Inhibition of Epidermal Growth Factor/HER2 Receptor Signaling Using ZD1839

Reviewer: Thomas Dilling, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 18, 2002

Presenter: S. Massarweh
Presenter's Affiliation: Baylor Breast Center
Type of Session: Scientific


  • Resistance of some breast cancers to endocrine therapy remains a problem for clinicians.
  • Research into preventing or reversing endocrine resistance in breast cancer is needed.
  • Some prior studies have shown Her2-positive tumors to be less responsive to Tamoxifen therapy.
  • The presenter first showed some data, utilizing a nude mouse xenograft model for ER+/HER2+ tumors (MCF-7/HER2-18 cells).
  • Mice were randomized to estrogen deprivation, estradiol (E2) administration, or tamoxifen. Tumors in the E2-deprived mice were stable in size. Tumors in the E2-supplemented mice grew rapidly. Mice which received tamoxifen had tumors which were initially stable in size, but later became endocrine unresponsive, growing in size.
  • Data seem to suggest "cross-talk" between epidermal growth factor receptor (EGFR) and the HER2 receptor pathway, leading to endocrine resistance in the tumor.
  • The researchers then evaluated the role of ZD1839 ("Iressa"), an orally active, selective EGFR tyrosine kinase inhibitor that blocks EGFR and HER2 activation. The goal was to evaluate whether Iressa modulated endocrine resistance in these mice.

Materials and Methods

  • The researchers repeated their prior nude mouse tumor model experiment, this time utilizing a six-arm design. Mice were randomized initially to estradiol supplementation, estrogen repression, or Tamoxifen.
  • Mice in these 3 arms were then randomized to Iressa or control.


  • Iressa modestly diminished tumor growth in the E2-positive mice.
  • In E2-negative mice, development of tumor resistance/growth was delayed in those mice which received Iressa.
  • Tamoxifen and Iressa together lead to longer term repression of tumor growth than Tamoxifen alone.

Author's Conclusions

  • These studies support the idea that EGFR/HER2 receptor cross-talk influences de novo and acquired resistance to various endocrine therapies.
  • Combinations of ER and HER2 receptor blockade might be the optimal approach in patients with tumors which are ER+ and HER2+.

Clinical/Scientific Implications

  • Human clinical trials will need to be performed to address these issues.
  • Per discussion at the presentation, such trials are in the planning stages.

Oncolink's ASCO Coverage made possible by an unrestricted Educational Grant from Bristol-Myers Squibb Oncology.


Where Are the Adults in the Room?
by Rodney Warner, JD
November 20, 2015

Related News

ASCO Issues Guidelines for Advanced HER2+ Breast Cancer

May 8, 2014

Recommendations provided for management of advanced disease without, with brain mets

Dual Inhibition of HER2 Beats Single Agent in Breast Cancer

Jan 18, 2012

For HER2-positive breast cancer, inhibition with lapatinib and trastuzumab superior to single agent

Alternate Chromosome 17 Genes Detect True HER2 Status

Sep 29, 2011

Three alternative chromosome 17 genes determine true HER2 status in breast cancer with polysomy 17