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HER2-directed therapy: current treatment options for HER2-positive breast cancer

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Abstract

Over the past decade, the management of HER2-positive breast cancer has evolved dramatically. In addition to advances in screening, genetic testing, imaging, surgical and radiation techniques, innovations in medical therapy including widespread use of HER2-directed therapy in early and advanced breast cancer have revolutionized breast cancer care and changed the natural history of HER2-positive breast cancer. A substantial number of HER2-targeted agents are being developed including monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates. Trastuzumab is the prototype HER2-directed therapy that was introduced in the late 1990s for the management of metastatic breast cancer and later showed efficacy in early stage disease. Despite the practice changing impact of trastuzumab and improvement in outcomes of women with HER2-positive breast cancer resistance to trrastuzumab is a major clinical issue, occurring in both early stage and advanced disease, and new treatment strategies are clearly required. Combining HER2-targeted agents and dual HER2 blockade has been successful in early and advanced breast cancer. Furthermore, selected delivery of potent chemotherapeutic agent coupled with HER2 inhibition promises new treatment options. This review is focused on current HER2-directed treatments for women with HER2-positive breast cancer including monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates.

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References

  1. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumors. Nature. 2000;406:747–52.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Klapper LN, Kirschbaum MH, Sela M, Yarden Y. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res. 2000;77:25–79.

    Article  CAS  PubMed  Google Scholar 

  4. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.

    Article  CAS  PubMed  Google Scholar 

  5. Bailey TA, Luan H, Clubb RJ, et al. Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance. J Carcinog. 2011;6:28. doi:10.4103/1477-3163.90442.

    Google Scholar 

  6. Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012;6:16–32.

    Google Scholar 

  7. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.

    Article  CAS  PubMed  Google Scholar 

  8. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009;27:5700–6.

    Article  PubMed Central  PubMed  Google Scholar 

  9. NCCN. Clinical Practice Guidelines in Oncology (NCCN Guidelines), Breast Cancer (version 1.2014). 2014. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 28 Jan 2014.

  10. Cardoso F, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO clinical practice guidelines. Ann Oncol. 2013;24(Suppl 6):vi7–23.

    PubMed  Google Scholar 

  11. Sturgeon CM, Hoffman BR, Chan DW, et al. National Academy Of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in clinical practice: quality requirements. Clin Chem. 2008;54:e1.

    Article  CAS  PubMed  Google Scholar 

  12. Wolff AC, Hammond ME, Hicks DG, 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.

    Article  PubMed  Google Scholar 

  13. Walker RA, Bartlett JM, Dowsett M, et al. HER2 testing in the UK: further update to recommendations. J Clin Pathol. 2008;61:818.

    Article  CAS  PubMed  Google Scholar 

  14. Niikura N, Liu J, Hayashi N, et al. Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol. 2012;30:593–9.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Wilking U, Karlsson E, Skoog L, et al. HER2 status in a population-derived breast cancer cohort: discordances during tumor progression. Breast Cancer Res Treat. 2011;125:553–61.

    Article  CAS  PubMed  Google Scholar 

  16. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287.

    Article  CAS  PubMed  Google Scholar 

  17. Cuello M, Ettenberg SA, Clark AS, et al. Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res. 2001;61:4892–900.

    CAS  PubMed  Google Scholar 

  18. Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (herceptin), a humanized anti-HER2 receptor monoclonal antibody, inhibits basal and activated HER2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001;61:4744–9.

    CAS  PubMed  Google Scholar 

  19. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15:429–40.

    Article  CAS  PubMed  Google Scholar 

  20. Arnould L, Gelly M, Penault-Llorca F, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94:259–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;6:783–92.

    Article  Google Scholar 

  22. Perez EA, Romond EH, Suman VJ, 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  PubMed Central  CAS  PubMed  Google Scholar 

  23. Perez EA, Suman VJ, Davidson N, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011;29:4491–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Gianni L, Dafni U, Gelber RD, 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;12:236–44.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Joensuu H, Bono P, Kataja V, 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  PubMed  Google Scholar 

  27. Spielmann M, Roché H, Delozier T, 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  PubMed  Google Scholar 

  28. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4:CD006243.

    PubMed  Google Scholar 

  29. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al. HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. Cancer Res. 2012;6(24 Suppl):103s–4s.

