Article  CAS  Google Scholar 

  38. Mavroudis D, Saloustros E, Malamos N, Kakolyris S, Boukovinas I, Papakotoulas P, Breast Cancer Investigators of Hellenic Oncology Research Group (HORG), et al. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2015;26(7):1333–40.

    CAS  PubMed  Google Scholar 

  39. Earl HM, Cameron DA, Miles D, Wardley AM, Ogburn E, Vallier A-L, et al. Persephone: duration of trastuzumab with chemotherapy in patients with HER2 positive early breast cancer: six versus twelve months. J Clin Oncol. 2017;32(Suppl 15):abstract TPS656.

    Article  Google Scholar 

  40. Joensuu H, Fraser J, Wildiers H, Huovinen R, Auvinen P, Utriainen M, et al. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: The SOLD randomized clinical trial. JAMA Oncol. 2018;4(9):1199–206.

    Article  Google Scholar 

  41. Guarneri V, Frassoldati A, Bruzzi P, D’Amico R, Belfiglio M, Molino A, et al. Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2-positive breast cancer (Short-HER Trial; NCT00629278). Clin Breast Cancer. 2008;8(5):453–6.

    Article  CAS  Google Scholar 

  42. Banerjee S, Smith IE. Management of small HER2-positive breast cancers. Lancet Oncol. 2010;11(12):1193–9.

    Article  CAS  Google Scholar 

  43. O’Sullivan CC, Holmes E, Spielmann M, Perez EA, Joensuu H, Costantino JP, et al. The prognosis of small HER2+ breast cancers: a meta-analysis of the randomized trastuzumab trials. Program and abstracts of the 36th annual San Antonio breast cancer symposium December 10–14, 2013, San Antonio, Texas.

    Google Scholar 

  44. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. A phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). Program and abstracts of the 36th Annual San Antonio Breast Cancer Symposium; December 10–14, 2013, San Antonio, Texas.

    Google Scholar 

  45. Tolaney SM, Barry WT, Guo H, Dillon D, Dang CT, Yardley DA, et al. Seven-year(yr) follow-up of adjuvant paclitaxel(T) and trastuzumab(H) (APT trial) for npde-negative, Her2-positive breast cancer (BC). J Clin Oncol. 2017;35(15_suppl):abstr 511.

    Article  Google Scholar 

  46. Goss PE, Smith IE, O’Shaughnessy J, Ejlertsen B, Kaufmann M, Boyle F, et al. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(1):88–96.

    Article  CAS  Google Scholar 

  47. Denduluri N, Chavez-MacGregor M, Telli ML, Eisen A, Graff SL, Hassett MJ, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol. 2018;36(23):2433–43.

    Article  CAS  Google Scholar 

  48. Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, ExteNET Study Group, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367–77.

    Article  CAS  Google Scholar 

  49. Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, ExteNET Study Group, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688–700.

    Article  CAS  Google Scholar 

  50. Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol. 2016;34(10):1034–42.

    Article  CAS  Google Scholar 

  51. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, APHINITY Steering Committee and Investigators, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122–31.

    Article  Google Scholar 

  52. Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN, et al. NSABP B-47 (NRG oncology): phase III randomized controlled trial comparing adjuvant chemotherapy with adriamycin and cyclophosphamide followed by weekly paclitaxel, or docetaxel and cyclophosphamide with or without a year of trastuzumab in women with node-positive or high-risk node-negative invasive breast cancer expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH. 2017 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 6, 2017.

    Google Scholar 

  53. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E, et al. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer. 1992;28A:859–64.

    Article  CAS  Google Scholar 

  54. Loi S. Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy. Oncoimmunology. 2013;2(7):e24720.

    Article  Google Scholar 

  55. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.

    Article  CAS  Google Scholar 

  56. Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012;13(9):869–7.

    Article  CAS  Google Scholar 

  57. Pivot X, Gligorov J, Müller V, Barrett-Lee P, Verma S, Knoop A, et al. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. Lancet Oncol. 2013;14:962–70.

    Article  CAS  Google Scholar 

  58. Slamon DL, Swain SM, Buyse M, Martin M, Geyer CE, Im YH, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1–03.

    Google Scholar 

  59. Liberato NL, Marchetti M, Barosi G. Cost effectiveness of adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2007;25:625–33.

    Article  Google Scholar 

  60. Shiroiwa T, Fukuda T, Shimozuma K, Ohashi Y, Tsutani K. The model-based cost- effectiveness analysis of 1-year adjuvant trastuzumab treatment: based on 2-year follow-up HERA trial data. Breast Cancer Res Treat. 2008;109:559–66.

    Article  CAS  Google Scholar 

  61. Neyt M, Albrecht J, Cocquyt V. An economic evaluation of Herceptin in adjuvant setting: the Breast Cancer International Research Group 006 trial. Ann Oncol. 2006;17:381–90.

    Article  CAS  Google Scholar 

  62. Millar JA, Millward MJ. Cost effectiveness of trastuzumab in the adjuvant treatment of early breast cancer: a lifetime model. PharmacoEconomics. 2007;25:429–42.

    Article  CAS  Google Scholar 

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Basaran, G., Cabuk, D. (2019). Adjuvant Therapy for HER-2-Positive Early Breast Cancer. In: Aydiner, A., Igci, A., Soran, A. (eds) Breast Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-16792-9_9

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