title: Hitting multiple targets in HER2-positive breast cancer: proof of principle or therapeutic opportunity?
abstract: BACKGROUND
  Pharmacological targeting of the tyrosine kinase receptor HER2 with the monoclonal antibody trastuzumab has dramatically changed the outlook of HER2-positive breast cancer patients. However, HER2 is part of a more complex biological network that, when deregulated, plays a central role in sustaining the cancer phenotype. These interactions account for primary or acquired resistance to drugs that hit a single biological target, like trastuzumab. Several preclinical models suggest that simultaneous targeting of crucial metabolic pathways has the potential to circumvent or delay the onset of resistance phenomena in HER2-positive breast cancer cells.
  
  
  METHODS
  This review describes the rationale and results of clinical trials using biologically targeted agents in HER2-positive breast cancer patients. Single drugs that hit multiple targets and cocktails of biologically targeted agents are considered, whereas combinations with chemotherapy are not addressed.
  
  
  CONCLUSIONS
  Most of the studies using biological agents to hit multiple targets in HER2-positive breast cancer patients confirm that resistance to single-agent HER2-targeting can be overcome. Further developments will include combination of multi-targeting strategies with chemotherapy in patients with earlier-stage disease. In addition, it is possible that newer molecular predictive factors may allow a more rationale choice of the most appropriate targeting for each individual patient.
authors.affiliation: Fondazione del Piemonte per l'Oncologia/Division of Medical Oncology I, Institute for Cancer Research and Treatment (IRCC), Strada Provinciale 142, Candiolo, Turin, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Geuna
authors.forename: Andrea
authors.initials: A
authors.lastname: Milani
authors.forename: Stefania
authors.initials: S
authors.lastname: Redana
authors.forename: Valentina
authors.initials: V
authors.lastname: Rossi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valabrega
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.forename: Filippo
authors.initials: F
authors.lastname: Montemurro
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases