Table 3.
Summary of a number of Circulating Tumor Cell studies in lung cancer.
| Study | Histology | Sample number | Isolation method | Major findings | References |
|---|---|---|---|---|---|
| Das et al., 2012 | NSCLC | 57 | FastCell | CTCs were detected in 42% of patients. | (78) |
| Devriese et al., 2012 | NSCLC | 46 | Cellsearch | CTCs were detected in 62% of patients. 30% of patients positive for CK7 and 9% positive for CK19. | (79) |
| Hiltermann et al., 2012 | SCLC | 59 | Cellsearch | Lower number of CTCs in patients with early stage SCLC. CTC decrease after one cycle of chemotherapy- no change after four cycles | (80) |
| Hirose et al., 2012 | NSCLC | 33 | Cellsearch | CTCs were detected in 36.4% of patients and 15.2% had five or more CTCs before chemotherapy. No difference in response to chemotherapy between CTC-positive and CTC-negative patients. Progressive disease higher in CTC-positive patients. | (81) |
| Hofman et al., 2012 | NSCLC | 250 | ISET | CNHC's were detected in 49% of patients corresponding to malignant (41%), uncertain malignant (6% and benign cells (2%) respectively. | (82) |
| Hou et al. 2012 | SCLC | 97 | Cellsearch | CTCs present in 85% of patients. OS of 5.4mths for ≥50 CTCs/7.5ml blood | (83) |
| Illie et al., 2012 | NSCLC | 87 | ISET | CTCs positive for ALK from 5 patients corresponded to patients having ALK-rearrangement in tumors. | (84) |
| Isobe et al., 2012 | NSCLC | 24 | Cellsearch | CTCs detected in 33.3% of patients | (85) |
| Krebs et al., 2012 | NSCLC | 45 | Cellsearch/ISET | CTCs detected in 80% of patients using ISET compared to 23% of patients using Cellsearch. Subpopulation of cells detected by ISET did not express epithelial markers | (86) |
| Naito et al., 2012 | SCLC | 51 | Cellsearch | Patients with ≥8 had worse survival than those with < 8 CTCs. | (87) |
| Punnoose et al., 2012 | NSCLC | 41 | Cellsearch | CTCs were detected in 78% of patients at baseline. High baseline CTC counts associated with response to treatment. Decreased CTCs associated with PFS. | (88) |
| Saucedo-Zeni et al., 2012 | NSCLC | 24 | GILUPI CellCollector | CTCs were successfully enriched from over 90% of patients with breast cancer or non-small cell lung cancer. | (55) |
| Wendel et al., 2012 | NSCLC | 78 | HD-CTC assay | CTCs were detected in 73% of patients. No significant difference between stages. | (89) |
| Funaki et al., 2013 | NSCLC | 130 | Rosette Sep | ITCs were detected in 74% of patients. | (90) |
| Hosokawa et al., 2013 | NSCLC | 22 | MCA | CTCs were detected in 77% of patients using the MCA system versus 32% using the Cellsearch system. MCA system also isolated CTC clusters from patients identified as CTC-negative using Cellsearch. | (91) |
| Ni et al., 2013 | NSCLC and SCLC | 11 | Cellsearch | Copy number variations reported from single CTCs similar to that of the metastatic tumor of the same patient. | (92) |
| Pailler et al., 2013 | NSCLC | 18 | Cellsearch/ISET | ALK rearrangements detected in CTCs of patients with ALK positive NSCLC enabling monitoring and testing of crizotinib. | (93) |
| Swennenhuis et al., 2013 | NSCLC and SCLC | 10 | Cellsearch | CTCs from 25% of patients were identified and single CTCs were isolated and amplified. | (94) |
| Carlsson et al., 2014 | NSCLC | 129 | HD-CTC assay | Presence of CTM combined with clinical and imaging data assisted in discriminating for diagnostic accuracy in all NSCLC patients. | (95) |
| Earhart et al., 2014 | NSCLC | 6 | Magnetic Sifter | CTCs detected in 100% of patients. | (96) |
| Illie et al., 2014 | 168 | ISET | CTCs were detected in 3% of COPD patients | (97) | |
