Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer

Breast Cancer Res Treat. 2015 Oct;153(3):493-505. doi: 10.1007/s10549-015-3578-x. Epub 2015 Sep 23.


HER2 receptor is overexpressed approximately in 20 % of human breast cancer (BC) and is a poor prognostic factor. Although therapies targeting this receptor have improved the prognosis of this cancer, up to 62 % patients treated with these drugs experiment progression during the first year of treatment. Some molecular mechanisms have been proposed to be responsible for this resistance, such as activation of alternative signaling pathways (through ERBB receptors and non-ERBB receptors or increased expression of ligands and alterations in HER2 signaling components). In this article, we will review the influence of genetic markers in non-HER2 signaling pathways investigated to date as cause of resistance to HER2-targeted drugs in HER2-positive BC patients. GRB7, included in the 17q12 amplicon, has been associated to poor prognosis in BC patients. Biomarkers like EPHAR and SRC, have demonstrated clinical relevance and prognostic value in HER2-positive BC patients. Non-invasive biomarkers, such as elevated IGF1 serum levels have been revealed as interesting biomarkers to be considered as predictors of trastuzumab clinical outcomes in BC patients. However, the prognostic value of most of the biomarkers investigated to date, such as HER3, IGF1R, PIK3CA, or AKT1 cannot be fully established yet, since results have not been conclusive.

Keywords: Breast cancer; HER2-targeted therapies; Lapatinib; Pharmacogenetics; Resistance; Trastuzumab.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Carcinogens
  • Chromosomes, Human, Pair 17 / metabolism
  • Drug Resistance, Neoplasm* / genetics
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Ligands
  • Molecular Targeted Therapy*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptors, Somatomedin / metabolism
  • Signal Transduction / drug effects*


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Carcinogens
  • Ligands
  • Receptors, Somatomedin
  • ErbB Receptors
  • Receptor, ErbB-2