Skip to main content

Advertisement

Log in

Dual Targeting of Human Epidermal Growth Factor Receptor 2 (HER2) in Neoadjuvant Trials for Operable HER2 Positive (HER2+) Disease

  • Clinical Trials (MN Dickler, Section Editor)
  • Published:
Current Breast Cancer Reports Aims and scope Submit manuscript

Abstract

The neoadjuvant strategy, initially developed to render primary inoperable tumors operable, is now increasingly being utilized for patients with triple-negative and HER2 positive breast cancer in clinical trials in order to assess for response and resistance with the incorporation of tissue biopsy studies. Pathological complete response (pCR) has been accepted as a primary endpoint in a number of neoadjuvant trials for operable HER2+ disease. This article provides a comprehensive summary of the knowledge gained from neoadjuvant trials conducted with HER2 directed agents to date, focuses on the concept of dual blockade of HER2, highlights the importance of predictive biomarkers, and finally puts them into perspective with current treatment recommendations and future research and trends.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  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;235:177–82.

    Google Scholar 

  2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    Article  PubMed  CAS  Google Scholar 

  3. Ocana A, Cruz JJ, Pandiella A. Trastuzumab and antiestrogen therapy: focus on mechanisms of action and resistance. Am J Clin Oncol. 2006;29:90–5.

    Article  PubMed  CAS  Google Scholar 

  4. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39–51.

    Article  PubMed  CAS  Google Scholar 

  5. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.

    Google Scholar 

  6. 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;365:1273–83.

    Google Scholar 

  7. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    Article  PubMed  Google Scholar 

  8. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778–85.

    Google Scholar 

  9. Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant vs adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:188–94.

    Article  PubMed  Google Scholar 

  10. Guarneri V, Broglio K, Kau SW, Cristofanilli M, Buzdar AU, Valero V, et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol. 2006;24:1037–44.

    Google Scholar 

  11. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25:4414–22.

    Google Scholar 

  12. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol. 1999;17:460–9.

    Google Scholar 

  13. Carey LA, Metzger R, Dees EC, Collichio F, Sartor CI, Ollila DW, et al. American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst. 2005;97:1137–42.

    Google Scholar 

  14. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784–92.

    Google Scholar 

  15. Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003;21:4165–74.

    Google Scholar 

  16. Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, et al. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol. 2005;23:5983–92.

    Google Scholar 

  17. von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol. 2010;28:2015–23.

    Google Scholar 

  18. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab vs neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomized controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377–84.

    Google Scholar 

  19. Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol. 2010;28:2024–31.

    Google Scholar 

  20. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11:5678–85.

    Google Scholar 

  21. von Minckwitz G, Untch M, Blohmer J-U, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;15:1796–804.

    Google Scholar 

  22. Cortazar PZ, Untch M, Mehta K, Costantino J, Wolmark N, Bonnefoi H, et al. Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). Poster presentation at the Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symposium-- Dec 4–8, 2012; San Antonio, TX. Cancer Res. 2012;72(Suppl 3).

  23. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005;23:3676–85.

    Google Scholar 

  24. Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007;13:228–33.

    Google Scholar 

  25. Buzdar AS, Meric-Bernstam V, Leitch F, Ellis M, Boughey M, Unzeitig J, et al. ACOSOG Z1041 (Alliance): definitive analysis of randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC - P + T) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (P + T - FEC + T) in HER2+ operable breast cancer. Oral presentation; ASCO Annual meeting. J Clin Oncol. 2013;31(Suppl; Abstr 502).

  26. Gianni LE, Semiglazov W, Manikhas V, Lluch A, Tjulandin A, Zambetti S, et al. Follow-up results of NOAH, a randomized phase III trial evaluating neoadjuvant chemotherapy with trastuzumab (CT + H) followed by adjuvant H vs CT alone, in patients with HER2-positive locally advanced breast cancer. Oral presentation; ASCO Annual Meeting; 2013. J Clin Oncol. 2013;31(Suppl; Abstr 503).

  27. Romond ES, Jeong VJ, Sledge Jr JH, Geyer Jr GW, Martino CE, Rastogi S, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. SABCS Annual Meeting; 2012.