| Juan et al., 2014 | NSCLC | 37 | Cellsearch/ISET | ALK rearrangements detected in CTCs of patients with ALK positive NSCLC enabling monitoring and testing of crizotinib. | (98) |
| Marchetti et al., 2014 | NSCLC | 37 | Cellsearch | CTCs were detected in 41% of patients. EGFR mutations identified by NGS in 84% of patients. | (99) |
| Muinelo –Romay et al., 2014 | NSCLC | 43 | Cellsearch | At baseline 41.9% of patients were positive for CTCs. Patients with ≥5 baseline had worse PFS and OS. Patients with increased levels of CTCs has worse PFS and OS. | (100) |
| Nel et al., 2014 | NSCLC | 43 | Negative depletion | Increased CD133-positive to pan-CK-positive cell type ratio (stem like to epithelial ratio) and presence of mesenchymal N-cad-positive cells, associated with shorter PFS. | (101) |
| Normanno et al., 2014 | SCLC | 60 | Cellsearch | At baseline 90% of patients were positive for CTCs and strongly associated with organs involved. CTC reduction as high as 89% following chemotherapy. | (102) |
| Chudsama et al., 2015 | NSCLC | 20 | Screen Cell | An increase in CTCs following EC observed in 75% of patients. Could have implications for tumor dissemination and metastatic spread. | (103) |
| Dorsey et al., 2015 | NSCLC | 23 | Density gradient centrifugation | CTCs positive in 65% of patients. CTC count reflect clinical course and response to treatment. | (104) |
| Tu et al., 2015 | NSCLC and SCLC | 18 | Cellsearch | CSFTC were positive in 78% of MRI confirmed LM samples. CSFTC clusters were observed in 67% of patients. | (105) |
| Aieta et al., 2016 | NSCLC | 1 | Cellsearch | Presense of EML4-ALK+ CTCs at baseline. EML4-ALK+ CTCs could be interpreted as resistance sign to crizotinib treatment leading to progressive disease. | (106) |
| Cheng et al., 2016 | SCLC | 89 | Cellsearch | CTCs positive in 87.6% of patients. CTC count independent indicator for PFS and OS. | (107) |
| Crosbie et al., 2016 | NSCLC | 27 | Cellsearch | CTCs positive in 22% of patients at baseline. CTC detection at baseline associated with reduced DFS and 3-year survival. | (108) |
| Hanssen et al., 2016 | NSCLC | 48 | Cellsearch | CTCs positive in 15% of patients. CTC positivity was associated with patient disease state. | (109) |
| He et al., 2016 | NSCLC | 66 | Cellsearch | Presence of CTCs at baseline associated with significantly shorter PFS. | (110) |
| Morrow et al., 2016 | NSCLC | 1 | Cellsearch | CDX derived from CTCs enriched from NSCLC patient. | (111) |
| Nicolazzo et al., 2016 | NSCLC | 24 | Cellsearch | Patients with PD-L1 negative CTCs all had clinical benefit, while patients with PD-L1 (+) CTCs all experienced progressive disease. | (112) |
| Tan et al., 2016 | NSCLC | 27 | ClearCell FX | CTCs positive in 100% of patients, 14 were ALK-positive. | (113) |
| Zhang et al., 2016 | NSCLC | 46 | Negative immunoselection | CTCs positive in 87% of patients. CTC count of more than eight prior to chemotherapy was a strong predictor of PFS. | (114) |
| Chudsama et al., 2017 | NSCLC | 10 | ScreenCell | A significant increase in CTCs was observed from baseline levels following lung manipulation. | (115) |
| Chudsama et al., 2017 | NSCLC | 23 | ScreenCell | CTCs positive in 78.3% and 73.9% reviewed by 2 pathologists. | (116) |
| Coco et al., 2017 | NSCLC | 73 | ScreenCell | Baseline CTC count had no significant association with OS or PFS. | (117) |
| Illie et al., 2017 | NSCLC | Cellsearch/ISET | CTCs positive in 32% of patients evaluated on Cellsearch. CTCs positive in 75% of patients evaluated on ISET. Expression of MET was positive in 72% of cases. | (118) | |
