1 Identifying regulators and biomarker of tumor dormancy using liquid biopsy
2 Methodology and technical challenges of liquid biopsy
3 Breast cancer
3.1 Clinical relevance of MRD in patients with breast cancer
3.2 Monitoring MRD in breast cancer patients by detection and characterization of DTCs
3.3 Monitoring MRD in breast cancer patients using blood-based biomarker
3.3.1 Circulating tumor cells (CTCs)
3.3.2 Circulating tumor DNA (ctDNA)
Breast cancer | |||||
Study/trial (year) | Inclusion criteria | n Pat | Methods/design | Clinical relevance | Ref |
DARE (ongoing) Randomized phase II trial of ctDNA-guided second-line adjuvant therapy | High residual risk, Stage II-III, hormone receptor positive, HER2 negative | 100 | Signatera assay Palbocilcib and Fulvestrant are tested against standard of care endocine therapy | Primary outcome of ctDNA screening consists in ctDNA baseline incidence and prevalence of high-risk patients under standard of care. Secondary, correlation of ctDNA incidence and ouvert metastasis, association of ctDNA clearance to PFS and OS. Recurrence- free survival as additional endpoint | NCT04567420 |
TRAK TN (ongoing) Randomized trial utilizing ctDNA mutation tracking to detect MRD and trigger intervention in pat. with moderate and high-risk early stage triple neg | Early-stage, irrespective of hormone receptor and ERBB2 status, receiving neoadjuvant CTX followed by surgery or surgery before adj. CTX | 314 | Digital PCR Serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months | ctDNA detection during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7–95.6; P < 0.001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2–27.1; P = 0.01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1–19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%) | [84] |
SUCCESS A (2019) Multicenter, open-label, phase III trial compared two adjuvant CTX regimens followed by 2 vs 5 years of zoledronate | Early-stage, high-risk breast cancer patients | 1087 | ICC (CellSearch) | CTC status 2 years after chemotherapy had statistically significant prognostic relevance for OS (HR 3.91; 95% CI 2.04–7.52; P < 0.001) and DFS (HR 2.31; 95% CI 1.50–3.55; P < 0.001) | [76] |
Papadaki et al. (2019) Investigation of the prognostic relevance of single CSC+/partial-EMT+ CTCs in patients with metastatic breast cancer and the effect of first-line chemotherapy on their incidence | Stage IV breast cancer | 130 | Triple immunofluorescence (keratins, TWIST, ALDH1) | CTCs that co-express keratin, high ALDH1 levels and nuclear TWIST1 correlated with reduced PFS (median 10.2 (8.9–11.6) vs 13.5 (11.3–15.7) months; P = 0.024). In HER2-negative patients, CSC + /partial EMT + CTCs were additionally associated with OS (median 39 (26.2–51.9) vs. 51 (15.7–86.4) months; P = 0.020) | [161] |
Prostate cancer | |||||
Study/trial (year) | Inclusion criteria | n Pat | Methods/design | Clinical relevance | Ref |
Chen et al. (2019) | Metastatic and early PC (all stages) | 54 | ICC (CanPatrol platform, multi-RNA-ISH) | Positive rate of PGK1+/G6PD+ CTCs was higher in metastatic patients than in nonmetastatic patients (51.7% vs 8.0% (P = 0.002)). Hybrid CTCs were associated with Gleason score, tumor stage, tPSA level and cancer metastasis (P < 0.05). PGK1+/G6PD+ CTC number was correlated with the number of hybrid CTCs (r = 0.807; P < 0.001) | [114] |
Budna-Tukan and Swierczewska et al. (2019) | High-risk PC (PSA ≥ 20 ng/mL and/or Gleason score on biopsy ≥ 8 and/or clinical tumor stage ≥ 2c), before and after RT | 68 | Antibody-based assays (CellSearch, CellCollector, EPISPOT Assay) | No difference in matched-pair analysis of CTC counts before and after RT for all three assays (CellSearch P = 0.28, dual fluoro-EPISPOT P = 0.27, CellCollector P = .36) | [116] |
Haldrup et al. (2018) | PC before transurethral resections of the prostate or radical prostatectomy | Gene panel: ST6GALNAC3, CCDC181, HAPLN3 | 7% sensitivity and 100% specificity for patients with PC compared to patients with BPH (AUC = 0.833), combination improved sensitivity over best performing single marker (HAPLN3) | [122] | |
Study/trial (year) | Inclusion criteria | n Pat | Methods/design | Clinical relevance | Ref |
Melanoma | |||||
SECOMBIT (2021) | Stage III (unresectable) or stage IV melanoma with the BRAF V600 mutation | 251 | A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy (ipilimumab/nivolumab) and combo target therapy (encorafenib/binimetinib) | Sandwich approach starting with targeted therapy for 8 weeks, then immunotherapy for 8 weeks; upon disease progression, following more targeted treatment showed improved progression-free survival of 15.1 vs. 10.6 months with vemurafenib/cobimetinib alone (P = 0.025). The OS rate at 2 and 3 years showed a better trend in arm B (immunotherapycombination) and C (sandwich approach) | [162] |
COMBI AD (2020) | High risk, resected stage III melanoma with BRAF V600E or V600K mutations | 870 | A Phase III randomized double blind study of dabrafenib (GSK2118436) in combination with trametinib vs. two placebos in the adjuvant treatment after surgical resection | At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval (CI), 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70) | [163] |
Tan et al. (2019) | Resected stage III | 133 | Digital droplet PCR | ctDNA detection predicted patients at high risk of relapse at baseline (relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5–5.6; P = 0.002) and postoperatively (HR 10; 95% CI 4.3–24; P < 0.001). ctDNA detection at baseline (HR 2.9; 95% CI 1.3–5.7; P = 0.003 and postoperatively (HR 11; 95% CI 4.3–27; P < 0.001) was also associated with inferior distant metastasis-free survival (DMFS) | [151] |
Lee et al. (2019) | IV | 76 | Digital droplet PCR | Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumor response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis with a median OS 9.2 months (HR 0.02; P < 0.001), and this may guide combination and sequencing of subsequent therapies | [152] |