    Google Scholar 

  30. Pivot X, Romieu G, Debled M, 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.

    Article  CAS  PubMed  Google Scholar 

  31. Perez EA, Thompson EA, Anderson SK, et al. Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial. American Society of Clinical Oncology (ASCO) Annual Meeting. J Clin Oncol (Meeting Abstracts). 2014;32(15 suppl):509.

    Google Scholar 

  32. Perez EA, Ballman KV, Anderson SK, et al. Stromal tumor-infiltrating lymphocytes(S-TILs): In the alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit. San Antonio Breast Cancer Symposium (SABCS) 2014. Abstract bS1-06, presented December, 2014.

  33. Montemurro F, Valabrega G, Aglietta M. Lapatinib: a dual inhibitor of EGFR and HER2 tyrosine kinase activity. Expert Opin Biol Ther. 2007;6:257–68.

    Article  Google Scholar 

  34. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adjuvant treatment of HER2-positive early breast cancer. J Clin Oncol. 2014;32:5s (suppl; abstr LBA4).

    Article  Google Scholar 

  35. Goss PE, Smith IE, O’Shaughnessy J, et al. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomized, controlled, phase 3 trial. Lancet Oncol. 2013;14:88–96.

    Article  CAS  PubMed  Google Scholar 

  36. Capelan M, Pugliano L, De Azambuja E, et al. Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol. 2013;24:273–82.

    Article  CAS  PubMed  Google Scholar 

  37. ClinicalTrials.gov. A study of pertuzumab in addition to chemotherapy and herceptin (Trastuzumab) as adjuvant therapy in patients with HER2-positive primary breast cancer. 2014. http://clinicaltrials.gov/show/NCT01358877. Accessed 8 July 2014.

  38. Gradishar WJ. HER2 therapy-an abundance of riches. N Engl J Med. 2012;6:176–8.

    Article  Google Scholar 

  39. Oostra DR, Macrae ER. Role of trastuzumab emtansine in the treatment of HER2-positive breast cancer. Breast Cancer Targ Ther. 2014;6:103–13.

    Article  Google Scholar 

  40. A study of trastuzumab emtansine versus tras-tuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor in the breast or axillary lymph nodes following preoperative therapy (KATHERINE). 2014. http://clinicaltrials.gov/show/NCT01772472. NLM identifier: NCT01772472. Accessed 5 Dec 2014.

  41. A study of kadcyla (trastuzumab emtansine) plus perjeta (pertuzumab) following anthracyclines in comparison with herceptin (trastuzumab) plus perjeta and a taxane following anthracyclines as adjuvant therapy in patients with operable HER2-positive primary breast cancer. 2014. http://clinicaltrials.gov/show/NCT01966471. NLM identifier: NCT01966471. Accessed 5 Dec 2014.

  42. Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol. 2008;26:814.

    Article  PubMed  Google Scholar 

  43. Kaufmann M, Hortobagyi GN, Goldhirsch A, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol. 2006;24:1940.

    Article  PubMed  Google Scholar 

  44. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–85.

    CAS  PubMed  Google Scholar 

  45. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;30:96–102.

    Article  PubMed  Google Scholar 

  46. Buzdar AU, Ibrahim NK, Francis D, 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.

    Article  CAS  PubMed  Google Scholar 

  47. Petrelli F, Borgonovo K, Cabiddu M, et al. Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials. Anticancer Drugs. 2011;22:128.

    Article  CAS  PubMed  Google Scholar 

  48. Gianni L, Eiermann W, Semiglazov V, et al. Follow-up results of NOAH, a randomized phase III trial evaluating neoadjuvant chemotherapy with trastuzumab (CT+H) followed by adjuvant H versus CT alone, in patients with HER2-positive locally advanced breast cancer. J Clin Oncol. 2013;31:503 (abstract).

    Article  Google Scholar 

  49. Ismael G, Hegg R, Muehlbauer S. 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;13:869.

    Article  CAS  PubMed  Google Scholar 

  50. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40.

    Article  CAS  PubMed  Google Scholar 

  51. Guarneri V, Frassoldati A, Bottini A, 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.

    Article  CAS  PubMed  Google Scholar 

  52. Untch M, Loibl S, Bischoff J, Eidtmann H, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012;13:135–44.

    Article  CAS  PubMed  Google Scholar 

  53. Rimawi MF, Mayer IA, Forero A, 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25.

    Article  CAS  PubMed  Google Scholar 

  55. Schneeweiss A, Chia S, Hickish T, 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). Cancer Res. 2011;71(24 Suppl):S5–6.

