HER2 (ErbB2), a member of the HER family of tyrosine kinase receptors (HER1–4), is a major driver of tumor growth in 20% of breast cancers. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. Growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings. As a result, the list of more effective and well tolerated FDA-approved new regimens for patients with HER2+ tumors is constantly growing.


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Literature Cited

  1. Citri A, Yarden Y. 1.  2006. EGF-ERBB signalling: towards the systems level. Nat. Rev. Mol. Cell Biol. 7:505–16 [Google Scholar]
  2. Nahta R, Yuan LX, Zhang B. 2.  et al. 2005. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 65:11118–28 [Google Scholar]
  3. Maroun CR, Rowlands T. 3.  2014. The Met receptor tyrosine kinase: a key player in oncogenesis and drug resistance. Pharmacol. Ther. 142:316–38 [Google Scholar]
  4. Schiff R, Massarweh SA, Shou J. 4.  et al. 2004. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin. Cancer Res. 10:331S–36S [Google Scholar]
  5. 5. The Cancer Genome Atlas Network 2012. Comprehensive molecular portraits of human breast tumours. Nature 490:61–70 [Google Scholar]
  6. Berns K, Horlings HM, Hennessy BT. 6.  et al. 2007. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402 [Google Scholar]
  7. Weinstein IB, Joe A. 7.  2008. Oncogene addiction. Cancer Res. 68:3077–80 [Google Scholar]
  8. Pegram M, Hsu S, Lewis G. 8.  et al. 1999. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18:2241–51 [Google Scholar]
  9. Pietras RJ, Pegram MD, Finn RS. 9.  et al. 1998. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17:2235–49 [Google Scholar]
  10. Harari D, Yarden Y. 10.  2000. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 19:6102–14 [Google Scholar]
  11. Ghosh R, Narasanna A, Wang SE. 11.  et al. 2011. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. Cancer Res. 71:1871–82 [Google Scholar]
  12. Bates M, Sperinde J, Kostler WJ. 12.  et al. 2011. Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab. Ann. Oncol. 22:2014–20 [Google Scholar]
  13. Clynes RA, Towers TL, Presta LG, Ravetch JV. 13.  2000. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6:443–46 [Google Scholar]
  14. Vogel CL, Cobleigh MA, Tripathy D. 14.  et al. 2002. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20:719–26 [Google Scholar]
  15. Cobleigh MA, Vogel CL, Tripathy D. 15.  et al. 1999. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17:2639–48 [Google Scholar]
  16. Slamon DJ, Leyland-Jones B, Shak S. 16.  et al. 2001. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344:783–92 [Google Scholar]
  17. Sheth S, Pal SK, Pegram M. 17.  2014. Treatment of HER2-overexpressing metastatic breast cancer. Diseases of the Breast JR Harris, ME Lippman, M Morrow, CK Osborne 960–73 Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins, 5th ed.. [Google Scholar]
  18. Giordano SH, Temin S, Kirshner JJ. 18.  et al. 2014. Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 32:2100–8 [Google Scholar]
  19. Burstein HJ, Storniolo AM, Franco S. 19.  et al. 2008. A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann. Oncol. 19:1068–74 [Google Scholar]
  20. Geyer CE, Forster J, Lindquist D. 20.  et al. 2006. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355:2733–43 [Google Scholar]
  21. Cameron D, Casey M, Press M. 21.  et al. 2008. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res. Treat. 112:533–43 [Google Scholar]
  22. Guan Z, Xu B, DeSilvio ML. 22.  et al. 2013. Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2–overexpressing metastatic breast cancer. J. Clin. Oncol. 31:1947–53 [Google Scholar]
  23. Blackwell KL, Burstein HJ, Storniolo AM. 23.  et al. 2012. 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. 30:2585–92 [Google Scholar]
  24. Zhang X, Munster PN. 24.  2014. New protein kinase inhibitors in breast cancer: afatinib and neratinib. Expert Opin. Pharmacother. 15:1277–88 [Google Scholar]
  25. Herter-Sprie GS, Greulich H, Wong KK. 25.  2013. Activating mutations in ERBB2 and their impact on diagnostics and treatment. Front. Oncol. 3:Article 861–10 [Google Scholar]
  26. Cortes J, Fumoleau P, Bianchi GV. 26.  et al. 2012. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2–positive breast cancer. J. Clin. Oncol. 30:1594–600 [Google Scholar]
