• 2019-07
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  • 2021-03
  • br Methods br Results br COMMENT br Conclusions


    Declaration of Competing Interest
    Introduction Non-small cell lung cancer (NSCLC) accounts for ˜85% of lung malignancies, which are the leading cause of cancer-related deaths worldwide. In 2011, the National Lung Cancer Screening Trial (NLST) demonstrated in subjects at high-risk that mortality can be reduced 20% by screening with low-dose CT (LDCT) [1]. The U.S. Preventive Services Task Force recommends LDCT screening in individuals 55–80 years of age with ≥30 pack-year smoking history, current smokers or who have quit within the last 15 years (grade B evidence). However, LDCT screening has the limitation of a very high rate of false-positive lung nodule findings [1]. Many lung nodules are further evaluated with radiographic imaging or invasive interventions, leading to unnecessary radiation exposures, morbidities and costs. A clinically applicable biomarker reducing the high false-positive rate in LDCT imaging will fill an unmet need in lung cancer screening. Circulating tumor Hexa His tag peptide (CTCs) are considered to have detached from a primary tumor and are consistently found in the blood of cancer patients. CTCs are defined as cancer-associated cells in the blood that express cytokeratins (CKs) 8/18 and/or 19 and EpCAM (epithelial cell markers) and that do not express CD45 (a leukocyte marker), with a well-defined nucleus identifiable with DAPI. Using appropriate detection technologies such as size-based isolation, CTCs are frequently observed in aggregates, and these CTC clusters (≥2 CTCs; also described as tumor microemboli) have shown to harbor a unique tumor biology and microenvironment with significantly enhanced metastatic potential in comparison to non-clustered, single CTCs [2]. Consistent with findings in other cancers, presence of CTC clusters in the blood has been reported to be associated with poor prognosis of NSCLC patients [3].
    Materials and methods
    Discussion Despite recent implementation of novel targeted agents, five-year survival of lung cancer remains at a low rate of 19%. Screening of high-risk subjects with LDCT can reduce lung cancer-related mortality by 20%, but the high false-positive rate of lung nodules leads to morbidities from interventions, unnecessary imaging, and costs [1]. Liquid biomarkers, including CTCs, have been suggested to improve accuracy of LDCT lung cancer screening, which would ultimately reduce morbidities and costs. In a prospective study on high-risk screening subjects (aged 55–80 and smoking history ≥30 pack-years) undergoing LDCT and patients diagnosed with NSCLC, we demonstrate that presence of CTC clusters (≥2 CTCs aggregate) is limited to NSCLC patients only. However, non-clustered CTCs can be detected in high-risk screening subjects with no (Lung-RADS 1) or benign nodules (Lung-RADS 2) on LDCT. Therefore, CTC clusters have a potential role as liquid biomarkers in LDCT screening due to their specificity to NSCLC. In our cohort of lung cancer screening subjects with no or benign nodules, single CTCs were identified in some individuals at low levels. Similarly, non-clustered CTCs were also described in women with benign conditions undergoing breast cancer screening [6]. The reason for these false-positive rates are unclear, but could be due to another undiagnosed cancer (such as colorectal or prostate) since screening populations are obviously at risk for other malignancies. In particular the high-risk LDCT subjects with CTCs will need to be followed longitudinally. Although we did not observe CTC clusters in all NSCLC patients (41.4%), their exclusiveness to NSCLC and occurrence in early stages makes CTC clusters attractive for detection of at least a subset of NSCLCs. In the present pilot study, we intended to compare presence of CTC clusters between patients with NSCLC and a group with similar risk factors (defined by age and smoking history) that has no cancer (Lung-RADS 1 and 2). Yet, a CTC cluster analysis on screening subjects with probably benign (Lung-RADS 3) and suspicious lung nodules (Lung-RADS 4A/B/X) will need to be performed, as kilocalorie will further clarify the specificity of CTC clusters for NSCLC diagnosis.