Table 3.
CTC-based clinical trials.
| Trial Number, Year of Completion, Study Type and Phase. | Name | Cancer Type | Cancer Stage and Other Information |
Key Findings |
|---|---|---|---|---|
|
NCT00429793. 2012. Interventional. Phase 2. |
NA | Ovarian Cancer | Advanced. Grade 1,2,3. Tumor types-adenocarcinoma, clear cell carcinoma, endometrioid adenocarcinoma and serous adenocarcinoma. | Positive CTC pre-treatment showed lack of response to mTOR inhibitor, temsirolimus and high expression of apoptosis marker in CTCs was associated with longer progression-free survival [135]. |
|
NCT00156273. 2008. Observational. |
NA | Breast cancer | Advanced (Stage IV). Metastatic breast cancer. ECOG status 0–2. |
In patients with elevated CTC, higher levels of CTC-apoptosis were associated with worse prognosis, while higher CTC-BCL-2 levels correlated with better outcomes [136]. |
|
NCT00967031. 2012. Interventional. Phase 2. |
LANDSCAPE | Breast cancer | Advanced. Brain metastases overexpressing HER2. ECOG performance status of 0–2. | After 21 days of lapatinib treatment, a disappearance of CTC was observed in 11 of 36 patients. The 1-year overall survival rate was 83.9% in patients with no CTC at day 21 versus 42.9% in patients with ≥1 CTC [137]. |
|
NCT00428896. 2008. Interventional. Phase 2. |
NA | Breast Cancer | Advanced. Metastatic breast cancer with EGFR expression. |
A median reduction of 96.4 and 94.1% in CTC count was observed in 11 (64.7%) and 12 (70.6%) of patients after the first and the second gefitinib treatment cycles, respectively. Treatment-resistant CTCs could be eliminated by gefitinib in metastatic breast cancer, and EGFR expression on CTCs merits further validation as a potential biomarker for specific and effective targeting of CTCs [138]. |
|
NCT00382018. 2017. Interventional. Phase 3. |
SWOG S0500 | Breast Cancer | Advanced. Metastatic breast cancer. ECOG status 0–2. Patients enrolled before initiation of first line of chemotherapy. ER-positive, HER2-negative, triple-negative and HER2-positive patients were included in the study. |
Prognostic significance of CTCs in patients with metastatic breast cancer receiving first-line chemotherapy was confirmed. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging overall survival [130]. |
|
NCT01349842. 2018. Interventional. Phase 3. |
CirCe01 | Breast Cancer | Advanced (Stage III–IV). Metastatic lobular or ductal adenocarcinoma. Eastern Cooperative Oncology Group (ECOG) status 0–4. |
Early changes in CTC count were correlated with first cycle of third line chemotherapy treatment outcome. Among patients with <5 CTC/7.5 mL at baseline showed better prognostication for progression-free survival [134]. However, due to the limited accrual and compliance, this trial failed to demonstrate the clinical utility of CTC monitoring in third- and fourth-lines chemotherapy [139]. |
|
NCT01722903. 2015. Observational. |
NA | Colorectal Cancer | Advanced (Stage IV). Colorectal cancer with resectable metastases limited to liver and lungs. | CTCs were quantified in blood of patients collected at incision, during resection, 30 min after resection, and on postoperative day 1 by EpCAM-based CellSearch and size-based isolation method. CTC quantity was significantly higher with size-based filtration method than CellSearch at all points of blood collection [140]. |
|
NCT01322893. 2016. Observational. |
CTC-MBC | Breast Cancer | Advanced (Stage IV). Metastatic breast cancer with estrogen receptor alpha and HER2 expression. Invasive lobular and ductal carcinoma of no special type. ECOG status 0–2. |
Study demonstrated the feasibility to ascertain the status of important predictive biomarkers expressed in breast cancer CTCs using the newly developed CTC-DropMount technique [141]. Patients with a continuous presence of apoptotic or CTC clusters in follow up during systemic therapy had worse prognosis than patients without similar CTC characteristics [66]. Longitudinal evaluation of CTC and CTC clusters were shown to improve prognostication and monitoring in patients with metastatic breast cancer starting first-line systemic therapy [10]. The number of CTCs were found to be higher in invasive lobular carcinoma compared to invasive ductal carcinoma highlighting the importance of different CTC cut-off considerations in different breast cancer types [142]. |
|
NCT00694252. 2011. Interventional. Phase 2. |
NA | Breast Cancer | Advanced (Stage IIIB and IV). ECOG status 0–2. | Lapatinib treatment is effective in decreasing HER2-positive CTCs in patients with metastatic breast cancer irrespective of the HER2 status of the primary tumor [143]. |
| NCT01713699. 2017. Interventional. | NA | Leptomeningeal metastases from 9 tumor types * | Advanced. Patients treated for advanced EpCAM-positive solid tumors. ECOG status 0–4. |
EpCAM-based flow cytometry assay to detect CTCs in cerebrospinal fluid is superior to cytology for the diagnosis of leptomeningeal metastases in patients with a clinical suspicion of metastases but a negative or inconclusive MRI [144]. |