  27. Baselga J, Cortes J, Kim SB. 27.  et al. 2012. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 366:109–19 [Google Scholar]
  28. Swain SM, Kim SB, Cortes J. 28.  et al. 2013. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 14:461–71 [Google Scholar]
  29. Nahta R, O'Regan RM. 29.  2012. Therapeutic implications of estrogen receptor signaling in HER2-positive breast cancers. Breast Cancer Res. Treat. 135:39–48 [Google Scholar]
  30. Kaufman B, Mackey JR, Clemens MR. 30.  et al. 2009. 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. 27:5529–37 [Google Scholar]
  31. Johnston S, Pippen J Jr, Pivot X. 31.  et al. 2009. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor–positive metastatic breast cancer. J. Clin. Oncol. 27:5538–46 [Google Scholar]
  32. Burris HA 3rd, Rugo HS, Vukelja SJ. 32.  et al. 2011. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer after prior HER2-directed therapy. J. Clin. Oncol. 29:398–405 [Google Scholar]
  33. Krop IE, LoRusso P, Miller KD. 33.  et al. 2012. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J. Clin. Oncol. 30:3234–41 [Google Scholar]
  34. Krop IE, Kim SB, Gonzalez-Martin A. 34.  et al. 2014. 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. 15:689–99 [Google Scholar]
  35. Verma S, Miles D, Gianni L. 35.  et al. 2012. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367:1783–91 [Google Scholar]
  36. Hurvitz SA, Dirix L, Kocsis J. 36.  et al. 2013. 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. 31:1157–63 [Google Scholar]
  37. Romond EH, Perez EA, Bryant J. 37.  et al. 2005. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353:1673–84 [Google Scholar]
  38. Romond E, Suman V, Jeong J-H. 38.  et al. 2012. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: final planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. Proc. Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symp., Cancer Res. 72:Suppl.Abstr. S5–5 [Google Scholar]
  39. Piccart-Gebhart MJ, Procter M, Leyland-Jones B. 39.  et al. 2005. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353:1659–72 [Google Scholar]
  40. Spielmann M, Roche H, Delozier T. 40.  et al. 2009. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J. Clin. Oncol. 27:6129–34 [Google Scholar]
  41. Goldhirsch A, Piccart-Gebhart MJ, Procter M. 41.  et al. 2012. 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. Proc. Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symp., Cancer Res. 72:Suppl.Abstr. S5–2 [Google Scholar]
  42. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ. 42.  et al. 2013. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 382:1021–28 [Google Scholar]
  43. Pivot X, Romieu G, Debled M. 43.  et al. 2013. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 14:741–48 [Google Scholar]
  44. Joensuu H, Bono P, Kataja V. 44.  et al. 2009. 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. 27:5685–92 [Google Scholar]
  45. Slamon D, Eiermann W, Robert N. 45.  et al. 2011. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365:1273–83 [Google Scholar]
  46. Tolaney SM, Barry WT, Dang CT. 46.  et al. 2013. A phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). Proc. Thirty-Sixth Annual CTRC-AACR San Antonio Breast Cancer Symp. Cancer Res. 73:Suppl.Abstr. S1–04 [Google Scholar]
  47. Buzdar AU, Ibrahim NK, Francis D. 47.  et al. 2005. 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. 23:3676–85 [Google Scholar]
  48. Untch M, Rezai M, Loibl S. 48.  et al. 2010. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J. Clin. Oncol. 28:2024–31 [Google Scholar]
  49. Gianni L, Eiermann W, Semiglazov V. 49.  et al. 2014. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 15:640–47 [Google Scholar]
  50. Spector NL, Blackwell KL. 50.  2009. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2–positive breast cancer. J. Clin. Oncol. 27:5838–47 [Google Scholar]
  51. Esteva FJ, Yu D, Hung MC, Hortobagyi GN. 51.  2010. Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat. Rev. Clin. Oncol. 7:98–107 [Google Scholar]
  52. Rexer BN, Arteaga CL. 52.  2012. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit. Rev. Oncol. 17:1–16 [Google Scholar]
  53. Arteaga CL, Sliwkowski MX, Osborne CK. 53.  et al. 2012. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 9:16–32 [Google Scholar]
