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

Breast Cancer

Volumn 22, Issue 2, 2015, Pages 101-116

  Ahmed, Shahid ^a   Sami, Amer ^a   Xiang, Jim ^a  

^a UNIVERSITY OF SASKATCHEWAN   (Canada)

Author keywords

Adjuvant therapy; Ado trastuzumab emtansine; Bresat cancer; HER2 directed therapy; HER2 targeted therapy; Lapatinib; Neoadjuvant treatment; Pertuzumab; Trastuzumab

Indexed keywords

AFATINIB; ANASTROZOLE; CANCER VACCINE; CARBOPLATIN; CYCLOPHOSPHAMIDE; DOCETAXEL; DOXORUBICIN; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIRUBICIN; FLUOROURACIL; HEAT SHOCK PROTEIN 90; LAPATINIB; LETROZOLE; NAVELBINE; PACLITAXEL; PERTUZUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; TRASTUZUMAB; TRASTUZUMAB EMTANSINE; ANTINEOPLASTIC AGENT; ERBB2 PROTEIN, HUMAN; MAYTANSINE; MOLECULAR LIBRARY; MONOCLONAL ANTIBODY; QUINAZOLINE DERIVATIVE;

ADVANCED CANCER; ARTICLE; BREAST CANCER; CANCER ADJUVANT THERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER HORMONE THERAPY; CANCER IMMUNIZATION; CANCER RESISTANCE; CANCER STAGING; CANCER SURVIVAL; DRUG EFFICACY; DRUG TARGETING; ENZYME INHIBITION; HUMAN; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; OUTCOME ASSESSMENT; OVERALL SURVIVAL; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; PROTEIN TARGETING; RANDOMIZED CONTROLLED TRIAL (TOPIC); TREATMENT DURATION; ADJUVANT THERAPY; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; DRUG EFFECTS; DRUG RESISTANCE; FEMALE; METABOLISM; MOLECULAR LIBRARY; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PHARMACOLOGY;

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BREAST NEOPLASMS; DRUG RESISTANCE, NEOPLASM; FEMALE; HUMANS; MAYTANSINE; MOLECULAR TARGETED THERAPY; NEOADJUVANT THERAPY; QUINAZOLINES; RECEPTOR, ERBB-2; SMALL MOLECULE LIBRARIES; TRASTUZUMAB;

EID: 84925481938     PISSN: 13406868     EISSN: 18804233     Source Type: Journal    
DOI: 10.1007/s12282-015-0587-x     Document Type: Article

References (121)

1. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumors. Nature. 2000;406:747–52.
2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.
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.
4. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.
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.
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.
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.
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.
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.
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.
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.
13. Walker RA, Bartlett JM, Dowsett M, et al. HER2 testing in the UK: further update to recommendations. J Clin Pathol. 2008;61:818.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
28. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4:CD006243.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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. ® 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.
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.
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.
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.
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.
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.
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.
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.