Fig 1.
Twenty-eight patients were randomized to the following treatment groups: lapatinib 500 mg PO BID; lapatinib 1000 mg PO QD; lapatinib 1500 mg PO QD. Patient follow up and data analysis were conducted as indicated.
Fig 2.
Lapatinib in human breast cancer xenograft tissue.
Steady-state (Day 3) lapatinib concentrations in blood, tumor, kidney, and liver measured in CB-17 SCID female mice bearing established HER2+ BT474 breast cancer xenografts (n = 45) following treatment with lapatinib (100 mg/kg BID) administered by oral gavage x 5 doses. Results represent the mean +/- standard error.
Table 1.
Median (range) lapatinib exposure in mouse (n = 3) tumor, blood, and plasma after the fifth dose of 100 mg/kg BID (AUC 0–12) or third dose of 200 mg/kg QD (AUC 0–24).
Fig 3.
The relationship between lapatinib concentrations in tumor and plasma from clinical samples.
Women with early stage HER2+ breast cancer were randomized to oral lapatinib monotherapy at 500 mg twice daily (BID), 1000 mg once daily (QD), or 1500 mg QD. Lapatinib concentrations (μM) in plasma (CP) and tumor (CT) tissue samples obtained simultaneously 9–15 days after initiating therapy (steady state) concentrations (Cmin). (A). Lapatinib concentrations for each patient in the indicated treatment groups. The dotted blue line represents the reported IC90 value for lapatinib in HER2+ breast cancer cell lines. Large circles represent group medians. (B) The complex relationship between lapatinib concentration in tumor and plasma showing a speculative model that suggests determinants: target protein binding (lower Emax curve), and net uptake/efflux (upper Emax curve): grey circle (patient with dysfunctional ABCB1 SNP C3435T); open circle (patient taking lapatinib 500 mg BID also taking grape seed oil), shown with simulation and deviations (dashed lines) illustrating speculation of diminished efflux (left shift) and increased EGFR target binding (right shift). The horizontal dotted line at 4 μM represents the IC50 for the ABCB1 transporter.
Table 2.
Patient Demographics.1
Table 3.
Median (range) of lapatinib concentrations in tumor, plasma, and their ratios.
Fig 4.
Phosphorylation of HER receptors relative to tumor and plasma concentrations of lapatinib.
Changes (post-/pre-treatment ratios of optical density (OD values)) in EGFR, HER2, and HER3 phosphorylation in response to lapatinib in clinical tumor samples, and their relationship to tumor (left panel) and plasma (right panel) concentrations of lapatinib.