Circulating Tumour DNA to Guide Treatment of Gastrointestinal Malignancies.
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ABSTRACT: Background
Gastrointestinal cancers are among the most common cancers worldwide and account for a high proportion of cancer-related mortality. Advancements to improve outcomes are constrained by the lack of biomarkers that can offer early diagnostic and prognostic information as traditional serological tumour markers and conventional imaging approaches are not able to provide early information regarding disease recurrence and treatment outcomes. Recent advances in technology have allowed the detection of circulating tumour DNA (ctDNA) in plasma, nucleic acid fragments released into the circulation from primary or metastatic lesions undergoing apoptosis and necrosis. A growing body of evidence has emerged supporting the use of ctDNA in many aspects of cancer care.Summary
This review focuses on the potential role of ctDNA in the management of patients with gastrointestinal cancers including colorectal, pancreatic, and upper gastrointestinal cancers. In this review, we discuss its possible utility in screening, detection of minimal residual disease and prognostication, longitudinal surveillance, and identification of therapeutic targets and resistance incorporating recent literature and ongoing randomised clinical trials.Key messages
ctDNA has substantial potential as a clinically useful marker in the management of gastrointestinal cancers from cancer screening through to treatment of advanced disease.
SUBMITTER: To YH
PROVIDER: S-EPMC7590785 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Technologies for genomic analyses have revealed more details in cancer biology and have changed standard treatments for cancer, including the introduction of targeted gene-specific therapy. Currently, liquid biopsies are increasingly being utilized in clinical trials and research settings to analyze circulating tumor DNA (ctDNA) from peripheral blood. Several studies have shown the potential of ctDNA in the screening, prognostication, molecular profiling, and monitoring of gastrointestinal malignancies. Although limitations continue to exist in the use of ctDNA, such as method standardization, the sensitivity, concordance with tumor tissue, and regulatory issues, this field offers promising benefits for cancer treatment. A deeper understanding of tumor biology via ctDNA analyses and ctDNA-guided clinical trials will lead to the increasing use of ctDNA in clinical practice in the near future; this development will result in the improvement of outcomes among patients with gastrointestinal malignancies.
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Project description:BackgroundMetastatic breast cancer (mBC) is a heterogenous disease with increasing availability of targeted therapies as well as emerging genomic markers of therapeutic resistance, necessitating timely and accurate molecular characterization of disease. As a minimally invasive test, analysis of circulating tumour DNA (ctDNA) is well positioned for real-time genomic profiling to guide treatment decisions. Here, we report the results of a prospective testing program established to assess the feasibility of ctDNA analysis to guide clinical management of mBC patients.Methods and findingsTwo hundred thirty-four mBC patients (median age 54 years) were enrolled between June 2015 and October 2018 at the Peter MacCallum Cancer Centre, Melbourne, Australia. Median follow-up was 15 months (range 1-46). All patient samples at the time of enrolment were analysed in real time for the presence of somatic mutations. Longitudinal plasma testing during the course of patient management was also undertaken in a subset of patients (n = 67, 28.6%), according to clinician preference, for repeated molecular profiling or disease monitoring. Detection of somatic mutations from patient plasma was performed using a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2, and AKT1. In parallel, subsets of samples were also analysed via next-generation sequencing (targeted panel sequencing and low-coverage whole-genome sequencing [LC-WGS]). The sensitivity of ddPCR and targeted panel sequencing to identify actionable mutations was compared. Results were discussed at a multidisciplinary breast cancer meeting prior to treatment decisions. ddPCR and targeted panel sequencing identified at least 1 actionable mutation at baseline in 80/234 (34.2%) and 62/159 (39.0%) of patients tested, respectively. Combined, both methods detected an actionable alteration in 104/234 patients (44.4%) through baseline or serial ctDNA testing. LC-WGS was performed on 27 patients from the cohort, uncovering several recurrently amplified regions including 11q13.3 encompassing CCND1. Increasing ctDNA levels were associated with inferior overall survival, whether assessed by ddPCR, targeted sequencing, or LC-WGS. Overall, the ctDNA results changed clinical management in 40 patients including the direct recruitment of 20 patients to clinical trials. Limitations of the study were that it was conducted at a single site and that 31.3% of participants were lost to follow-up.ConclusionIn this study, we found prospective ctDNA testing to be a practical and feasible approach that can guide clinical trial enrolment and patient management in mBC.
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Project description:Several novel therapeutics are poised to change the natural history of chronic lymphocytic leukaemia (CLL) and the increasing use of these therapies has highlighted limitations of traditional disease monitoring methods. Here we demonstrate that circulating tumour DNA (ctDNA) is readily detectable in patients with CLL. Importantly, ctDNA does not simply mirror the genomic information contained within circulating malignant lymphocytes but instead parallels changes across different disease compartments following treatment with novel therapies. Serial ctDNA analysis allows clonal dynamics to be monitored over time and identifies the emergence of genomic changes associated with Richter's syndrome (RS). In addition to conventional disease monitoring, ctDNA provides a unique opportunity for non-invasive serial analysis of CLL for molecular disease monitoring.
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Project description:BACKGROUND: Circulating DNA (ctDNA) is acknowledged as a potential diagnostic tool for various cancers including colorectal cancer, especially when considering the detection of mutations. Certainly due to lack of normalization of the experimental conditions, previous reports present many discrepancies and contradictory data on the analysis of the concentration of total ctDNA and on the proportion of tumour-derived ctDNA fragments. METHODOLOGY: In order to rigorously analyse ctDNA, we thoroughly investigated ctDNA size distribution. We used a highly specific Q-PCR assay and athymic nude mice xenografted with SW620 or HT29 human colon cancer cells, and we correlated our results by examining plasma from metastatic CRC patients. CONCLUSION/SIGNIFICANCE: Fragmentation and concentration of tumour-derived ctDNA is positively correlated with tumour weight. CtDNA quantification by Q-PCR depends on the amplified target length and is optimal for 60-100 bp fragments. Q-PCR analysis of plasma samples from xenografted mice and cancer patients showed that tumour-derived ctDNA exhibits a specific amount profile based on ctDNA size and significant higher ctDNA fragmentation. Metastatic colorectal patients (n?=?12) showed nearly 5-fold higher mean ctDNA fragmentation than healthy individuals (n?=?16).
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Project description:BackgroundCirculating tumour DNA (ctDNA) is an emerging candidate biomarker for malignancies and may be useful for monitoring the disease status of gastric cancer.MethodsWe performed targeted deep sequencing of plasma cell-free DNA (cfDNA) by massively parallel sequencing in patients with tumours harbouring TP53 mutations. The quantitative values of TP53-ctDNA during the clinical course were compared with the tumour status.ResultsThree out of ten patients with TP53 mutations in primary tumours showed detectable TP53 mutation levels in preoperative cfDNA. Although the cfDNA concentrations were not always reflective of the disease course, the ctDNA fraction correlated with the disease status.ConclusionsctDNA may serve as a useful biomarker to monitor gastric cancer progression and residual disease.
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