Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer

Abstract

Background: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.

Methods: Patients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([(11)C]lapatinib)-PET. Less than 20 μg of [(11)C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted.

Results: Six patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [(11)C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [(11)C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [(11)C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib.

Conclusions: Increased lapatinib uptake was observed in brain metastases but not in normal brain.

Trial registration: ClinicalTrials.gov: NCT01290354.

Keywords: Blood-brain barrier; Her-2-positive breast cancer; Lapatinib bio-distribution in brain metastases; PET imaging.

Figures

Figure 1

Study hypothesis. It was hypothesised that brain penetration in normal brain would increase with therapeutic serum concentrations of lapatinib due to the effect of lapatinib on drug efflux pumps. Higher brain penetration in metastases compared with normal brain was also hypothesised due to the disruption of the BBB in cranial metastases. 11C, carbon-11 radiolabelled; BBB, blood-brain barrier; PET, positron emission tomography.

Figure 2

Fully automated and good manufacturing process-compatible synthesis developed to label lapatinib with radiolabelled carbon-11 in the benzylic position. [11C]Lapatinib was prepared in a two-pot four-step synthesis, with intermediate preparation of [11C]-3-fluorobenzyl iodide that was reacted in the last step with the lapatinib precursor. 11C, carbon-11.

Figure 3

Radioactivity versus time curves and tissue exposure. Time-activity curves (TACs) for individual metastases for all the subjects from the day 8 PET scan (A) show variability in uptake between and within patients. Mean TAC is also shown for comparison (green) and shows minimal variability. In (B), mean TACs for normal brain (green) is plotted for comparison with mean whole blood (red) and plasma (plasma) TACs. Uptake has been corrected for injected activity and normalised for body weight and quantified in the Y-axis as standardised uptake value (SUV; g/mL). Tissue exposure (area under the TAC SUV (min.g/mL) for normal brain (C) and metastases (D) shows variability in uptake in metastases. However, there is minimal variability in uptake within metastases on day 1 (red bars) compared to day 8 (green bars). Minimal variability in lapatinib uptake is seen in normal brain between subjects. AUC, area under the curve concentration; contrib, contribution; min, minutes; Sub, subject; SUV, standardised uptake value; TAC, time-averaged concentration.

Figure 4

Blood volume contribution to activity to intracerebral uptake. Mean radioactivity versus time curves for (A) normal brain and (B) brain metastases and scaled-down blood radioactivity versus time curves to illustrate cerebral blood volumes of 5%. Sub, subject; SUV, standardised uptake value; min, minutes.

Figure 5

Image data for patient 10. The image data show radioactivity distribution in normal brain and cerebral metastases (enclosed in blue circle) (top panel) and are separated into non-blood (middle upper panel), blood (middle lower panel) and corresponding contrast-enhanced MRI images (bottom panel). Since the blood volume in metastases may not be 5%, a blood volume fraction model was fitted to dynamic data on a voxel-by-voxel basis. The uptake of radioactivity in the brain metastases was higher than that contributed from a model-fitted blood volume. MRI, magnetic resonance imaging; SUV, standardised uptake value.