Growth factor receptor 1 and 2 (HER1 and HER2) gene and protein assessment and evaluation of lapatinib plasma concentrations (PCs) in breast cancer patients

Abstract

Trastuzumab is a monoclonal antibody targeting HER2. Lapatinib, a tyrosine kinase inhibitor, targets HER2 and HER1 (also EGFR), but the HER1 status is not assessed in clinical practice. Drug plasma concentrations (PCs) may influence the treatment outcome. This study focuses on HER1 status, lapatinib PCs, and lapatinib treatment response. Retrospective tumor and blood samples from 28 lapatinib plus capecitabine treated patients (Pts) were used. HER1 gene, chromosome 7 (Ch7), and protein status were assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in archival tumors. Lapatinib PCs were evaluated by ultra performance liquid chromatography–tandem mass spectrometry. Blood samples were taken in 16 to 30 hours after lapatinib administration. The data were evaluated by standard statistical methods. Pts were treated with lapatinib plus capecitabine for advanced disease. Most tumors were invasive ductal carcinomas 82% (23/28); 43% (12/28) displayed hormonal receptor positivity. Lapatinib treatment lasted from 1.2 to 15.6 months. Twenty Pts ended lapatinib due to progression, 6 owing to toxicity. Ch7 polysomy was found in 30% (6/20) of Pts. HER1 amplification was not observed. HER1 membrane expression was found in 22% (5/23). Median of lapatinib PCs was 5.09 g/ml, with small interindividual variations. The exception was 1 patient (11.25 g/ml) with hepatotoxicity. HER1 IHC membrane positivity correlated negatively with disease-free survival (DFS) (p < 0.014) and cytoplasmic positivity correlated negatively with DFS (p < 0.017) and overall survival (OS) (p < 0.035). Longer trastuzumab to lapatinib intervals correlated with longer OS (p < 0.008). Intercalation of 5-FU based regimens between trastuzumab and lapatinib influenced negatively survival on lapatinib plus capacitabine (p < 0.02). Intercalation of chemotherapy based on 5-FU before lapatinib plus capecitabine regimen reduces the treatment effect and suggests preselection of resistant cells before lapatinib plus capecitabine administration. Lapatinib PCs were higher in one patient who developed liver toxicity. Thus, measurement of PCs may be a way of identifying hepatotoxicity high risk patients and titering their lapatinib doses to avoid side effects. Supported by internal grant of the Faculty of Medicine and Dentistry, Palacky University, no. 91110301 and MSM 6198959216.