|
NCT02075606. 2017. Interventional. Phase 4. |
CALMNET | Neuroendocrine cancers #
Midgut neuroendocrine cancers % |
Early and advanced. Only patients with well or moderately differentiated tumors with a Ki67 proliferation index of <20% was recruited. | Somatostatin receptors 2 and 5 were detected on CTCs in patients with neuroendocrine tumors which might be a useful biomarker for evaluating somatostatin receptor-targeted therapies [145]. Patients without CTC at baseline may be more likely to achieve a symptomatic response following lanreotide autogel treatment than patients with CTC [146]. |
| NCT01577511. 2017. Observational. | NA | Colorectal Cancer | Advanced (Stage IV). Chemotherapy-naïve patients with metastatic colorectal cancer. | Patient-derived colorectal CTC lines contain functional cancer stem cells and express high levels of drug metabolism genes rendering them resistant to conventional therapies [147]. |
|
NCT01439568. 2016. Interventional. Phase 2. |
NA | SCLC | Advanced. A total of 60–70% of patients had extensive-stage disease. | Weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs was observed in patients treated with CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide. Baseline CXCR4+ CTCs ≥ 7% was prognostic of shorter progression-free survival [148]. |
| NCT00898014. 2010. Observational. | IC2006-04 | Breast Cancer | Advanced (Stage IV). No prior chemotherapy for metastatic disease. | Detectable CTC was the only factor observed to be significantly associated with an increased risk of arterial thrombotic events [149]. |
| NCT01625702. 2015. Interventional. | NA | Gastric cancer | Advanced gastric adenocarcinoma. Karnofsky performance status ≥ 60. | CTC number was found to be significantly correlated to prognosis in histologically HER2-negative patients treated with fluorouracil-based chemotherapy. In patients that are histologically HER2-positive, CTC number was not obviously correlated to the progression-free or overall survival during combined anti-HER2-targeted therapy [131]. |
| NCT02372448. 2019. Interventional. | STALKLUNG01 | NSCLC | Early and advanced. Lung adenocarcinoma with ALK rearrangement on tumor tissue was included. |
As a part of standardization of the pre-analytical conditions for CTC-based clinical trials, study found out that blood processed after 24 h and 48 h in BCT tubes showed stable CTCs counts and integrity, whereas CTCs in K3EDTA tubes showed an altered morphology in all patients. Moreover, CTCs recovered in BCT or K3EDTA tubes were evaluable for MET expression, ALK rearrangement studies [150]. CTCs can be used as a complementary tool to a tissue biopsy for the detection of ALK rearrangements. Longitudinal analyses of CTCs are promising for real-time patient monitoring and improved delivery of molecularly guided therapy [151]. |
|
NCT01548677. 2017. Interventional. Phase 2. |
TREAT-CTC | Breast Cancer | Early. HER2-negative primary non metastatic adenocarcinoma of the breast. | Study aimed to assess whether trastuzumab treatment decreases the detection rate of CTCs in HER2 nonamplified, early breast cancer patients and found that Trastuzumab does not decrease the detection rate of CTCs [152]. |
|
NCT02937116. 2020. Interventional. Phase 1. |
IBI308 | Ten types of gastrointestinal tumors @ | Advanced (Stage IIIB-IV). ECOG status 0–1. | Abundance of PD-L1high CTCs at baseline serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes in CTC indicate the therapeutic response at early time [153]. |
| NCT03032913. 2017. Observational. | PANC-CTC | Pancreatic cancer | Early (Stage I, IIb and III). Pancreatic ductal adenocarcinoma. | Combined CTC and exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found [154]. |
|
NCT01975142. 2019. Interventional. Phase 2. |
CirCe T-DM1 | Breast Cancer | Advanced. Metastatic breast cancer. HER2-negative primary tumor. ECOG status of 0–2. |
CTC with HER2 amplification can be detected in a limited subset of HER2-negative metastatic breast cancer patients indicating the importance of clonal evolutionary changes within the tumor [155]. |
|
NCT01640444 (VISNU-2). 2018. Interventional. Phase 2. NCT01640405 (VISNU-1). 2018. Interventional. Phase 3. |
VISNÚ-1/2 | Colorectal Cancer | Advanced. Metastatic colorectal adenocarcinoma. ECOG status of 0–1. |
Elevated baseline CTCs and RAS mutations were associated with clinicopathologic features known to be associated with poor prognosis [156]. Patients with baseline CTC ≥ 3 count had poor prognosis [157]. First-line 5-fluorouracil/leucovorin, oxaliplatin, irinotecan plus bevacizumab treatment significantly improved progression-free survival in patients with ≥3 CTCs at baseline compared to 5-fluorouracil/leucovorin, oxaliplatin plus bevacizumab doublet therapy [158]. |
| NCT01800058. 2018. Observational. | NA | Prostate Cancer | Early (Stage II and III). Prostate adenocarcinoma. Karnofsky performance score of ≥70. |