    Google Scholar 

  56. A multicenter, multinational phase II study to assess the cinical safety and feasibility of trastuzumab emtansine sequentially with anthracycline-based chemotherapy, as adjuvant or neoadjuvant therapy for patients with early stage HER2-positive breast cancer. 2014. http://clinicaltrials.gov/ct2/show/NCT01196052 Accessed 5 Dec 2014.

  57. Neoadjuvant TDM1 With Lapatinib and Abraxane Compared With Trastuzumab With Lapatinib and Paclitaxel (TEAL). 2014. http://clinicaltrials.gov/ct2/show/NCT02073487 Accessed 5 Dec 2014.

  58. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first–line treatment: the M77001 study group. J Clin Oncol. 2005;23:4265–74.

    Article  CAS  PubMed  Google Scholar 

  59. Gasparini G, Gion M, Mariani L, et al. Randomized phase II trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first–line therapy of patients with Her–2 positive advanced breast cancer. Breast Cancer Res Treat. 2007;101:355–65.

    Article  CAS  PubMed  Google Scholar 

  60. Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2–overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007;110:965–72.

    Article  CAS  PubMed  Google Scholar 

  61. Yamamoto D, Iwase S, Kitamura K, et al. A phase II study of trastuzumab and capecitabine for patients with HER2–overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial. Cancer Chemother Pharmacol. 2008;61:509–14.

    Article  CAS  PubMed  Google Scholar 

  62. Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptor–enhanced chemo-sensitivity using recombinant humanized anti–p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu–overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol. 1998;16:2659–71.

    CAS  PubMed  Google Scholar 

  63. Pegram MD, Pienkowski T, Northfelt DW, et al. Results of two open–label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2—positive advanced breast cancer. J Natl Cancer Inst. 2004;96:759–69.

    Article  CAS  PubMed  Google Scholar 

  64. Yardley DA, Burris HA 3rd, et al. A phase II trial of gemcitabine/carboplatin with or without trastuzumab in the first–line treatment of patients with metastatic breast cancer. Clin Breast Cancer. 2008;8:425–31.

    Article  CAS  PubMed  Google Scholar 

  65. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2–positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264–71.

    Article  CAS  PubMed  Google Scholar 

  66. Valero V, Forbes J, Pegram MD, 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.

    Article  CAS  PubMed  Google Scholar 

  67. Hamberg P, Bos MM, Braun HJ, et al. Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial. Clin Breast Cancer. 2011;11:103.

    Article  CAS  PubMed  Google Scholar 

  68. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03–05 study. J Clin Oncol. 2009;27:1999.

    Article  Google Scholar 

  69. Gori S, Montemurro F, Spazzapan S, et al. Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer. Ann Oncol. 2012;23:1436.

    Article  CAS  PubMed  Google Scholar 

  70. 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 Central  CAS  PubMed  Google Scholar 

  71. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.

    Article  CAS  PubMed  Google Scholar 

  72. Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.

    Article  CAS  PubMed  Google Scholar 

  73. Saez R, Molina MA, Ramsey EE, et al. p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res. 2006;12:424–31.

    Article  CAS  PubMed  Google Scholar 

  74. Scaltriti M, Rojo F, Ocana A, 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.

    Article  CAS  PubMed  Google Scholar 

  75. Xia W, Liu LH, Ho P, Spector NL. Truncated ErbB2 receptor (p95ErbB2) is regulated byheregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene. 2004;23:646–53.

    Article  CAS  PubMed  Google Scholar 

  76. Sergina NV, Rausch M, Wang D, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65:11118–28.

    Article  CAS  PubMed  Google Scholar 

  78. Shattuck DL, Miller JK, Carraway KL 3rd, Sweeney C. Met receptor contributes to trastuzumab resistance of HER2-overexpressing breast cancer cells. Cancer Res. 2008;68:1471–7.

    Article  CAS  PubMed  Google Scholar 

  79. Zhuang G, Brantley-Sieders DM, Vaught D, et al. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res. 2010;70:299–308.

