Circulating tumor cells as a response monitor in stage IV non-small cell lung cancer

Abstract

Background Monitoring circulating tumor cells (CTC) has been shown to be prognostic in most solid malignancies. There is no CTC assay in clinical use for lung cancer therapy monitoring due to inconclusive clinical utility data. Limited data has been published outside of the standard CTC enumerations, regarding clinical significance of phenotypic heterogeneity of CTCs in late stage NSCLC and its ability to correlate with treatment outcomes. Methods In 81 patients with stage IV NSCLC, multiple timepoints for CTC analysis were collected after initiation of treatment across 139 lines of therapy using single cell high definition diagnostic pathology imaging of all nucleated cells from 362 peripheral blood samples as a liquid biopsy. Results We analyzed the subset of 25 patients with complete time series data, totaling 117 blood samples, to determine the significance of HD-CTC kinetics during the initiation of treatment. These kinetics follow three distinct patterns: an increase in HD-CTCs with therapy (mean + 118.40 HD-CTCs/mL), unchanged HD-CTCs numbers (stable; mean 0.54 HD-CTCs/mL), and a decrease in HD-CTCs numbers (mean − 81.40 HD-CTCs/mL). Patients with an increasing CTC count during the first 3 months post initiation of new treatment had a better PFS and OS compared to the other groups. There was weak correlation between the absolute number of HD-CTCs at a single time point of therapy and patient outcomes (OS p value = 0.0754). In the whole cohort of 81 patients, HD-CTCs were detected in 51 (63%) patients at initiation of therapy with a median of 2.20 (range 0–509.20) and a mean of 26.21 HD-CTCs/mL (± 15.64). Conclusions CTCs are identifiable in most patients with stage IV NSCLC. While absolute HD-CTC counts do not correlate with prognosis, the changes in CTC counts were predictive of survival in patients with metastatic lung cancer receiving chemotherapy. The level and dynamics of CTCs indicate very different biological and pharmacological phenomena at different stages of disease and timepoints of treatment, highlighting the complex role of CTCs in cancer research and clinical management.

Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer

“…In a combined study for metastatic breast and prostate cancer, Coumans et al demonstrated that for initially CTC-positive patients, a decrease of CTC count below the cut-off after 6-8 weeks of therapy is the best indicator of treatment response [38]. The association of therapy response and conversion from positive to negative CTC status was also demonstrated for metastatic non-small cell lung cancer, locally advanced head and neck cancer and gastric cancer [39][40][41]. Lorente et al described a 30% CTC decline 4 weeks after treatment for castration-resistant prostate cancer with initially ≥5 CTCs/7.5 mL as independently associated with OS and a more sensitive biomarker than 50% CTC decline [27].…”

High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients

“…The discovery and development of small molecule TKIs has revolutionized therapy for specific molecular subsets of NSCLC patients [45]. However, the majority of patients will develop resistance to TKIs within a few months/years [45,46]. The resistance is often mediated by a secondary mutation in the target gene or alternative pathways that supervene and bypass the original signaling pathway [47].…”

Tumor microenvironment complexity and therapeutic implications at a glance

“…Cancer cells that are detached from the primary tumor site and entered the bloodstream are categorized as CTCs [143]. The implication of CTCs is well established in tumor cell dormancy, as a major cause of metastatic outgrowth, multi drug resistance (MDR) and cancer relapse [144]. These cells are precise representations of primary and metastatic tumors that convey information for the detection, diagnosis (monitoring) and the treatment of cancer [145].…”