Dataset Information

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer.

ABSTRACT: Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I-III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I-III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.

SUBMITTER: Gong J

PROVIDER: S-EPMC8471730 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer.

Gong Jun J Hendifar Andrew A Gangi Alexandra A Zaghiyan Karen K Atkins Katelyn K Nasseri Yosef Y Murrell Zuri Z Figueiredo Jane C JC Salvy Sarah S Haile Robert R Hitchins Megan M

Cancers 20210910 18

Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highl ...[more]

PMID: 34572774

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Project description:BackgroundCirculating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection.MethodsTumor-specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient-specific, multiplex PCR-based NGS assays in MRD detection. Plasma-free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced.ResultsThe detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression.ConclusionOur study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.

Project description:Background & aimsBiomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy.MethodsWe performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6-8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy).ResultsThe median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P < .0001), formation of distant metastases (hazard ratio, 32.1; P < .0001), and shorter disease-specific survival times (hazard ratio, 23.1; P < .0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P = .03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P < .001 for comparison of either technique to combined analysis).ConclusionsIn an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.

Project description:BackgroundAccurate biomarkers to monitor tumor load and response in metastatic colorectal cancer patients undergoing surgery could optimize treatment regimens.ObjectiveThis study explores the clinical validity of tumor-informed quantification of circulating tumor DNA in blood using ultra-deep sequencing.DesignResection specimens from 53 colorectal cancer patients were analyzed for tumor-specific mutations in 15 genes. These mutations were used to measure the presence of circulating tumor DNA in preoperatively collected plasma samples using hybrid capture-based sequencing. Additional postoperative measurements were performed one week after surgery in sixteen patients.SettingsThe study was conducted at the Radboud university medical center.PatientsA total of 53 colorectal cancer patients undergoing surgery of metastases were included.Main outcome measuresThe detection of circulating tumor DNA.ResultsAt least one tumor-specific mutation was detected in all tumor samples. In preoperative plasma samples circulating tumor DNA was detected in 88% (37/42) of systemic treatment-naïve patients and in 55% (6/11) of patients who received preoperative chemotherapy. More specifically, in 0% (0/3) of cases with a subtotal or partial pathological response and in 75% (6/8) of cases without a pathological response in the resection specimen (p = 0.06). In postoperative plasma samples circulating tumor DNA was detected in 80% (4/5) of patients with an incomplete resection and in 0% (0/11) of those with a complete resection (p = 0.003).LimitationsThe study was limited by the heterogeneity of the cohort and the small number of postoperative plasma samples.ConclusionsThese data indicate that tumor-informed circulating tumor DNA detection in plasma of patients undergoing surgery for metastatic colorectal cancer is feasible and may have clinical value in response monitoring and predicting residual disease. Prospective studies are needed to establish the clinical utility of circulating tumor DNA analysis to guide treatment decisions in these patients. See Video Abstract at http://links.lww.com/DCR/B990.

Dataset Information

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer.

Publications

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer.

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