A systematic review of dual targeting in HER2-positive breast cancer

Cancer Treat Rev. 2014 Mar;40(2):259-70. doi: 10.1016/j.ctrv.2013.09.002. Epub 2013 Sep 11.


Background: Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15-20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.

Materials and methods: A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.

Results: This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.

Conclusion: Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.

Keywords: ADCC; ASCO; American Society of Clinical Oncology; Breast cancer; CBR; CHF; CI; DFS; EGFR; ER; FDA; Food and Drug Administration; HER; HR; Human epidermal growth factor receptor; LVEF; Lapatinib; MAPK; MBC; NYHA; New York Heart Association; OS; PFS; PI3K; Pertuzumab; RR; TKI; TTP; Targeted therapy; Trastuzumab; antibody-dependent cell-mediated cytotoxicity; clinical benefit rate; confidence interval; congestive heart failure; disease free survival; epidermal growth factor receptor; estrogen receptor; hazard ratio; human epidermal growth factor receptor; left ventricular ejection fraction; locoregional total complete response; mAB; mTOR; mammalian target of rapamycin; metastatic breast cancer; mitogen-activated protein kinases; monoclonal anti body; overall survival; pCR; pathological complete response; phosphatidylinositol 3-kinase; progression free survival; response rate; time to progression; tpCR; tyrosine kinase inhibitor.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Ado-Trastuzumab Emtansine
  • Afatinib
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Clinical Trials as Topic
  • Disease-Free Survival
  • Everolimus
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lapatinib
  • Maytansine / administration & dosage
  • Maytansine / analogs & derivatives
  • Molecular Targeted Therapy / methods*
  • Neoadjuvant Therapy / methods
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Quinazolines / administration & dosage
  • Quinolines / administration & dosage
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / metabolism*
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Trastuzumab
  • Treatment Outcome
  • Up-Regulation / drug effects


  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Quinazolines
  • Quinolines
  • Lapatinib
  • Maytansine
  • Afatinib
  • ridaforolimus
  • temsirolimus
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ERBB2 protein, human
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • neratinib
  • pertuzumab
  • Trastuzumab
  • Ado-Trastuzumab Emtansine
  • Sirolimus