Efficacy of Lapatinib in Therapy-Resistant HER2-Positive Circulating Tumor Cells in Metastatic Breast Cancer

Abstract

BackgroundTo evaluate the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in therapy-resistant HER2-positive CTCs in metastatic breast cancer (MBC).Patients and MethodsPatients with MBC and HER2-positive CTCs despite disease stabilization or response to prior therapy, received lapatinib 1500 mg daily in monthly cycles, till disease progression or CTC increase. CTC monitoring was performed by immunofluorescent microscopy using cytospins of peripheral blood mononuclear cells (PBMCs) double stained for HER2 or EGFR and cytokeratin.ResultsA total of 120 cycles were administered in 22 patients; median age was 62.5 years, 15 (68.2%) patients were post-menopausal and 20 (90.1%) had HER2-negative primary tumors. At the end of the second course, HER2-positive CTC counts decreased in 76.2% of patients; the median number of HER2-positive CTCs/patient also declined significantly (p = 0.013), however the decrease was significant only among patients presenting disease stabilization (p = 0.018) but not among those with disease progression during lapatinib treatment. No objective responses were observed. All CTC-positive patients harbored EGFR-positive CTCs on progression compared to 62.5% at baseline (p = 0.054). The ratio of EGFR-positive CTCs/total CTCs detected in all patients increased from 17.1% at baseline to 37.6% on progression, whereas the mean percentage of HER2-negative CTCs/patient increased from 2.4% to 30.6% (p = 0.03).ConclusionsThe above results indicate that lapatinib is effective in decreasing HER2-positive CTCs in patients with MBC irrespectively of the HER2 status of the primary tumor and imply the feasibility of monitoring the molecular changes on CTCs during treatment with targeted agents.Trial RegistrationClinical trial.gov NCT00694252

Phenotypic characterization of circulating tumor cells in triple negative breast cancer patients

“…The potential to target CK+HER2+ CTCs with lapatinib or trastuzumab, has been recently reported [35, 36]. These observations suggest that therapies directed against specific targets could be necessary in order to eliminate CK+HER2+ chemotherapy-resistant CTCs.…”

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

“…Furthermore the same group evaluated the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in therapyresistant HER2-positive CTCs in MBC in a phase 2 single-center study (NCT00694252). Lapatinib was effective in decreasing HER2-positive CTC counts in patients with MBC, irrespectively of the HER2 status of the primary tumor [169] . Two prospective trials are currently ongoing to demonstrate the clinical benefit of anti-HER2 therapy in patients with MBC considered as HER2-negative and HER2-positive CTCs.…”

Clinical Relevance of Serum HER2 and Circulating Tumor Cell Detection in Metastatic Breast Cancer Patients

“…Interestingly, in the meta-analysis by Lee et al, patients with high sHER2 levels benefited from lapatinib therapy regardless of the HER2 status of the tumor (13). It has also been shown that HER2-targeted agents can eliminate HER2-positive CTCs in metastatic BC irrespectively of the HER2 status of the primary tumor (40). The question whether the choice of systemic treatment might be driven by blood-based biomarkers, is currently being clarified in the DETECT trials (2).…”