  28. Goldhirsch AP-G, Procter MJ, Azambuja M, Weber E, Untch HA, Smith M, et al. The HERA Study Team, HERA TRIAL: 2 years vs 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow-up. SABCS Annual Meeting; 2012. Cancer Res. 2012;72(Suppl 3).

  29. • Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med. 2012;366:2438–41. The FDA released outlined a pathway to accelerated approval for neoadjuvant breast therapies and using pCR as a surrogate endpoint for accelerated approval.

  30. • Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, et al. Lapatinib vs trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomized phase 3 trial. Lancet Oncol. 2012;13:135–44. This trial was a direct comparison of lapatinib and trastuzumab in the neoadjuvant setting.

  31. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9:463–75.

    Article  PubMed  CAS  Google Scholar 

  32. Hughes JB, Berger C, Rodland MS, Hasmann M, Stang E, Madshus IH. Pertuzumab increases epidermal growth factor receptor down-regulation by counteracting epidermal growth factor receptor-ErbB2 heterodimerization. Mol Cancer Ther. 2009;8:1885–92.

    Google Scholar 

  33. Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, et al. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst. 2007;99:694–705.

    Google Scholar 

  34. Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803–14.

    Google Scholar 

  35. Rimawi MF, Wiechmann LS, Wang YC, Huang C, Migliaccio I, Wu MF, et al. Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. Clin Cancer Res. 2011;17:1351–61.

    Google Scholar 

  36. Garrett JT, Sutton CR, Kuba MG, Cook RS, Arteaga CL. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function. Clin Cancer Res. 2013;19:610–9.

    Google Scholar 

  37. • Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–30. This trial demonstrated the role of chemotherapy-free option after progression on trastuzumabbased therapy.

  38. • Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19. This trial demosntrated prolonged progression free survival benefit with pertuzumab, trastuzumab and a taxane in first-line metastatic HER2 positive breast cancer.

  39. • Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomized, open-label, multi-center, phase 3 trial. Lancet. 2012;379:633–40. This trial showed increased pCR with dual anti HER2 therapy in neoadjuvant HER2 positive breast cancer.

  40. • Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–32. This trial showed increased pCR with dual anti HER2 therapy in neoadjuvant HER2 positive breast cancer.

  41. Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol. 2012;30:1989–95.

    Google Scholar 

  42. Holmes FAN, Espina YM, Liotta VA, Danso LA, Gallagher MA, McIntyre RI, et al. Correlation of molecular effects and pathologic complete response to preoperative lapatinib and trastuzumab, separately and combined prior to neoadjuvant breast cancer chemotherapy.Oral abstract session, Breast Cancer - HER2/ER. ASCO Annual Meeting; 2011. J Clin Oncol. 2011;29:(Suppl; Abstr 506).

  43. Robidoux AT, Rastogi G, Geyer P, Azar C, Atkins C, Fehrenbacher JN, et al. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. Oral presentation; ASCO; 2012. J Clin Oncol. 2012; 30(Suppl; Abstr LBA506).

  44. Carey LB, Ollila D, Harris D, Krop L, Weckstein I, Henry D, et al. and Alliance. Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. Oral presentation; ASCO Annual meeting; 2013. J Clin Oncol. 2013 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2013;500(Suppl).

  45. Pegram MD, Konecny GE, O'Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst. 2004;96:739–49.

    Google Scholar 

  46. Sikov WM, Dizon DS, Strenger R, Legare RD, Theall KP, Graves TA, et al. Frequent pathologic complete responses in aggressive stages II to III breast cancers with every-4-week carboplatin and weekly paclitaxel with or without trastuzumab: a Brown University Oncology Group Study. J Clin Oncol. 2009;27:4693–700.

    Google Scholar 

  47. Chen XS, Nie XQ, Chen CM, Wu JY, Wu J, Lu JS, et al. Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Ann Oncol. 2010;21:961–7.

    Google Scholar 

  48. Coudert BP, Largillier R, Arnould L, Chollet P, Campone M, Coeffic D, et al. Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. J Clin Oncol. 2007;25:2678–84.

    Google Scholar 

  49. Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, et al. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011;29:149–56.

    Google Scholar 

  50. Von Minckwitz GSAS, Rezai C, Zahm M, Klare DM, Blohmer P, Tesch JU, et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Oral presentation, ASCO Annual meeting; 2013. J Clin Oncol. 2013;31(Suppl; Abstr 1004).

