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Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer
Kunal S Taskar1, Vinay Rudraraju, Rajendar K Mittapalli
1Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, Texas 79106, USA.
Purpose:
Lapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following (14)C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer.
Methods:
Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.
Results:
(14)C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, average lapatinib concentration in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains.
Conclusions:
Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.
Insights
Lapatinib, an EGFR/HER2 inhibitor, shows limited distribution to brain metastases in breast cancer models. Blood-tumor barrier permeability significantly impacts lapatinib concentration in brain lesions, varying between individual tumors.
Area of Science:
- Pharmacology
- Oncology
- Neuroscience
Background:
- Lapatinib (EGFR/HER2 inhibitor) shows partial efficacy against HER2+ brain metastases.
- Understanding lapatinib's CNS penetration is crucial for treating brain metastases.
Purpose of the Study:
- To evaluate lapatinib's CNS concentration in preclinical models of HER2+ breast cancer brain metastases.
- To investigate the correlation between blood-tumor barrier permeability and lapatinib distribution.
Main Methods:
- Administration of (14)C-lapatinib to mice with brain metastases.
- Quantification of drug concentrations using autoradiography and chromatography.
Main Results:
- Lapatinib concentration in brain metastases was higher than in surrounding brain tissue but lower than in peripheral metastases.
- Blood-tumor barrier permeability influenced lapatinib distribution, with only 17% of lesions showing concentrations comparable to systemic metastases.
- No lapatinib resistance was observed in ex vivo tumor cell cultures.
Conclusions:
- Lapatinib distribution to brain metastases is restricted, with blood-tumor barrier permeability being a critical, variable factor.
- Therapeutic efficacy of lapatinib in brain metastases is influenced by individual tumor characteristics and BBB integrity.