    Article  CAS  PubMed  Google Scholar 

  80. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.

    Article  CAS  PubMed  Google Scholar 

  81. Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15:924.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Blackwell KL, Burstein HJ, Storniolo AM, 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.

    Article  CAS  PubMed  Google Scholar 

  83. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585.

    Article  CAS  PubMed  Google Scholar 

  84. Gelmon KA, Boyle F, Kaufman B, et al. Open-label phase III randomized controlled trial comparing taxane-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: Interim analysis (IA) of NCIC CTG MA. 31/GSK EGF 108919. J Clin Oncol 2012;30 (suppl; abstr LBA671).

  85. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19.

    Article  CAS  PubMed  Google Scholar 

  86. Swain S, Kim S-B, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival from a randomized, double-blind, placebo-controlled, phase III study. Lancet Oncol. 2013;14:461–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91.

    Article  CAS  PubMed  Google Scholar 

  88. Krop IE, Kim SB, González-Martín A, et al: Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): A randomised, open-label, phase 3 trial. Lancet Oncol. May 1, 2014 (early release online).

  89. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013;6:1157–63.

    Article  Google Scholar 

  90. MARIANNE. A study of trastuzumab-DM1 plus pertuzumab versus trastuzumab plus a taxanes in patients with metastatic breast cancer). http://www.clinicaltrials.gov (NCT01120184).

  91. Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27:5529–53.

    Article  CAS  PubMed  Google Scholar 

  92. Huober J, Fasching PA, Barsoum M, et al. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer: results of the eLEcTRA trial. Breast. 2012;21:27–33.

    Article  CAS  PubMed  Google Scholar 

  93. Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27:5538.

    Article  CAS  PubMed  Google Scholar 

  94. Schwartzberg LS, Franco SX, Florance A, et al. Lapatinib plus letrozole as first-line therapy for HER-2 hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15:122–9.

    Article  PubMed Central  PubMed  Google Scholar 

  95. Rimawi MF, Poole CJ, Ferrero J-M, et al. Pertuzumab in combination with trastuzumab plus an aromatase inhibitor in patients with hormone receptor-positive, HER2-positive metastatic breast cancer: A randomized phase II study (PERTAIN). J Clin Oncol 2012;30 (suppl; abstr TPS654).

  96. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. Published Ahead of Print on May 19, 2014 as doi:10.1200/JCO.2013.54.0948.

  97. Hickish T, Wheatley D, Lin N, et al. Use of BIBW 2992, a novel irreversible EGFR/HER1 and HER2 tyrosine kinase inhibitor to treat patients with HER2-positive metastatic breast cancer after failure of treatment with trastuzumab. Cancer Res. 2009;69:2191–4 (Abstract 5060).

    Article  Google Scholar 

  98. Rimawi MF, Aleixo SB, Alarcon Rozas A, et al. A neoadjuvant, randomized, open-label phase II trial of afatinib (A) versus trastuzumab (T) versus lapatinib (L) in patients (pts) with locally advanced HER2-positive breast cancer (BC). J Clin Oncol 2012;30 (suppl; abstr 606).

  99. LUX-Breast 1: BIBW 2992 (Afatinib) in HER2-positive metastatic breast cancer patients after one prior herceptin treatment. http://clinicaltrials.gov (NCT01125566).

  100. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28:1301–7.

    Article  CAS  PubMed  Google Scholar 

  101. Goss PE, Barrios CH, Chan A, et al. A phase III trial of adjuvant neratinib (NER) after trastuzumab (TRAS) in women with early-stage HER2+ breast cancer (BC). J Clin Oncol 2011;29 (suppl; abstr TPS137).

  102. Park JW, Liu MC, Yee D, et al. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 trial. 2014 AACR Annual Meeting. Abstract CT227. Presented April 7, 2014.

  103. Jhaveri K, Taldone T, Modi S, et al. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta. 1823;2012:742–55.

    Google Scholar 

  104. Modi S, Sugarman S, Stopeck AT, et al. Phase II trial of the Hsp90 inhibitor tanespimycin plus trastuzumab in patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2008;26:s1027.

    Article  Google Scholar 

  105. Baselga J, Majewski I, Nuciforo PG, et al. PIK3CA mutations and correlation with pCR in the NeoALTTO trial (BIG 01-06). Presented at: The European Cancer Congress, Amsterdam, The Netherlands, Sept 27–Oct 1, 2013. Abstr 1859.

