Molecular predictors of response to trastuzumab and lapatinib in breast cancer
Francisco J Esteva1, Dihua Yu, Mien-Chie Hung
1Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA. fjesteva@mdanderson.org
Abstract:
Trastuzumab is a monoclonal antibody directed against the human EGFR2 (HER2) protein that has been shown to improve survival in patients with HER2-positive breast cancer. Lapatinib is an oral small-molecule tyrosine kinase inhibitor directed against EGFR and HER2. Lapatinib therapy was shown to prolong the time to progression and increase the rate of response to capecitabine in patients who had received anthracycline-based and taxane-based chemotherapy, and whose tumors had progressed on trastuzumab. HER2 status, either gene copy number or the protein expression level, is the best predictive marker available for assessing response to trastuzumab and lapatinib. Whether the power of this predictive marker is the same in advanced and early-stage cancers is unknown. There is great interest in developing diagnostic tests that predict which patients are more likely to benefit from specific HER2-directed therapies. Novel therapeutics that will overcome resistance to trastuzumab and lapatinib are under intense clinical development. In the future, it will be important to characterize mechanisms of resistance in metastatic tumors to determine which novel targeted therapy will be most appropriate for individual patients.
Insights
HER2-targeted therapies like trastuzumab and lapatinib show promise for HER2-positive breast cancer. Further research is needed to predict patient response and overcome treatment resistance.
Area of Science:
- Oncology
- Pharmacology
Background:
- Trastuzumab, a monoclonal antibody, targets human epidermal growth factor receptor 2 (HER2) and improves survival in HER2-positive breast cancer.
- Lapatinib, an oral tyrosine kinase inhibitor, targets EGFR and HER2, showing efficacy in patients progressing on trastuzumab.
Purpose of the Study:
- To evaluate the predictive power of HER2 status in early-stage versus advanced cancers.
- To explore novel diagnostic tests for predicting response to HER2-directed therapies.
- To investigate novel therapeutics overcoming resistance to trastuzumab and lapatinib.
Main Methods:
- Review of existing clinical data on trastuzumab and lapatinib efficacy.
- Analysis of HER2 gene copy number and protein expression levels as predictive markers.
- Exploration of ongoing clinical trials for novel HER2-targeted agents.
Main Results:
- HER2 status is the best predictive marker for trastuzumab and lapatinib response.
- Efficacy of lapatinib in prolonging progression-free survival and increasing response rates to capecitabine in pre-treated patients.
- Unknown if HER2 predictive marker power is consistent across early and advanced stages.
Conclusions:
- HER2 status is crucial for guiding HER2-directed cancer therapy.
- Development of predictive diagnostic tests is essential for personalized treatment.
- Understanding resistance mechanisms is key to advancing novel targeted therapies for breast cancer.
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