Table 2.
Non-exhaustive list of published trials with non-personalized methods to identify MRD through ctDNA detection.
| Reference | Number of Patients ( n ) | Tumor Type and Indication | Methodology | Conclusions |
|---|---|---|---|---|
| Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling [118] | 40 54 healthy controls |
Curative intent for Stage I–III lung cancer | Plasma sequencing: CAPP-Seq 128 genes most frequently mutated in lung cancer. |
94% of patients with MRD were ctDNA-positive in post-treatment plasma samples. Patients were ctDNA-positive before radiological relapse (72%) (5.2months). 53% of ctDNA-positive patients had actionable targets. |
| Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophagealcancer [119] |
45 | Stage IA to Stage IIIB esophageal cancers (adenocarinoma or squamous cell carinoma) | Plasma sequencing: CAPP-Seq Esophageal specific panel | Baseline ctDNA-positive: 27/45 (60%). Post CRT ctDNA-positive: 5/31 (16%). Patients with detectable ctDNA post-CRT also had significantly increased risk of disease progression (HR 18.7, p < 0.0001), distant metastasis (HR 32.1, p < 0.0001), and disease specific death (HR 23.1, p < 0.0001). |
| Post-radiation circulating tumor DNA as a prognostic factor in locally advanced esophageal squamous cell carcinoma [120] | 25 | Resectable esophageal squamous cell carcinoma | Plasma sequencing: NGS on a custom designed 180 genes panel | At baseline, 100% ctDNA-positive. Post radiotherapy: 14/24 (58%) ctDNA-positive 10/24 (42%) ctDNA-negative In the 14 ctDNA-positive patients, 11 patients had a documented follow-up: 90.9% (10/11) had documented disease recurrence. In the 10 ctDNA-negative patients, 8 patients had documented follow-up: 50% (4/8) had documented disease recurrence. Patients who were ctDNA-positive exhibited a marginally significant reduction in PFS (p = 0.047) and a significantly decreased OS (p = 0.005) compared to patients who were ctDNA-negative. |
| Minimal residual disease detection using a plasma-only circulating tumor DNA assay in colorectal cancer patients [121] | 84 | Resectable colorectal cancer | Plasma sequencing: Guardant Reveal™ test using NGS custom based panel for the detection of somatic and epigenitic abberations. | Fifteen patients had detectable ctDNA and all 15 recurred. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Integrating epigenomic signatures increased sensitivity by 25–36% versus genomic alterations alone. |
| Prognostic implications of preoperative versus postoperative circulating tumor DNA in surgically resected lung cancer patients: a pilot study [125] | 20 | Stage IIA–IIIA lung cancer | Plasma sequencing: CAPP-Seq on a commercial 197 genes panel (Roche Diagnostics). |
Eight patients (40%) were positive for preoperative ctDNA.
Four patients (20%) were positive for postoperative ctDNA, and this was significantly correlated with histological grade (3 vs. 1 or 2, p = 0.032). Postoperative positivity for ctDNA also predicted shorter recurrence-free survival (RFS). |
| Circulating tumor DNA as a prognostic biomarker in localized non-small cell lung cancer [123] | 77 | Resectable NSCLC | Plasma sequencing: NGS (cSMART assay) on a custom 127 gene panel | Postoperative ctDNA-positive patients also associated with a lower RFS (HR = 3.076, p = 0.0015) and OS (HR = 3.195, p = 0.0053). Disease recurrence occurred among 63.3% (19/30) of postoperative ctDNA-positive patients. Most of these patients 89.5% (17/19) had detectable ctDNA within 2 weeks after surgery. |
| Circulating tumor DNA as a potential marker to detect minimal residual disease and predict recurrence in pancreatic cancer [115] | 27 | Operable pancreatic cancer | Plasma sequencing: NGS on a large (1.017) gene panel | ctDNA was detected in 18 of 27 preoperative plasma samples, resulting in a detectable rate of 66.67%. Seven days after surgical resection, the status of ctDNA changed in 19 patients. Of these, one turned positive and 10 became completely negative. Patients who were ctDNA-positive postoperatively had a markedly reduced disease-free survival (DFS) compared to those who were ctDNA-negative. A positive postoperative ctDNA status was an independent prognostic factor for DFS. |
| Deep sequencing of circulating tumor DNA detects molecular residual disease and predicts recurrence in gastric cancer [124] | 46 | Stage I–III gastric cancer | Plasma sequencing: NGS with Enrich Rare Mutation Sequencing (ER-Seq) assay on a custom driver mutation panel | ctDNA was detected in 45% of treatment-naïve plasma samples. All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. Post-operative samples (collected prior to any adjuvant chemotherapy; 9–48 days after surgery) showed that ctDNA was detected in 18% (7 out of 38) of evaluable patients. ctDNA positivity after surgery was strongly associated with an increased risk of relapse (100% recurrence in the positive group vs. 32% in the negative group), worse DFS (p < 0.0001), and worse OS (p = 0.0007). |
| Circulating tumor DNA analyses as a potential marker of recurrence and effectiveness of adjuvant chemotherapy for resected non-small cell lung cancer [126] | 38 | Resectable NSCLC | Plasma sequencing: NGS on a custom 425 genes panel | Preoperative plasma samples, ctDNA+ in 19 (50%) patients ctDNA was detected post-chemotherapy in 8 out of 36 (22.2%) patients and was associated with an inferior RFS (HR, 8.76; p < 0.001). |
NGS: next generation sequencing; NSCLC: non-small cell lung cancer; PFS: progression-free survival; OS: overall survival; DFS: disease-free survival; RFS: relapse-free survival; HR: hazard ratio; CAPP-Seq: cancer personalized profiling by deep se-quencing.