Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact.
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ABSTRACT:
SUBMITTER: Honore N
PROVIDER: S-EPMC8582541 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Long-term management for leukemia is challenging due to the painful and invasive procedure of bone marrow (BM) biopsy. At present, non-invasive liquid (blood) biopsy is not utilized for leukemia, due to lower counts of leukemia blast cells in the blood. Here, we described a robust system for the simultaneous detection and enrichment of rare blast cells. Enrichment of blast cells was achieved from blood with a one-step microfluidic blast cell biochip (BCB) sorting system, without specific targeting of proteins by antibodies. Non-target cells encountered a differential net force as compared to stiffer blast cells and were removed. The efficiency of the BCB promotes high detection sensitivity (1 in 106 cells) even from patients with minimal residual disease. The procedure was validated using actual blast cells from patients with various types of leukemia. Outcomes were compared to current evaluation standards, such as flow cytometry, using BM aspirates. Blast cell detection efficiency was higher in 55.6% of the patients using the BCB as compared to flow cytometry, despite the lower concentrations of blast cells in liquid biopsy. These studies promote early-stage detection and routine monitoring for minimal residual disease in patients.
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Project description:Liquid biopsy (LB) provides a unique minimally invasive tool to follow-up cancer patients over time, to detect minimal residual disease (MRD), to study metastasis-biology and mechanisms of therapy-resistance. Molecular characterization of CTCs offers additionally the potential to understand resistance to therapy and implement individualized targeted treatments which can be modified during the disease evolution and follow-up period of a patient. In this study, we present a long-term follow-up of operable breast cancer patients based on a comprehensive liquid biopsy analysis. We performed a comprehensive liquid biopsy analysis in peripheral blood of 13 patients with early-stage operable breast cancer at several time points for a period of ten years, consisting of: (a) CTC enumeration using the CellSearch system, (b) phenotypic analysis of CTCs using Immunofluorescence, (c) gene expression analysis, in EpCAM(+) CTCs for CK-19, CD24,CD44, ALDH1, and TWIST1, (d) analysis of PIK3CA and ESR1 mutations in EpCAM(+) CTCs and corresponding plasma ctDNA and (e) DNA methylation of ESR1 in CTCs. 10/13 (77%) patients were found negative for LB markers in PB during the whole follow-up period, and these patients did not relapse during the follow-up. However, 3/13(18%) patients that were positive for at least one LB marker relapsed within the follow-up period. The molecular characteristics of CTCs were highly different even for the same patient at different time points, and always increased before the clinical relapse. Our results indicate that liquid biopsy can reveal the presence of MRD at least 4 years before the appearance of clinically detectable metastatic disease demonstrating that a comprehensive liquid biopsy analysis provides highly important information for the therapeutic management of breast cancer patients.
| S-EPMC9870904 | biostudies-literature
Project description:Minimal residual disease (MRD) assessment using peripheral blood instead of bone marrow aspirate/biopsy specimen or the biopsy of the cancerous infiltrated by lymphoid malignancies is an emerging technique with enormous interest of research and technological innovation at the current time. In some lymphoid malignancies (particularly ALL), Studies have shown that MRD monitoring of the peripheral blood may be an adequate alternative to frequent BM aspirations. However, additional studies investigating the biology of liquid biopsies in ALL and its potential as an MRD marker in larger patient cohorts in treatment protocols are warranted. Despite the promising data, there are still limitations in liquid biopsies in lymphoid malignancies, such as standardization of the sample collection and processing, determination of timing and duration for liquid biopsy analysis, and definition of the biological characteristics and specificity of the techniques evaluated such as flow cytometry, molecular techniques, and next generation sequencies. The use of liquid biopsy for detection of minimal residual disease in T-cell lymphoma is still experimental but it has made significant progress in multiple myeloma for example. Recent attempt to use artificial intelligence may help simplify the algorithm for testing and may help avoid inter-observer variation and operator dependency in these highly technically demanding testing process.
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Project description:Minimal residual disease (MRD) assessment through blood component sampling by liquid biopsies (LBs) is increasingly being investigated in myeloid malignancies. Blood components then undergo molecular analysis by flow cytometry or sequencing techniques and can be used as a powerful tool for prognostic and predictive purposes in myeloid malignancies. There is evidence and more is evolving about the quantification and identification of cell-based and gene-based biomarkers in myeloid malignancies to monitor treatment response. MRD based acute myeloid leukemia protocol and clinical trials are currently incorporating LB testing and preliminary results are encouraging for potential widespread use in clinic in the near future. MRD monitoring using LBs are not standard in myelodysplastic syndrome (MDS) but this is an area of active investigation. In the future, LBs can replace more invasive techniques such as bone marrow biopsies. However, the routine clinical application of these markers continues to be an issue due to lack of standardization and limited number of studies investigating their specificities. Integrating artificial intelligence (AI) could help simplify the complex interpretation of molecular testing and reduce errors related to operator dependency. Though the field is rapidly evolving, the applicability of MRD testing using LB is mostly limited to research setting at this time due to the need for validation, regulatory approval, payer coverage, and cost issues. This review focuses on the types of biomarkers, most recent research exploring MRD and LB in myeloid malignancies, ongoing clinical trials, and the future of LB in the setting of AI.