  106. Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30:282–90.

    Article  CAS  PubMed  Google Scholar 

  107. Dalenc F, Campone M, Hupperets P, et al. Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: a multicenter phase II clinical trial. J Clin Oncol. 2010;28:1013.

    Google Scholar 

  108. Andre F, Campone M, Hurvitz SA, et al. Multicenter Phase I clinical trial of daily and weekly RAD001 in combination with weekly paclitaxel and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. J Clin Oncol. 2008;26:1003.

    Article  Google Scholar 

  109. Hurvitz SA, Andre F, Jiang Z,et al. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1. San Antonio Breast Cancer Symposium (SABCS) 2014. Abstract bS6-01, presented December, 2014.

  110. Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 Positive breast cancer. 2014. http://clinicaltrials.gov/ct2/show/NCT02066532 Accessed 6 Dec 2014.

  111. Combination study of BMS-754807 and Herceptin® in patients with advanced or metastatic Her-2 positive breast cancer. 2014. http://clinicaltrials.gov/ct2/show/NCT00788333 Accessed 6 Dec 2014.

  112. A randomized, multicenter, open label study of MM-302 Plus Trastuzumab vs. Chemotherapy of Physician’s choice plus trastuzumab in anthracycline naive patients with locally advanced/metastatic HER2-positive breast cancer. 2014. http://clinicaltrials.gov/ct2/show/NCT02213744 Accessed 6 Dec 2014.

  113. A Phase 1b, Open-label Study to Assess the Safety and Tolerability of ONT-380 combined with ado-trastuzumab emtansine (Trastuzumab Emtansine;T-DM1). 2014. http://clinicaltrials.gov/ct2/show/NCT01983501 Accessed 6 Dec 2014).

  114. Milani A, Sangiolo D, Montemurro F, et al. Active immunotherapy in HER2 overexpressing breast cancer: current status and future perspectives. Ann Oncol. 2013;00:1–9.

    CAS  Google Scholar 

  115. Disis ML, Calenoff E, McLaughlin G, et al. Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res. 1994;54:16–20.

    CAS  PubMed  Google Scholar 

  116. Peoples GE, Goedegebuure PS, Smith R, et al. Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA. 1995;92:432–6.

    Article  Google Scholar 

  117. Wang L, Xie Y, Ahmed KA, et al. Exosomal pMHC-I complex targets T cell-based vaccine to directly stimulate CTL responses leading to antitumor immunity in transgenic FVBneuN and HLA-A2/HER2 mice and eradicating trastuzumab-resistant tumor in athymic nude mice. Breast Cancer Res Treat. 2013;140:273–84.

    Article  CAS  PubMed  Google Scholar 

  118. Benavides LC, Gates JD, Camichael MG, et al. The impact of HER2/neu expression level on response to the E75 vaccine: from US Military Cancer Institute Clinical Trails Group Study 1-01 and 1-02. Clin Cancer Res. 2009;15:2895–904.

    Article  CAS  PubMed  Google Scholar 

  119. Disis ML, Wallace DR, Gooley TA, et al. Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol. 2009;27:4685–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Emens LA, Gupta R, Petrik S, et al. A feasibility study of combination therapy with trastuzumab (T), cytophosphamide (CY) and allogeneic GM-CSF-secreting breast tumor vaccine for the treatment of HER2+ metastatic breast cancer. J Clin Oncol. 2011;29(15 suppl):2535.

    Google Scholar 

  121. Norell H, Poschke I, Charo J, et al. Vaccination with a plasmid DNA encoding HER2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma. A pilot clinical trial. J Transl Med. 2010;8:53.

    Article  PubMed Central  PubMed  Google Scholar 

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  1. Department of Oncology, Saskatchewan Cancer Agency, Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, Saskatoon, SK, S7N4H4, Canada

    Shahid Ahmed, Amer Sami & Jim Xiang

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  1. Shahid Ahmed
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Correspondence to Shahid Ahmed.

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Ahmed, S., Sami, A. & Xiang, J. HER2-directed therapy: current treatment options for HER2-positive breast cancer. Breast Cancer 22, 101–116 (2015). https://doi.org/10.1007/s12282-015-0587-x

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