Table 2.
Lung cancer.
| Stage | Finding | Known Mut. | Method | Patient Number | Reference |
|---|---|---|---|---|---|
| I–IV | Presence of plasma circulating tumor DNA (ctDNA) has higher positive predictive value than six biomarkers [CA125, CA19-9, CYFRA21-1, CEA, NSE, squamous cell carcinoma antigen (LSCC)]. Concordance rate between tDNA and ctDNA mutations was 78.1%. Decrease in AF of plasma ctDNA mutations observed 2 days postoperatively | Yes | NGS | 41 non-small cell lung cancer (NSCLC) (33 LAC, 6 LSCC, 1 Neuroendocrine carcinoma, 1 LCC) | Guo et al. (86) |
| IA–B, IIA | Overall concordance rate between tDNA and cfDNA was 50.4%. cell-free DNA (cfDNA) level correlate with tumor stage. cfDNA has higher PPV for early-stage NSCLC than CA125, CA19-9, CEA, NSE, and CYFRA21-1 tumor markers | Yes | NGS | 58 NSCLC (51 LAC, 7 LSCC) | Chen et al. (87) |
| I–IV | ctDNA detected in 100% of patients of stages II–IV, and in 50% of stage I | Yes | CAPP-Seq | 17 NSCLC (14 LAC, 2 LSCC, 1 LCC) | Newman et al. (47) |
| IIIB, IV | 78% of 97 of patients positive for EGFR variant in primary had these mutations in ctDNA; EGFR:p.L858R in either tumor tissue or cfDNA predicts shorter OS and progression-free survival (PFS). ctDNA level correlate with total tumor volume | Yes | TaqMan assay | 97 NSCLC (91 LAC, 2 BAC, 1 LCC, 1 LSCC, 2 other) | Karachaliou et al. (88) |
| I–II | Methylation profiles of five genes (APC, CDH13, KLK10, DLEC1, and RASSF1A) in cfDNA of NSCLC patients showed a significantly higher tumor-specific hypermethylation frequency | Yes | Methylation-specific PCR | 78 NSCLC (30 LAC, 36 LSCC, 12 other) 50 healthy | Zhang et al. (89) |
| I–IV | Plasma cfDNA level does not correlate with any particular histologic subtype of NSCLC, but with tumor stage. Significant correlation between plasma cfDNA concentration and lactate dehydrogenase (LDH) level. Patients with tumor progression have increase in plasma cfDNA concentrations but not in serum | No | Real-time PCR | 185 NSCLC (81 LAC, 49 LSCC, 37 LCC, 18 undifferentiated) 46 healthy | Gautschi et al. (40) |
| I–III | Plasma cfDNA level does not correlate with sex, age, histotype, and tumor stage. Increased cfDNA level does not correlate with recurrence-free survival and overall survival (OS). Plasma cfDNA level can be used as a biomarker for possible relapse during follow-up | No | PCR | 84 NSCLC (47 LAC, 25 LSCC, 12 other) 43 healthy | Sozzi et al. (90) |
| IIIB, IV | Total cfDNA level does not predict chemotherapy response. Higher cfDNA level at baseline associated with worse disease-free survival (DFS) and OS | No | Fluorometry | 218 NSCLC (147 LAC, 43 LSCC, 28 LCC) | Tissot et al. (91) |
| II–IV | Therapeutically targetable driver and resistance mutations can be detected in ctDNA. Higher ctDNA concentrations highly associated with decreased OS | Yes | NGS | 102 NSCLC (83 LAC, 4 LSCC, 12 poorly differentiated carcinoma, 3 other) | Thompson et al. (92) |
| IIIB, IV | Presence of ctDNA at diagnosis in 71% of patients; related to shorter OS. ctDNA clearance at first evaluation (6–8 week) after treatment initiation associated with objective response, longer PFS and OS | Yes | NGS ddPCR | 109 NSCLC (98 non-LSCC, 11 LSCC) | Pécuchet et al. (93) |
| III, IV | cfDNA levels do not correlate with hypermetabolic tumor volume | No | qPCR PET-CT | 53 NSCLC (33 LAC, 19 LSCC, 1 other) | Nygaard et al. (94) |
| I–IV | Plasma cfDNA concentration correlates with LDH activity and NSE level in small cell lung cancer (SCLC) and NSCLC | No | Labeling by nick translation | 22 SCLC 46 NSCLC (19 LAC, 18 LSCC, 9 undifferentiated) | Fournié et al. (95) |
