scholarly journals Development of circulating tumour DNA analysis for gastrointestinal cancers

ESMO Open ◽  
2020 ◽  
Vol 5 (Suppl 1) ◽  
pp. e000600 ◽  
Author(s):  
Yoshiaki Nakamura ◽  
Kohei Shitara
Keyword(s):  
Dna Analysis ◽  
Residual Disease ◽  
Turnaround Time ◽  
Resistance Mechanisms ◽  
Detection Methods ◽  
Comprehensive Genomic Profiling ◽  
Gi Cancers ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Circulating Tumour Dna

Comprehensive genomic profiling using next-generation sequencing (NGS) enables the identification of multiple genomic biomarkers established in advanced gastrointestinal (GI) cancers. However, tissue-based NGS has limitations, such as long turnaround time and failure to detect tumour heterogeneity. Recently, the analysis of circulating tumour DNA (ctDNA) using polymerase chain reaction-based or NGS-based methods has demonstrated the capability to detect genomic alterations with high accuracy compared with tumour tissue analysis with short turnaround time and identify heterogeneous resistance mechanisms. Furthermore, ctDNA analysis can be repeatedly performed on disease progression to clarify resistant clones. Clinical trials that test the outcome of a selected targeted therapy based on a ctDNA result are ongoing to prospectively evaluate the clinical utility of ctDNA analysis. Furthermore, the improvement of ctDNA analysis beyond current technical limits of mutation-based ctDNA detection methods has expanded the potential for detecting the presence of tumours in patients with no clinically evident disease, such as minimal residual disease and early cancer. Although a careful understanding of the advantages and limitations are required and further prospective studies are needed, the ctDNA analysis has the potential to overcome several challenges in the treatment of various types of cancers at all stages, including GI cancers.

scholarly journals Circulating Tumor DNA Testing Opens New Perspectives in Melanoma Management

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2914 ◽  
Author(s):  
Alessandra Sacco ◽  
Laura Forgione ◽  
Marianeve Carotenuto ◽  
Antonella De Luca ◽  
Paolo A. Ascierto ◽  
...  
Keyword(s):  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Prognostic Information ◽  
Skin Cancers ◽  
Highly Sensitive ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna

Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the diagnosis and monitoring of cancer. The availability of highly sensitive techniques, including next generation sequencing (NGS)-based panels, has increased the fields of application of ctDNA testing. While ctDNA-based tests for the early detection of melanoma are not available yet, perioperative ctDNA analysis in patients with surgically resectable melanoma offers relevant prognostic information: i) the detection of ctDNA before surgery correlates with the extent and the aggressiveness of the disease; ii) ctDNA testing after surgery/adjuvant therapy identifies minimal residual disease; iii) testing ctDNA during the follow-up can detect a tumor recurrence, anticipating clinical/radiological progression. In patients with advanced melanoma, several studies have demonstrated that the analysis of ctDNA can better depict tumor heterogeneity and provides relevant prognostic information. In addition, ctDNA testing during treatment allows assessing the response to systemic therapy and identifying resistance mechanisms. Although validation in prospective clinical trials is needed for most of these approaches, ctDNA testing opens up new scenarios in the management of melanoma patients that could lead to improvements in the diagnosis and therapy of this disease.

scholarly journals Clinical relevance of blood-based ctDNA analysis: mutation detection and beyond

2020 ◽  
Author(s):  
Laura Keller ◽  
Yassine Belloum ◽  
Harriet Wikman ◽  
Klaus Pantel
Keyword(s):  
Cancer Patients ◽  
Mutation Detection ◽  
Methylation Status ◽  
High Sensitivity ◽  
Resistance Mechanisms ◽  
Noninvasive Detection ◽  
Solid Malignancies ◽  
Ctdna Analysis ◽  
Detection Of Mutations ◽  
Circulating Tumour Dna

Abstract Cell-free DNA (cfDNA) derived from tumours is present in the plasma of cancer patients. The majority of currently available studies on the use of this circulating tumour DNA (ctDNA) deal with the detection of mutations. The analysis of cfDNA is often discussed in the context of the noninvasive detection of mutations that lead to resistance mechanisms and therapeutic and disease monitoring in cancer patients. Indeed, substantial advances have been made in this area, with the development of methods that reach high sensitivity and can interrogate a large number of genes. Interestingly, however, cfDNA can also be used to analyse different features of DNA, such as methylation status, size fragment patterns, transcriptomics and viral load, which open new avenues for the analysis of liquid biopsy samples from cancer patients. This review will focus on the new perspectives and challenges of cfDNA analysis from mutation detection in patients with solid malignancies.

scholarly journals Circulating Tumor DNA and Minimal Residual Disease (MRD) in Solid Tumors: Current Horizons and Future Perspectives

