Use of ERCC1 expression levels in circulating tumor cells to predict response to platinum-based chemotherapy in patients with non-small cell lung cancer

  • KMG Klinik Silbermühle GmbH
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7512 Background: ERCC-1 is a nucleotide excision repair gene associated with DNA repair of DNA adducts induced by platinum based chemotherapy. ERCC-1 mRNA levels have been shown to predict response in patients with NSCLC when treated with platinum based chemotherapy. We therefore examined whether ERCC1 expression levels in specifically enriched circulating tumor cells (CTC) are associated with response to platinum-based systemic first-line chemotherapy. Methods: Blood was drawn from 75 patients, treated consecutively in our institution, 1 hour before chemotherapy on days 1 and 22 of first-line chemotherapy. RECIST criteria were applied to evaluate clinical response (CT-scan). Mononuclear Cells and CTC were enriched from peripheral venous blood using a specifically designed buoyant density gradient centrifugation. After using immuno-magnetic beads with anti-CD15 and anti-CD45 monoclonal antibodies to negatively select hematopoietic cells, epithelial tumor cells were directly enriched from the residual cell suspension using magnetic beads coated with the monoclonal antibody BerEP4 against the human epithelial antigen, EpCAM. ERCC1 mRNA expression was measured using a quantitative real-time RT-PCR method. Results: ERCC1 expression levels in CTC were significantly correlated with response (p = 0.003) to platinum-based chemotherapy. Receiver Operating Characteristic (ROC) Curve Analysis was used to assess the sensitivity and the specificity of high ERCC1 expression (> 75th percentile) to distinguish disease control (response or stable disease) from progressive disease. The sensitivity (true positive rate) was 75% and the specificity (true negative rate) 81.3%. The area under the curve was 0.78 (CI 0.612 to 0.901) with a significance level of p = 0.04. Conclusions: These results suggest that ERCC1 gene expression levels in circulating tumor cells in patients with non-small cell lung cancer predict response prior to first-line chemotherapy. ERCC1 gene expression levels may therefore allow the selection of patients who benefit likely from platinum-based chemotherapy. Further studies are warranted to study this association. No significant financial relationships to disclose.

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... 27 Nevertheless, these studies were done in biopsy specimens and, in most instances, required a second biopsy to obtain sufficient tissue to perform the ERCC1 analysis. Hoffmann et al., 28 in an effort to eliminate the need for a second biopsy, examined whether ERCC1 expression levels in specifically enriched circulating tumor cells (CTCs) were associated with response to platinum-based chemotherapy. Blood was drawn from 75 consecutively treated patients with advanced NSCLC 1 hour before chemotherapy on days 1 and 22 of first-line chemotherapy. ...
The promising results of crizotinib in molecularly selected patients with advanced non-small cell lung cancer (NSCLC) whose tumor cells had a novel fusion protein involving anaplastic lymphoma kinase presented at the 2010 American Society of Clinical Oncology reinforce once again the importance of understanding molecular heterogeneity of lung cancer and careful patient selection. Several other important issues were the subject of presentations related to lung cancer at the recently concluded American Society of Clinical Oncology annual meeting. The articles covered a wide variety of topics including optimal staging techniques to detect mediastinal nodal involvement, the role of platinum-based doublet chemotherapy in the management of elderly patients with advanced NSCLC, use of maintenance therapy with gemcitabine, and the impact of early introduction of organized palliative care in improving the quality of life of patients with advanced NSCLC. This report provides a brief overview of the presentations related to lung cancer that are relevant to clinical practice and future research.
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Circulating tumor cells (CTC) could serve as a "liquid biopsy" for individualizing and monitoring treatment in patients with solid tumors as recently shown by our group. We assessed which non-hematopoietic cell types are identifiable in the peripheral blood of patients with non-small cell lung cancer (NSCLC) and correlated those to clinical characteristics. Blood from NSCLC patients (n=43) was processed as previously described. For subtype analyses CTC were negatively enriched by hematopoietic cell depletion. The remaining cell suspension included pre-enriched tumor cells and was spun onto glass slides and further characterized by multi-immunofluorescence staining against epithelial markers pan-cytokeratin (CK) and epithelial cell adhesion molecule (EpCAM), mesenchymal marker N-cadherin, stem cell marker CD133, hematopoietic marker CD45 and nuclear counterstain DAPI. Individual cell type profiles were analyzed and correlated to therapeutic outcome. Among other associations of CTC subtypes with clinical parameters Kaplan-Meier test revealed that an increased CD133-positive to pan-CK-positive cell type ratio (stem cell like to epithelial ratio) and the presence of mesenchymal N-cadherin+ cells, both were significantly associated to shortened PFS (2 vs. 8 months, P=0.003, HR =4.43; 5 vs. 8 months, P=0.03, HR =2.63). Our data suggest that different CTC populations are identifiable in peripheral blood and that these individual cell type profiles might be used to predict outcome to platinum based systemic therapies in lung cancer patients.
Treatment for patients with advanced NSCLC generally consists of chemotherapy, but response rates are modest and recurrence occurs for most patients after standard first-line platinum-based doublet therapy. Tailoring therapy to individual patient according to certain prognostic and predictive factors has the potential to improve outcome in NSCLC. This review focuses on the most important molecular prognostic and/or predictive factors in the treatment of advanced NSCLC; considering these molecular features, we also suggest a molecular-based treatment algorithm.
Lung cancer is a heterogenous group of disorders, and a difficult disease to treat. The traditional approach of surgical resection for early-stage disease, potentially followed by chemotherapy, as well chemotherapy (with or without radiation) in later stages of disease is being supplemented with a personalized approach. The personalized approach has classically been used by the oncologist based on clinical/pathological parameters such as the performance status of the patient and histology of lung cancer. As molecular mechanisms have been explored in lung cancer more recently, the personalized approach also has incorporated molecular abnormalities. In particular, EGFR, K-ras, ALK, MET, CBL, and COX2, have come to the forefront as potential biomarkers and therapeutic targets. Thus, we review the various molecular mechanisms in lung cancer and the role of novel therapeutics.
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