title: Emerging strategies for the dual inhibition of HER2-positive breast cancer.
abstract: OBJECTIVE
  To review the recently published trials to help us refine and optimize the use of approved HER2-targeted agents (trastuzumab and lapatinib) and highlight future combination strategies for the treatment of HER2-positive breast cancer.
  
  
  RESULTS
  Pertuzumab, which prevents the dimerization of HER2/HER3, and trastuzumab emtansine (T-DM1), a novel antibody drug conjugate (trastuzumab joined via a stable linker to a derivative of the potent cytotoxic agent maytansine), have both demonstrated promising clinical activity in HER2-positive breast cancer. Dual anti-HER2 regimens combining trastuzumab with lapatinib or pertuzumab show remarkable synergy and improved outcomes in patients previously thought to have refractory disease. In the neoadjuvant setting, dual anti-HER2 blockade and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti-HER2 therapy. A better understanding of the mechanisms of resistance has led to the development of rational combination therapies cotargeting the PI3K and vascular endothelial growth factor signaling pathways.
  
  
  CONCLUSIONS
  New therapeutic options such as pertuzumab or T-DM1 will yield clinically meaningful improvements for patients with HER2-positive breast cancer. Given the high prevalence of intrinsic and acquired resistance to single-agent regimens, the treatment paradigm is shifting toward a dual anti-HER2 therapeutic approach.
authors.affiliation: David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90404-2429, USA. gkonecny@mednet.ucla.edu
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004338:Drug Combinations; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C485206:pertuzumab