| IIIA–B, IV | Overall concordance rate of mutations between tDNA and cfDNA was 78.21%. SNV, indels and gene fusions (EML4-ALK, KIF5B-RET) can be detected in cfDNA by targeted sequencing | Yes | targeted sequencing | 39 NSCLC (34 LAC, 5 LSCC) | Yao et al. (96) |
| II–IV | Patients with cfDNA positive for KRAS mutation have shorter PFS and OS and have lower response rate to the chemotherapy | Yes | Amplification-Refractory Mutation System (ARMS) qPCR KRAS DxS | 246 NSCLC (150 LAC, 75 LSCC, 8 LCC, 13 other) | Nygaard et al. (97) |
| IIIB, IV | No significant differences between patients with KRAS mutation or wild-type KRAS status in serum cfDNA with regard to baseline patient characteristics, response rates, PFS, or OS | No | direct sequencing | 67 NSCLC (29 LAC, 19 LSCC, 9 LCC, 10 undifferentiated) | Camps et al. (98) |
| IIB–IV | EGFR activating mutations detected in plasma cfDNA of 72.7% patients and EGFR T790M mutation in 43.5% of patients | Yes | BEAMing | 44 NSCLC (43 LAC, 1 LSCC) | Taniguchi et al. (99) |
| IIIA, IIIB, IV | EGFR T790M mutation detectable in tumor biopsy (75%), cfDNA (80%) and circulating tumor cell (CTC, 70%) in patients progressing on EGFR-TKI therapy | Yes | hbCTC-Chip direct sequencing | 42 NSCLC | Sundaresan et al. (100) |
| n.s | ORR and median PFS are similar in patients with T790M-positive plasma or T790M-positive tumor. Detection of resistance mutation in plasma is unlikely if the activating mutation is not detected | Yes | BEAMing | 216 NSCLC | Oxnard et al. (101) |
| IIIB, IV | Qualitative and quantitative analysis of EGFR T790M mutation in plasma cfDNA can predict prognosis on EGFR-TKI therapy | Yes | DHPLC ARMS qPCR Digital array chip | 135 NSCLC (130 LAC, 5 non-LAC) | Wang et al. (102) |
| I–III | Phylogenetic profiling of ctDNA useful to track emerging subclones responsible for resistance and relapse. Tumor volume correlate with AF of clonal variants | Yes | Multi-region exome sequencing Multiplex-PCR NGS | 100 NSCLC (58 LAC, 31 LSCC, 2 Carcinosarc., 1 LSC, 3 adenosquamous carcinoma, 1 large cell neuroendocrine carcinoma) 24 NSCLC (16 LAC, 8 LSCC) | Abbosh et al. (103) |
| IIIA, IIIB, IV | CTC are detectable in stage IIIB and IV, but not stage IIIA of NSCLC | No | CellSearch | 32 LSCC 31 LAC 5 poorly differentiated 33 other | Krebs et al. (104) |
| I–IV | Cytopathologic features of CTC are not different between various histologic subtypes of LC. CTC are detectable in 49% of NSCLC patients preoperatively | No | ISET | 208 NSCLC (115 LAC, 54 LSCC, 19 LCC, 10 sarcomatoid carcinoma, 5 adenosquamous carcinoma) 39 healthy | Hofman et al. (105) |
| n.s | CTC count does not correlate with tumor volume. Activating EGFR and resistance EGFR T790M mutation could be detected in CTCs.CTCs count can be used for monitoring the tumor response to the therapy | Yes | EpCAM-functionalized CTC Chip | 27 NSCLC (19 LAC, 8 LAC/BAC) | Maheswaran et al. (106) |
| n.s | CTC can be detected in the COPD patients and could be used as an early indicator of invasive LC | No | ISET | 168 COPD | Ilie et al. (107) |
| IIIB, IV | CTC could be used as a source of tumor DNA for NGS detection of EGFR mutation. Genetic heterogeneity in CTCs | Yes | CellSearch NGS | 37 NSCLC 10 BC 12 healthy | Marchetti et al. (108) |
| n.s | CNA-based classifier derived from CTCs analysis can distinguish chemorefractory and chemosensitive disease | No | CellSearch DEPArray NGS WGS | 31 SCLC | Carter et al. (109) |