514 Background: Brain metastasis (BM) is a challenging complication of metastatic breast cancer (MBC). Although systemic therapy is not commonly considered as a primary therapeutic approach, its potential in BM management has recently become apparent (Bachelot T et al Lancet Oncol 2013). Capecitabine and lapatinib in particular have been evaluated in HER2+ breast cancer BM (BCBM), but evidence for drug/metabolite CNS penetration is solely derived from preclinical animal models. In this study, we examined capecitabine, its metabolites, and lapatinib uptake in BCBMs resected due to medically indicated craniotomy. Methods: Study patients had BCBM requiring surgical resection. Patients with HER2-negative MBC received a single preoperative oral dose of capecitabine (1250mg/m2) 2-3 hrs before surgery. Those with HER2+ MBC received 2-3 oral doses of lapatinib (1250mg) daily, the last dose 2-3 hrs before surgery. On the day of surgery, serum was collected serially starting just before drug administration, intraoperatively, and through one hour after the conclusion of surgery. The concentration of capecitabine, its metabolites, and lapatinib from serum and BM were measured using liquid chromatography with tandem mass spectroscopy (LC-MS/MS). Results: 10 patients enrolled; PK data is available for 9: 6 for capecitabine and 3 for lapatinib. Capecitabine, its intermediate metabolites, 5FU, and lapatinib were detected in all BMs. Tumor capecitabine and 5-FU concentrations ranged from 3% to 129% and from 168% to 1422%, respectively, of serum concentrations. For lapatinib, the range was 21% to 700%. In a number of the BMs, drug concentrations were in the therapeutic range, whereas in others the concentrations were up to 10 fold lower. Conclusions: This is the first study to show capecitabine and lapatinib were detected in clinically relevant concentrations in a number of non-irradiated human BCBMs. This provides evidence for their ability to cross the blood-brain barrier, is consistent with prior published clinical activity, and supports further evaluation in a clinical setting prior to whole brain radiotherapy. Clinical trial information: NCT00795678.
Population-based outcomes after whole brain radiotherapy and re-irradiation in patients with metastatic breast cancer in the trastuzumab era
