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Mechanisms of trastuzumab resistance in breast cancer

Sara M Tolaney1, Ian E Krop

  • 1Dana Farber Cancer Institute, Boston, MA 02115, USA.

Anti-Cancer Agents in Medicinal Chemistry
|March 12, 2009
PubMed

Insights

HER2-positive breast cancer treatment with trastuzumab improves outcomes, but resistance remains a challenge. This review explores trastuzumab

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunotherapy

Background:

  • HER2/neu gene amplification in 20-25% of invasive breast cancers correlates with poor prognosis.
  • Trastuzumab, a HER2-targeted antibody, has improved outcomes for HER2-positive breast cancer patients.
  • Resistance to trastuzumab limits its efficacy in metastatic and adjuvant settings.

Purpose of the Study:

  • To review the antitumor mechanisms of trastuzumab.
  • To elucidate mechanisms underlying trastuzumab resistance.
  • To discuss novel agents for overcoming trastuzumab resistance.

Main Methods:

  • Literature review of preclinical and clinical studies.
  • Analysis of molecular pathways involved in HER2 signaling.
  • Evaluation of emerging therapeutic strategies.

Main Results:

  • Trastuzumab mediates antitumor effects through antibody-dependent cell-mediated cytotoxicity and direct signaling inhibition.
  • Mechanisms of resistance include HER2 receptor mutations, downstream pathway activation, and immune evasion.
  • Several novel agents targeting HER2 or resistance pathways show promise.

Conclusions:

  • Understanding trastuzumab resistance mechanisms is crucial for improving patient outcomes.
  • Combination therapies and novel agents offer potential to overcome resistance.
  • Further research is needed to optimize treatment strategies for HER2-positive breast cancer.

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