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Peng ◽  
Wuxuan Mei ◽  
Kaidong Ma ◽  
Changchun Zeng
Keyword(s):  
Solid Tumors ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Malignant Tumors ◽  
Circulating Tumor Dna ◽  
Detection Methods ◽  
Risk Of Recurrence ◽  
Increased Risk ◽  
Ctdna Analysis ◽  
Tumor Dna

Circulating tumor DNA (ctDNA) is cell-free DNA (cfDNA) fragment in the bloodstream that originates from malignant tumors or circulating tumor cells. Recently, ctDNA has emerged as a promising non-invasive biomarker in clinical oncology. Analysis of ctDNA opens up new avenues for individualized cancer diagnosis and therapy in various types of tumors. Evidence suggests that minimum residual disease (MRD) is closely associated with disease recurrence, thus identifying specific genetic and molecular alterations as novel MRD detection targets using ctDNA has been a research focus. MRD is considered a promising prognostic marker to identify individuals at increased risk of recurrence and who may benefit from treatment. This review summarizes the current knowledge of ctDNA and MRD in solid tumors, focusing on the potential clinical applications and challenges. We describe the current state of ctDNA detection methods and the milestones of ctDNA development and discuss how ctDNA analysis may be an alternative for tissue biopsy. Additionally, we evaluate the clinical utility of ctDNA analysis in solid tumors, such as recurrence risk assessment, monitoring response, and resistance mechanism analysis. MRD detection aids in assessing treatment response, patient prognosis, and risk of recurrence. Moreover, this review highlights current advancements in utilizing ctDNA to monitor the MRD of solid tumors such as lung cancer, breast cancer, and colon cancer. Overall, the clinical application of ctDNA-based MRD detection can assist clinical decision-making and improve patient outcomes in malignant tumors.

scholarly journals Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Jacob J. Chabon ◽  
Andrew D. Simmons ◽  
Alexander F. Lovejoy ◽  
Mohammad S. Esfahani ◽  
Aaron M. Newman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Resistance Mechanism ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Egfr Inhibitor ◽  
Tumour Heterogeneity ◽  
Lung Cancer Patients ◽  
Ctdna Analysis ◽  
Inhibitor Resistance ◽  
Circulating Tumour Dna

Abstract Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

scholarly journals Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Laura Escudero ◽  
Anna Llort ◽  
Alexandra Arias ◽  
Ander Diaz-Navarro ◽  
Francisco Martínez-Ricarte ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Residual Disease ◽  
Tissue Sample ◽  
Secondary Effects ◽  
Diagnosis And Prognosis ◽  
Paediatric Brain Tumour ◽  
Ctdna Analysis ◽  
Disseminated Disease ◽  
Circulating Tumour Dna

Abstract The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.

Predicting response to radical (chemo)radiotherapy (R-CRT) with circulating HPV DNA and tumor DNA (ctDNA) analysis in locally-advanced head and neck squamous cell carcinoma (LAHNC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6043-6043
Author(s):  
Shreerang Bhide ◽  
Jen Lee ◽  
Isaac Garcia-Murillas ◽  
Ros Cutts ◽  
Tara Hurley ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Residual Disease ◽  
Locally Advanced ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Surgical Biopsy ◽  
Hpv Dna ◽  
Pet Ct ◽  
Ctdna Analysis ◽  
Tumor Dna

6043 Background: Following R-CRT for human papilloma virus positive (HPV+) and negative (HPV-) LAHNC, patients frequently undergo unnecessary neck dissection (ND) and/or repeated biopsies for abnormal PET-CT findings even in the presence of a complete pathological response (pCR), which causes significant morbidity. We assessed the role of circulating tumor DNA analysis in identifying patients with true residual disease. Methods: We prospectively recruited development (DC, n=55) and test (TC, n=33) cohorts of LAHNC patients having R-CRT. For HPV+ tumors we developed a novel amplicon based next generation sequencing assay (HPV-detect) to detect circulating HPV DNA and for HPV- tumors we used personalised droplet digital PCR assays of somatic mutations. Circulating tumor DNA levels at 12 weeks post-R-CRT were correlated to residual disease assessed by PET-CT and surgery. Results: In the DC (27 HPV+), baseline HPV-detect demonstrated 100% sensitivity and 93% specificity, confirmed in the TC (20 HPV+). 37 HPV+ patients (DC&TC) had complete samples-set. 36 had a negative HPV-detect at end of treatment, including 6 patients who underwent ND (3) and repeat primary site biopsies (3) for positive PET-CT but had pCR on surgical/biopsy specimen. 1 patient had positive HPV-detect and positive biopsy, indicating 100% agreement for HPV-detect and residual cancer. In a 10 HPV- patients with complete sample-set, there was 90% agreement between ctDNA and residual disease in HPV- tumors (3 ctDNA positive and tumor present, 1 ctDNA negative but tumor present, and 6 negative ctDNA negative tumor) with 80% sensitivity for residual disease and 100% specificity. Combined agreement between ctDNA testing (HPV+ and -) & residual disease was 98% (Table). Conclusions: Circulating HPV DNA quantified using HPV-detect and ctDNA identifies patients with residual disease post-R-CRT in LAHNC. Further studies are required to validate these findings. [Table: see text]