Positive CTC status at diagnosis, following neoadjuvant androgen deprivation therapy, at the end of radiotherapy, and 9 months after radiotherapy was not significantly associated with any clinical or pathologic factors and overall survival [159]. |
|
NCT02005770. 2018. Interventional. Phase 4. |
NA | Breast Cancer | Early (Stage 0–III). Primary preinvasive and invasive breast cancer without metastases. | Study evaluated the association of different types of anesthesia with postoperative CTC counts in surgically resectable breast cancer patients and found that there was no difference between sevoflurane and propofol with respect to CTC counts over time [160]. |
| NCT02453139. 2017. Interventional. | ExPeCT | Prostate Cancer | Advanced. Prostate adenocarcinoma participants were stratified based on body mass index. |
Platelet cloaking of CTCs was observed in the patient population for the first time but without any significant correlation with clinico-pathological information [161]. |
|
NCT01710605. 2018. Interventional. Phase 3. |
STIC CTC | Breast Cancer | Advanced. Metastatic ductal adenocarcinoma. | CTC count was found to be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, HER2-negative metastatic breast cancer patients [162]. |
| NCT01596790. 2019. Interventional. | NA | Colorectal Cancer | Advanced. Colon or rectum adenocarcinoma, visceral metastases. WHO performance status 0, 1 or 2. | Differential gene expression pattern was observed in CTCs of same patient during first- and second-line chemotherapy treatments and disease progression highlighting the CTCs adaptability to escape treatment pressure [132]. |
|
NCT02549430. 2017. Interventional. Phase 2. |
TREnd | Breast Cancer | Advanced. Endocrine resistant ER-positive, HER2-negative advanced breast adenocarcinoma. | CTC count was found to be a promising modality in monitoring palbociclib response in patients with ER-positive, HER2-negative advanced breast cancer [163]. |
|
NCT02137837. 2019. Interventional. Phase 3. |
SWOG1222 | Breast Cancer | Advanced. Invasive breast carcinoma with ER-positive and HER-2-negative status. | An association was observed of baseline CTC and ctDNA with poorer survival [164]. |
|
NCT02771314. 2020. Interventional. Phase 2. |
NA | NSCLC | Early and advanced. Patients with histologically documented EGFR-mutant NSCLC. | The decrease in both CTCs and ctDNA occurring early during osimertinib treatment in EGFR Mutant NSCLC patients was found to be predictive of better outcome [165]. |
| NCT03033927. 2024 (estimated). Observational. | NA | Pancreatic cancer | Advanced pancreatic adenocarcinoma. | Chemosensitivity assay profiling of CTCs was found to be a promising tool for guiding therapy in advanced pancreatic adenocarcinoma [133]. |
| NCT03935802. 2018. Observational. | NA | Breast Cancer | Early (Stage I–III). Invasive ductal carcinoma, Invasive lobular carcinoma. | Increase in CTC numbers over the course of adjuvant radiotherapy signified a potential predictive biomarker to judge relative risk or benefit in patients with early breast cancer [166]. |
| NCT04358718. 2021. Interventional. | NA | Bladder cancer | Early | μ-opioid receptor agonists used for pain treatment both during and after surgery in blader cancer patients was associated with high CTCs and CTC cluster counts [167]. |
| NCT01740804. 2026. Observational. | POLICE | NSCLC | Advanced (Stage IIIb and IV). Adenocarcinoma, squamous cell carcinoma and Mixed NSCLC ECOG status of 0–1. |
CTC persistent presence during treatment represented poor prognosis and resistance to chemotherapy in advanced NSCLC [129]. |
|
NCT01619111. 2022. Interventional. Phase 3. |
DETECT III | Breast Cancer | Advanced. HER2+ metastatic breast cancer. ECOG Score < 2. |
Study demonstrated that phenotyping of CTCs has clinical utility for stratification of metastatic breast cancer patients irrespective of HER-2-positive or -negative status for targeted therapy. Study highlighted the phenotypic changes in tumor cells during disease progression [168]. |
Abbreviations: NA—Not available, NSCLC—non-small-cell lung cancer, SCLC—small-cell lung cancer. * Nine tumor types including breast cancer, NSCLC, SCLC, gastrointestinal cancer, ovarian cancer, nasopharyngeal carcinoma, urothelial cell carcinoma, renal cell cancer and parotid gland carcinoma. # Study recruited patients with metastatic neuroendocrine tumors of either midgut or pancreas origin. @ Ten types of gastrointestinal tumors including neuroendocrine tumors of the right adrenal neuroblastoma, hepatocellular carcinoma, colorectal carcinoma, intrahepatic cholangiocarcinoma, pancreatic carcinoma, esophageal carcinoma, ampullary adenocarcinoma, small intestinal stromal tumor, and esophageal small-cell carcinoma. % Patients with neuroendocrine tumors of the ileum, caecum, jejunum, small bowel, duodenum, and right colon were recruited in the study.