| Lindsay et al., 2017 | NSCLC | 125 | Cellsearch | CTCs positive in 40.8% of patients. Patients with ≥2 CTCs at baseline had poorer prognosis. | (119) |
| Messaritakis et al., 2017 | SCLC | 64 | Cellsearch | CTCs positive in 50% of patients before treatment. Pazopanib treatment significantly reduced proportion of patients with increased CTC numbers. High CTC number at baseline correlated with reduced PFS and OS. Detection of VEGFR2+ CTCs during treatment could be associated with resistance to pazopanib. | (120) |
| Messaritakis et al., 2017 | SCLC | 108 | Cellsearch | CTCs positive in 60.2% of patients at baseline. Presence of proliferative (CK67+) and non-proliferative (Ki67-), apoptotic (M30+) and non-apoptotic (M30-) as well as EMT (Vim+) CTCs were present in the same patient. | (121) |
| Pailler et al., 2017 | NSCLC | 39 | Cellsearch/ISET | Significant association between the decrease in CTC number with ALK-CNG on crizotinib and longer PFS. ALK-CNG may be a predictive biomarker for crizotinib efficacy in ALK-rearranged NSCLC patients. | (122) |
| Salgia et al., 2017 | SCLC | 42 | Cellsearch | CTCs positive in 83% of patients at baseline. Presence of CTCs at baseline were prognostic of shorter PFS and OS. | (123) |
| Tong et al., 2017 | NSCLC | 127 | Negative immunoselection | CTCs positive in 80.31% of patients at baseline. Patients with post-treatment increases in CTC count had poorer OS and PFS than those without increases. Baseline CTC count and change in CTC count during treatment were valuable prognostic indicators for NSCLC. | (124) |
| Wang et al., 2017 | SCLC | 42 | Negative immunomagnetic enrichment | CTCs positive in 76.19% of patients with SCLC and negative in controls. PFS correlates with CTC numbers and the change in CTC numbers after 1 cycle of chemotherapy. | (125) |
| Yang et al., 2017 | NSCLC | 107 | Cellsearch | CTCs positive in 44% of patients at baseline. CTC >5 at baseline was a strong negative predictor of PFS and TTF. Five or more CTCs on day 28 were strongly associated with a poor PFS. | (126) |
| Yuanling et al., 2017 | NSCLC | 105 | Cellsearch | CTCs positive (≥2) in 29% of patients at baseline and 9% had ≥5 CTCs. CTC count of ≥5 CTCs correlated with poor PFS and OS. | (127) |
| Alamgeer et al., 2018 | SCLC | 28 | Cellsearch | At baseline, two or more CTCs were detected in 86.6% of patients. | (128) |
| Guibert et al., 2018 | NSCLC | 96 | ISET | CTCs positive in 93% of patients at baseline. CTCs more frequently PD-L1+ than tissue (83 vs. 41%). Pre-treatment high CTC counts associated with increased risk of death and progression. Pre-treatment PD-L1+CTCs associated with bad prognosis in patients treated with PD-1 inhibitors. | (129) |
| Milano et al., 2018 | NSCLC | 10 | Density gradient centrifugation | CTCs undergoing EMT (CTCsEMT) positive in 30% of patients. CTCsEMT detection related to poor therapeutic response. | (130) |
| Tong et al., 2018 | NSCLC | 43 | Negative immunoselection | CTCs positive in 76.7% of patients at baseline. CTC count was a strong predictor of PFS and OS. | (131) |
NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; CTC, circulating tumor cells; CNHCs, circulating non-hematological cells; ITC, isolated tumor cells; CTM, circulating tumor microemboli; OS, overall survival; PFS, progression-free survival; TTF, time-to-treatment failure; COPD, chronic obstructive pulmonary disease; EC, endobronchial cryotherapy; CSFTC, cerebrospinal fluid tumor cell; MRI, Magnetic Resonance Imaging; LM, leptomeningeal metastasis; NGS, next-generation sequencing; CDX, cell line-derived xenograft.