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Project description:Approximately two-thirds of all colorectal cancer patients undergo surgery with the aim of curing them. However, despite the surgery, 20-25% of them experience relapse. It is possible to reduce the risk of relapse with chemotherapy, but as chemotherapy is associated with significant side effects, it is only given to patients at high risk of relapse. Currently, the risk is assessed based on an examination of the removed tumor tissue.
In a previous research project, blood samples were taken after patients’ surgery and examined for the presence of circulating tumor DNA (ctDNA). When cancer cells in solid tumors die, they release DNA, which can be detected in the blood. DNA in the blood has a half-life of less than 2 hours, so if ctDNA is found in a blood sample taken, e.g., 14 days after surgery, the patient most likely still has cancer cells in their body.
The results show that if a patient has ctDNA in their blood after surgery, the risk of relapse is high. The presence of ctDNA in the blood has the potential to be a better indicator of the risk of future relapse than the tumor examination used today. Therefore, ctDNA analysis has the potential to become a marker that will be used in the future clinical setting for monitoring colorectal cancer.
The overall objective of this study is to confirm that ctDNA found in a blood sample after intended curative treatment for CRC is a marker of residual disease and risk of recurrence and is applicable in clinical practice.
| 109300 | ecrin-mdr-crc
Project description:Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy.
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Project description:Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results suggest that ctDNA MRD could identify candidates for adjuvant therapy and measure response to such treatment. Importantly, factors such as assay type, amount of ctDNA release, and technical and biological background can affect ctDNA MRD results. Furthermore, the clinical utility of ctDNA MRD for treatment personalization remains to be fully established. Here, we review the evidence supporting the value of ctDNA MRD in solid cancers and highlight key considerations in the application of this potentially transformative biomarker.SignificancectDNA analysis enables detection of MRD and predicts relapse after definitive treatment for solid cancers, thereby promising to revolutionize personalization of adjuvant and consolidation therapies.
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Project description:Internal tandem duplication (ITD) of the fms-related tyrosine kinase 3 (FLT3) gene is associated with a poor prognosis in acute myeloid leukemia (AML) patients with a normal karyotype. The current standard polymerase chain reaction (PCR) assay for FLT3/ITD detection is not sufficiently sensitive to monitor minimal residual disease (MRD). Clone-specific assays may have sufficient sensitivity but are not practical to implement, since each clone-specific primer/probe requires clinical validation.To develop an assay for clinical molecular diagnostics laboratories to monitor MRD in FLT3/ITD AMLs.We designed a simple novel assay, tandem duplication PCR (TD-PCR), and tested its sensitivity, specificity, and clinical utility in FLT3/ITD AML patients.TD-PCR was capable of detecting a single ITD molecule and was applicable to 75 % of ITD mutants tested. TD-PCR detected MRD in bone marrow prior to patient relapse. TD-PCR also identified low-level ITD mutants not only in FLT3/ITD AMLs but also in initial diagnostic specimens that were reportedly negative by the standard assay in patients who progressed with the same ITDs detected by the TD-PCR assay.Detection of MRD by TD-PCR may guide patient selection for early clinical intervention. In contrast to clone-specific approaches, the TD-PCR assay can be more easily validated for MRD detection in clinical laboratories because it uses standardized primers and a universal positive control. In addition, our findings on multi-clonality and low-level ITDs suggest that further studies are warranted to elucidate their clinical/biological significance.
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Project description:Purpose of reviewThere has been a huge development in the assessment of malignancies through liquid biopsies last years, especially for NSCLC, where its use has become part of clinical practice in some settings. We aim to summarize current evidence about minimal residual disease and its use in lung cancer.Recent findingsRecent studies using ctDNA in NSCLC but also in other types of cancer found strong correlations between the presence of ctDNA and the risk of disease progression or death after curative intent, despite current technical difficulties in performing this analysis (high sensitivity and specificity required). Evaluation of MRD in NSCLC, especially through ctDNA, could be an important point in future trial designs and could permit a more "targeted" adjuvant treatment.
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Project description:Multiple myeloma is an incurable cancer of bone marrow plasma cells, with a 5-year survival rate of 43%. Its incidence has increased by 126% since 1990. Treatment typically involves high-dose combination chemotherapy, but therapeutic response and patient survival are unpredictable and highly variable-attributed largely to the development of multidrug resistance (MDR). MDR is the simultaneous cross-resistance to a range of unrelated chemotherapeutic agents and is associated with poor prognosis and survival. Currently, no clinical procedures allow for a direct, continuous monitoring of MDR. We identified circulating large extracellular vesicles (specifically microparticles (MPs)) that can be used to monitor disease burden, disease progression and development of MDR in myeloma. These MPs differ phenotypically in the expression of four protein biomarkers: a plasma-cell marker (CD138), the MDR protein, P-glycoprotein (P-gp), the stem-cell marker (CD34); and phosphatidylserine (PS), an MP marker and mediator of cancer spread. Elevated levels of P-gp+ and PS+ MPs correlate with disease progression and treatment unresponsiveness. Furthermore, P-gp, PS and CD34 are predominantly expressed in CD138- MPs in advanced disease. In particular, a dual-positive (CD138-P-gp+CD34+) population is elevated in aggressive/unresponsive disease. Our test provides a personalised liquid biopsy with potential to address the unmet clinical need of monitoring MDR and treatment failure in myeloma.
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