  54. De P, Hasmann M, Leyland-Jones B. 54.  2013. Molecular determinants of trastuzumab efficacy: What is their clinical relevance?. Cancer Treat. Rev. 39:925–34 [Google Scholar]
  55. Whenham N, D'Hondt V, Piccart MJ. 55.  2008. HER2-positive breast cancer: from trastuzumab to innovatory anti-HER2 strategies. Clin. Breast Cancer 8:38–49 [Google Scholar]
  56. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. 56.  2011. p95HER2 and breast cancer. Cancer Res. 71:1515–19 [Google Scholar]
  57. Castiglioni F, Tagliabue E, Campiglio M. 57.  et al. 2006. Role of exon-16-deleted HER2 in breast carcinomas. Endocrine-Related Cancer 13:221–32 [Google Scholar]
  58. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D. 58.  et al. 2013. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 3:224–37 [Google Scholar]
  59. Prempree T, Wongpaksa C. 59.  2006. Mutations of HER2 gene in HER2-positive metastatic breast cancer. J. Clin. Oncol. 24:18SAbstr. 13118 [Google Scholar]
  60. Rimm D, Ballman KV, Cheng H. 60.  et al. 2012. EGFR expression measured by quantitative immunofluorescense is associated with decreased benefit from trastuzumab in the adjuvant setting in the NCCTG (Alliance) N9831 trial. Proc. Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symp., Cancer Res. 72:Suppl.Abstr. S5–4 [Google Scholar]
  61. Nahta R, Shabaya S, Ozbay T, Rowe DL. 61.  2009. Personalizing HER2-targeted therapy in metastatic breast cancer beyond HER2 status: What we have learned from clinical specimens?. Curr. Pharmacogenomics Personalized Med. 7:263–74 [Google Scholar]
  62. Arpino G, Gutierrez C, Weiss H. 62.  et al. 2007. Treatment of human epidermal growth factor receptor 2–overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J. Natl. Cancer Inst. 99:694–705 [Google Scholar]
  63. Rimawi MF, Wiechmann LS, Wang YC. 63.  et al. 2011. 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. 17:1351–61 [Google Scholar]
  64. Wang YC, Morrison G, Gillihan R. 64.  et al. 2011. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers—role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 13:R121, 1–19 [Google Scholar]
  65. Chen AC, Migliaccio I, Rimawi M. 65.  et al. 2012. Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies. Breast Cancer Res. Treat. 134:583–93 [Google Scholar]
  66. Funes M, Miller JK, Lai C. 66.  et al. 2006. The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3. J. Biol. Chem. 281:19310–19 [Google Scholar]
  67. Price-Schiavi SA, Jepson S, Li P. 67.  et al. 2002. Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. Int. J. Cancer 99:783–91 [Google Scholar]
  68. Raina D, Uchida Y, Kharbanda A. 68.  et al. 2013. Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene 33:3422–31 [Google Scholar]
  69. Fessler SP, Wotkowicz MT, Mahanta SK, Bamdad C. 69.  2009. MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. Breast Cancer Res. Treat. 118:113–24 [Google Scholar]
  70. Rimawi MF, Mayer IA, Forero A. 70.  et al. 2013. 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. 31:1726–31 [Google Scholar]
  71. Xia W, Bacus S, Hegde P. 71.  et al. 2006. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc. Natl. Acad. Sci. USA 103:7795–800 [Google Scholar]
  72. Giuliano M, Wang Y-C, Gutierrez C. 72.  et al. 2012. Parallel upregulation of Bcl2 and estrogen receptor (ER) expression in HER2+ breast cancer patients treated with neoadjuvant lapatinib. Proc. Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symp., Cancer Res. 72:Suppl.Abstr. S5–8 [Google Scholar]
  73. Xia W, Bacus S, Husain I. 73.  et al. 2010. Resistance to ErbB2 tyrosine kinase inhibitors in breast cancer is mediated by calcium-dependent activation of RelA. Mol. Cancer Ther. 9:292–99 [Google Scholar]
  74. Miller TW, Rexer BN, Garrett JT, Arteaga CL. 74.  2011. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 13:224, 1–12 [Google Scholar]
  75. Brady SW, Zhang J, Seok D. 75.  et al. 2014. Enhanced PI3K p110alpha signaling confers acquired lapatinib resistance that can be effectively reversed by a p110alpha-selective PI3K inhibitor. Mol. Cancer Ther. 13:60–70 [Google Scholar]
  76. Xia W, Husain I, Liu L. 76.  et al. 2007. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Cancer Res. 67:1170–75 [Google Scholar]