  51. • Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, et al. Multicenter phase ii study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal Growth Factor Receptor 2–overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013;31:1726–31. This trial supports the hypothesis of more complete HER2 blockade and ER blockade as an effective neoadjuvant strategy, worthy of further study.

  52. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75.

    Article  PubMed  CAS  Google Scholar 

  53. Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H, et al. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol. 2011;29:166–73.

    Google Scholar 

  54. Perez EA, Dueck AC, McCullough AE, Chen B, Geiger XJ, Jenkins RB, et al. Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal Growth Factor Receptor 2–positive breast cancer in the North Central Cancer Treatment Group N9831 Trial. J Clin Oncol. 2013;31:2115–22.

    Google Scholar 

  55. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.

    Google Scholar 

  56. Guiu S, Mouret Reynier MA, Toure M, Coudert B. Predictive factors of response in HER2-positive breast cancer treated by neoadjuvant therapy. J Oncol. 2013;2013:854121.

  57. Loibl SBJ, Von Minckwitz G, Huober JB, Press MF, darb-Esfahani S, Solbach, C, et al. Validation of p95 as a predictive marker for trastuzumab-based therapy in primary HER2-positive breast cancer: a translational investigation from the neoadjuvant GeparQuattro study.Poster discussion session; 2011 ASCO Annual Meeting. J Clin Oncol. 2011;29(Suppl; Abstr 530).

  58. Witzel I, Loibl S, von Minckwitz G, Eidtmann H, Fehm T, Khandan F, et al. Predictive value of HER2 serum levels in patients treated with lapatinib or trastuzumab — a translational project in the neoadjuvant GeparQuinto trial. Br J Cancer. 2012;107:956–60.

    Google Scholar 

  59. Mazouni C, Hall A, Broglio K, Fritsche H, Andre F, Esteva FJ, et al. Kinetics of serum HER-2/neu changes in patients with HER-2-positive primary breast cancer after initiation of primary chemotherapy. Cancer. 2007;109:496–501.

    Google Scholar 

  60. Bianchini GP, Pickl A, Belousov M, Koehler A, Semiglazov A, Eirmann V, et al. Response to neoadjuvant trastuzumab and chemotherapy in ER + and ER- HER2-positive breast cancers: gene expression analysis. Poster discussion session; 2011 ASCO Annual Meeting. J Clin Oncol. 2011;29(Suppl; Abstr 529).

  61. Gianni LB, Kiermaier G, Bianchi A, Im G, Pienkowski YH, Roman T, et al. Neoadjuvant pertuzumab (P) and trastuzumab (H): biomarker analyses of a 4-arm randomized phase ii study (NeoSphere) in patients (pts) with HER2-Positive Breast Cancer (BC). Presented at the San Antonio Breast Cancer Symposium; 2011.

  62. Perez EA, Eckel-Passow JE, Ballman KV, Anderson SK, Thompson EA, Asmann YW, Jen J, et al. Predictive genomic markers to chemotherapy and adjuvant trastuzumab via whole genome expression DASL profiling in the N9831 Adjuvant Study. Poster Discussion, San Antonio Breast Cancer Symposium; 2012.

  63. Untch M, Fasching PA, Konecny GE, Hasmuller S, Lebeau A, Kreienberg R, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol. 2011;29:3351–7.

    Google Scholar 

  64. Schneeweiss AC, Hickish S, Harvey T, Eniu V, Hegg A, Tausch R, et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase ii study (TRYPHAENA). Oral presentation, San Antonio Breast Cancer Symposium; 2011. Cancer Res. 2011;71(Suppl 3).

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Komal Jhaveri declares that she has no conflict no interest. Chau Dang has received research support from Rxhe/Genentech and GlaxoSmithKline.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chau Dang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jhaveri, K., Dang, C. Dual Targeting of Human Epidermal Growth Factor Receptor 2 (HER2) in Neoadjuvant Trials for Operable HER2 Positive (HER2+) Disease. Curr Breast Cancer Rep 5, 321–330 (2013). https://doi.org/10.1007/s12609-013-0124-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12609-013-0124-x

Keywords

Navigation