Table 5.
Key studies of prognostic ctDNA analyses
| Study (ref.) | Tumor type | Timing of blood withdrawal | Number of patients | Detection method | Prognostic relevance |
|---|---|---|---|---|---|
| Olsson et al. 2015 [124] | BC | After surgery during follow-up | 20 | WGS of primary tumors and quantification of tumor-specific rearrangements in plasma by ddPCR | post-surgical ctDNA monitoring enabled accurate discrimination between patients with and those without distant recurrence |
| Garcia-Murillas et al. 2015 [23] | BC | Before neoadjuvant therapy, after surgery and then every 6 months during follow-up | 55 | personalized dPCR assay | the detection of ctDNA was correlated with an increased risk of metastatic relapse |
| Chen et al. 2017 [125] | BC | After surgery and during adjuvant therapy | 38 | Oncomine Research Panel | 33 patients had at least one mutation identified in their primary tumour, only 4 of whom had mutations detected in cfDNA. the 4 patients with detectable ctDNA had disease relapse within 9 months |
| Riva et al. 2017 [126] | BC | before neoadjuvant therapy; after 1 cycle; before surgery; after surgery | 46 | customized ddPCR probes | slow decrease of ctDNA level during NCT was strongly associated with shorter survival |
| McDonald et al. 2019 [127] | BC | Before, during and after neoadjuvant therapy | 33 | targeted digital sequencing (TARDIS) | ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease |
| Coombes et al. 2019 [128] | BC | Every 6 months for 4 years after surgery | 49 | personalized assays targeting 16 variants selected from primary tumor whole-exome data | plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients; metastatic relapse was predicted with a lead time of up to 2 years |
| Garcia-Murillas et al. 2019 [129] | BC | Before neoadjuvant therapy; after surgery | 101 | personalized dPCR assay | detection of ctDNA at diagnosis and during follow-up was associated with worse relapse-free survival. Brain-only metastasis was less commonly detected by ctDNA |
| Parsons et all 2020 [130] | BC | After surgery | 142 | WES was used to identify patient-specific single-nucleotide variants. Patient-specific SNVs were used to design custom MRD tests, which were subsequently applied to cfDNA and germline DNA libraries | MRD detection at 1 year was strongly associated with distant recurrence |
| Magbanua et al. 2021 [131] | BC | Before and during neoadjuvant therapy and before surgery | 84 | personalized ctDNA test to detect up to 16 patient-specific mutations | Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence |
| Marla Lipsyc-Sharf, 2022 [132] | BC | After surgery | 103 | WES on primary tumor tissue was used to identify somatic mutations tracked via a personalized ctDNA test (RaDar) | ctDNA was identified a median of 1 year before all cases of distant metastasis |
| Tie et al. 2016 [22] | CRC | After surgery and after adjuvant therapy (two different cohorts) | 230 | NGS-based assay | ctDNA detection identified patients at very high risk of recurrence |
| Ng et al. 2017 [133] | CRC | Before and after surgery. After recurrence | 44 | patient-specific ctDNA assays based on multiplexed detection of somatic mutations identified from patient primary tumours | ctDNA was detected in 11 of 15 patients at or before the time of clinical or radiological recurrence of CRC |
| Schøler et al. 2017 [134] | CRC | Before and after surgery | 27 | Personalized ddPCR assays based on WES of primary tumor | patients treated with curative intend for localized disease who were ctDNA-positive within the first postoperative trimester had a very high risk (100%) of relapsing |
| Reinert et al. 2019 [135] | CRC | Before and after surgery | 130 | NGS-based assay | During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients |
| Tarazona et al. 2019 [136] | CRC | at baseline, 6–8 weeks after surgery, and every 4 months for up to 5 years | 150 | Personalized ddPCR assays based on WES of primary tumor | Detection of ctDNA after surgery and in serial plasma samples during follow-up were associated with poorer disease-free survival. In patients treated with adjuvant chemotherapy, presence of ctDNA after therapy was associated with early relapse |
| Taieb et al. 2019 [137] | CRC | After surgery | 805 | ctDNA was tested by using the detection of 2 methylated markers (WIF1 and NPY) by ddPCR | A notable improvement in the disease-free survival of patients who had detectable ctDNA postoperatively and received a longer duration (6 months vs 3 months) of adjuvant chemotherapy was demonstrated |
| Tie et al. 2021 [138] | CRC | After surgery | 485 | SafeSeqS | ctDNA detection was associated with poorer 5-year recurrence-free and overall survival |
| Parikh et al. 2021 [139] | CRC | After surgery or adjuvant therapy | 103 | Guardant Reveal test | In plasma drawn 1-month after definitive therapy and > 1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred.Of 49 patients without detectable ctDNA at the landmark timepoint, 12 recurred |
| Vidal et al. 2021 [140] | CRC | Before neoadjuvant therapy and before surgery | 72 | Guardant Reveal test | Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival and shorter overall survival |
| Henriksen et al. 2022 [141] | CRC | Before and after surgery and after adjuvant therapy | 168 | NGS-based assay | Detection of ctDNA was a strong recurrence predictor postoperatively and directly after ACT. The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80%. Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence. The ctDNA growth rate was prognostic of survival |
| Tie et al. 2022 [142] | CRC | After surgery | 455 | SafeSeqS | A ctDNA-guided approach to the treatment of stage II colon cancer reduced ad-juvant chemotherapy use without compromising recurrence-free survival |
| Abbosh et al. 2017 [143] | NSCLC | After surgery | 24 | NGS-based, patient-specific mutational panel assays | the detection of SNVs in ctDNA seemed to be correlated ith clinical evidence of NSCLC relapse |
| Chaudhuri er al. 2017 [144] | NSCLC | Before and after surgery and during follow-up | 40 | CAPP-Seq | ctDNA was detected in the first post-treatment blood sample, within 4 months of primary treatment, in 94% of patients with subsequent recurrence |
| Chen et al. 2019 [145] | NSCLC | Before surgery, after tumor resection, after surgery and during follow-up | cSMART | The ctDNA detection on the third day after R0 is associated with higher risk of relapse and mortality | |
| Xia et al. 2022 [146] | NSCLC | Before and after surgery | 330 | NGS-based | Preoperative ctDNA positivity was associated with lower recurrence-free survival. The presence of MRD (ctDNA positivity at postoperative 3 days and/or 1 month) was a strong predictor for disease relapse. MRD-positive patients who received adjuvant therapies had improved RFS over those not receiving adjuvant therapy, whereas MRD-negative patients receiving adjuvant therapies had lower RFS than their counterparts without adjuvant therapy |
| Gale et al. 2022 [147] | NSCLC | Before and after surgery and during follow-up | 88 | WES on primary tumor tissue was used to identify somatic mutations tracked via a personalized ctDNA test (RaDar) | Detection within 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival and overall survival. ctDNA was detected 1–3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival |
| Lau et al. 2020 [148] | PCa | Before and after surgery | 8 | Personalized ddPCR assays based on WGS of primary tumor | ctDNA was identified in 2 of 8 patients. Both of them had primary PSA persistence and very rapid disease trajectories, characterised by early progression to overt metastatic disease and death |
| Powles et al. 2021 [149] | UCB | At the start of adjuvant therapy | 581 | Personalized ddPCR assays based on WES of primary tumor | ctDNA testing at the start of therapy identified patients who had poor prognosis. Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm |