Journal Article

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

Markomanolaki, Harris, Kalykaki, Antonia, Hatzidaki, Dora, Papadaki, Maria A., Mavroudis, Dimitrios, Agelaki, Sofia, Kallergi, Galatea, Kalbakis, Kostas, Georgoulias, Vassilis

2015

Overview

To 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 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. A 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). The 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. Clinical trial.gov NCT00694252.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Antineoplastic agents / Antineoplastic Agents - therapeutic use / Biology / Bone marrow / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - enzymology / Breast Neoplasms - mortality / Breast Neoplasms - pathology / Cancer / Cancer metastasis / Cancer therapies / Cell Count / Chemotherapy / Cytokeratin / Disease Progression / Drug Resistance, Neoplasm - genetics / Enzyme inhibitors / Epidermal growth factor receptors / ErbB-2 protein / Feasibility studies / Female / Gene Expression / Hospitals / Humans / Inhibitor drugs / Laboratories / Leukocytes (mononuclear) / Mastectomy / Medical imaging / Medical treatment / Medicine / Menopause / Metastases / Metastasis / Microscopy / Middle Aged / Monitoring / Neoplastic Cells, Circulating - drug effects / Neoplastic Cells, Circulating - metabolism / Neoplastic Cells, Circulating - pathology / NMR / Nuclear magnetic resonance / Oncology / Patients / Peripheral blood mononuclear cells / Postmenopausal women / Postmenopause / Premenopause / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase / Quinazolines - therapeutic use / Receptor, Epidermal Growth Factor - antagonists & inhibitors / Receptor, Epidermal Growth Factor - genetics / Receptor, Epidermal Growth Factor - metabolism / Receptor, ErbB-2 - antagonists & inhibitors / Receptor, ErbB-2 - genetics / Receptor, ErbB-2 - metabolism / Stabilization / Survival Analysis / Targeted cancer therapy / Therapy / Treatment Outcome / Tumor cells / Tumors / Tyrosine