  77. Dave B, Migliaccio I, Gutierrez MC. 77.  et al. 2011. 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. 29:166–73 [Google Scholar]
  78. Perez EA, Dueck AC, McCullough AE. 78.  et al. 2013. 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. 31:2115–22 [Google Scholar]
  79. Contreras A, Herrera S, Wang T. 79.  et al. 2013. PIK3CA mutations and/or low PTEN predict resistance to combined anti-HER2 therapy with lapatinib and trastuzumab and without chemotherapy in TBCRC006, a neoadjuvant trial of HER2-positive breast cancer patients. Proc. Thirty-Sixth Annual CTRC-AACR San Antonio Breast Cancer Symp., Cancer Res. 73:24 Suppl.Abstr. PD1–2 [Google Scholar]
  80. Loibl S, Denkert C, Schneeweis A. 80.  et al. 2013. PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer—prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies. Proc. Thirty-Sixth Annu. CTRC-AACR San Antonio Breast Cancer Symp., Cancer Res. 73:Abstr. S4–06 [Google Scholar]
  81. Baselga J, Majewski I, Nuciforo PG. 81.  et al. 2013. PI3KCA mutations and correlation with pCR in the NeoALTTO trial (BIG 01–06). Proc. 17th ECCO–38th ESMO–32nd ESTRO European Cancer Congress, Amsterdam, Eur. J. Cancer 49:Suppl.Abstr. 1859 [Google Scholar]
  82. Zhang S, Huang WC, Li P. 82.  et al. 2011. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med. 17:461–69 [Google Scholar]
  83. Scaltriti M, Eichhorn PJ, Cortes J. 83.  et al. 2011. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc. Natl. Acad. Sci. USA 108:3761–66 [Google Scholar]
  84. Nahta R, Takahashi T, Ueno NT. 84.  2004. P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 64:3981–86 [Google Scholar]
  85. Beano A, Signorino E, Evangelista A. 85.  et al. 2008. Correlation between NK function and response to trastuzumab in metastatic breast cancer patients. J. Transl. Med. 6:25, 1–10 [Google Scholar]
  86. Varchetta S, Gibelli N, Oliviero B. 86.  et al. 2007. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res. 67:11991–99 [Google Scholar]
  87. Musolino A, Naldi N, Bortesi B. 87.  et al. 2008. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J. Clin. Oncol. 26:1789–96 [Google Scholar]
  88. Mellor JD, Brown MP, Irving HR. 88.  et al. 2013. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J. Hematol. Oncol. 6:1, 1–10 [Google Scholar]
  89. Loi S, Michiels S, Salgado R. 89.  et al. 2013. Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer (HER2+ BC). Cancer Res. 73:24 Suppl.Abstr. S1–05 [Google Scholar]
  90. Kohrt HE, Houot R, Weiskopf K. 90.  et al. 2012. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J. Clin. Invest. 122:1066–75 [Google Scholar]
  91. Yang XH, Flores LM, Li Q. 91.  et al. 2010. Disruption of laminin-integrin-CD151-focal adhesion kinase axis sensitizes breast cancer cells to ErbB2 antagonists. Cancer Res. 70:2256–63 [Google Scholar]
  92. Huang C, Park CC, Hilsenbeck SG. 92.  et al. 2011. β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 13:R84, 1–15 [Google Scholar]
  93. Guo W, Pylayeva Y, Pepe A. 93.  et al. 2006. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126:489–502 [Google Scholar]
  94. Zoeller J, Bronson R, Gilmer T. 94.  et al. 2012. Basement membrane localized tumor cells are protected from HER2-targeted therapy in vivo. Proc. Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symp., Cancer Res. 72:Suppl.Abstr. P4–085 [Google Scholar]
  95. Untch M, Loibl S, Bischoff J. 95.  et al. 2012. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 13:135–44 [Google Scholar]
  96. Baselga J, Bradbury I, Eidtmann H. 96.  et al. 2012. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379:633–40 [Google Scholar]
  97. Robidoux A, Tang G, Rastogi P. 97.  et al. 2013. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. Lancet Oncol 14:1183–92 [Google Scholar]
  98. Gianni L, Pienkowski T, Im YH. 98.  et al. 2012. 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. 13:25–32 [Google Scholar]
  99. Schneeweiss A, Chia S, Hickish T. 99.  et al. 2013. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann. Oncol. 24:2278–84 [Google Scholar]
  100. de Azambuja E, Piccart M. 100.  2011. Adjuvant treatment of ERBB2 positive breast cancer. Diseases of the Breast M Morrow, JR Harris, ME Lippman, CK Osborne 657–67 Philadelphia: Lippincott Williams & Wilkins, 4th ed.. [Google Scholar]

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