Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers

Abstract

Early detection of metastasis can be aided by circulating tumor cells (CTCs), which also show potential to predict early relapse. Due to the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared to pre-operative Pe (p<0.0001) and intra-operative Pe (p<0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long term surveillance indicated that presence of clusters in pre-operative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence.

Decoding tumor mutation burden and driver mutations in early stage lung adenocarcinoma using CT‐based radiomics signature

“…For early stage lung cancer, due to the difficulty of tissue biopsy, there is still a lack of sensitive biomarkers to predict TMB and oncogenic driver mutations before surgery. With the development of liquid biopsy techniques, such as circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs), it is possible to obtain the genomic mutation status from a blood sample; however both the sensitivity and cost are prohibitive Our study demonstrated that selected radiomics signatures using machine learning technique are feasible and effective to predict TMB and some driver mutations (EGFR and TP53) in patients with early stage LUAD.…”

Tracking cancer progression: from circulating tumor cells to metastasis

“…Traditional approaches for molecular interrogation of CTCs include testing for genomic aberrations using immunostaining combined with fluorescence in situ hybridization (FISH) and real-time quantitative PCR (RT-qPCR) to evaluate the transcript levels of specific genes [17]. Yet, it is the development of single-cell technologies during the past decade that has enabled a comprehensive interrogation of CTCs from patients with various cancer types.…”

“…Although they typically represent a minority of the CTCs found in the peripheral circulation, they have a metastatic potential that has been estimated to be 23 to 50 times greater than that of their single-cell counterparts [21]. In addition, the presence of CTC clusters and cluster size are associated with worse clinical outcome than the presence of single CTCs in multiple cancer types [17,21,[47][48][49][50]. Although the existence of CTC clusters has been known for decades [51][52][53][54][55], the biological mechanisms behind their formation, survival, dissemination, and superior metastatic ability are only partially understood [48].…”

Wedge Resection of Tumor Before Lobectomy for Lung Cancer Could Be a No-touch Isolation Technique

“…Interestingly, even for early stage lung cancer, CTCs can be detected in 60-80% in patients (18,19). Recently, Murlidhar et al (20) reported that PV had significantly not only higher number of CTCs, but also larger CTC clusters compared to pre-operative and intra-operative peripheral vein among early stage lung cancer patients. Duan et al (17) demonstrated that CTC counts after lobectomy for lung cancer were significantly higher than those before PV interruption.…”