scholarly journals Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3342
Author(s):  
Chul Kim ◽  
Liqiang Xi ◽  
Constance M. Cultraro ◽  
Fang Wei ◽  
Gregory Jones ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Dna Analysis ◽  
Early Time ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Tumor Burden ◽  
Egfr Mutant ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies—blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)—were employed to investigate their complementary roles. Methods: Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. Results: A total of 25 patients were included. We analyzed 534 samples by ddPCR (n = 25), 256 samples by NGS (n = 24) and 371 samples by eLB (n = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61–272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant EGFR by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. EGFR/ERBB2/MET/KRAS amplifications, EGFR C797S, PIK3CA E545K, PTEN V9del, and CTNNB1 S45P were key resistance mechanisms identified by NGS. Conclusion: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles.

scholarly journals A Case Report of Primary Resistance to EGFR TKI in Lung Adenocarcinoma Due to Coexisting MET Exon 14 Skipping Mutation with Excellent Response to Combination of Gefitinib and Capmatinib

2021 ◽  
Author(s):  
Nirmal Vivek Raut ◽  
Siddharth Srivastava ◽  
Guarav Dilip Gangwani ◽  
Heena Sajid Ali
Keyword(s):  
Kinase Inhibitors ◽  
Single Gene ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Primary Resistance ◽  
Gene Testing ◽  
Comprehensive Genomic Profiling ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Next Generation Sequencing Ngs ◽  
Egfr Tki

AbstractTreatment of nonsmall cell lung cancer (NSCLC) carrying an epidermal growth factor receptor (EGFR) mutation depends on EGFR tyrosine kinase inhibitors (TKIs). However, all patients treated with EGFR TKI eventually develop progressive disease. Approximately, 20% of patients do not respond to EGFR TKIs, which is defined as primary resistance. The prognosis of these patients is similar to NSCLC with nondriver mutations. We report a case of a patient with EGFR exon 21 mutation who rapidly progressed in 15 days on Gefitinib. Next-generation sequencing (NGS) showed a MET exon 14 skip mutation coexisting with EGFR exon 21 mutation, causing primary resistance to EGFR TKI. Based on NGS reports, a treatment combining Gefitinib and Capmatinib, a MET inhibitor, induced a rapid response in the patient, which was sustained at the end of 8 months. This clearly emphasizes the need for comprehensive genomic profiling using NGS over single gene testing.

scholarly journals BTK, NUTM2A, and PRPF19 Are Novel KMT2A Partner Genes in Childhood Acute Leukemia

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 924
Author(s):  
Elena Zerkalenkova ◽  
Svetlana Lebedeva ◽  
Aleksandra Borkovskaia ◽  
Olga Soldatkina ◽  
Olga Plekhanova ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Residual Disease ◽  
Chromosomal Rearrangements ◽  
Strong Impact ◽  
Acute Leukemias ◽  
Dna And Rna ◽  
Targeted Ngs ◽  
Childhood Acute Leukemia ◽  
Next Generation Sequencing Ngs ◽  
The Given

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with acute leukemias, especially in infants. KMT2A is rearranged with a big variety of partner genes and in multiple breakpoint locations. Detection of all types of KMT2A rearrangements is an essential part of acute leukemia initial diagnostics and follow-up, as it has a strong impact on the patients’ outcome. Due to their high heterogeneity, KMT2A rearrangements are most effectively uncovered by next-generation sequencing (NGS), which, however, requires a thorough prescreening by cytogenetics. Here, we aimed to characterize uncommon KMT2A rearrangements in childhood acute leukemia by conventional karyotyping, FISH, and targeted NGS on both DNA and RNA level with subsequent validation. As a result of this comprehensive approach, three novel KMT2A rearrangements were discovered: ins(X;11)(q26;q13q25)/KMT2A-BTK, t(10;11)(q22;q23.3)/KMT2A-NUTM2A, and inv(11)(q12.2q23.3)/KMT2A-PRPF19. These novel KMT2A-chimeric genes expand our knowledge of the mechanisms of KMT2A-associated leukemogenesis and allow tracing the dynamics of minimal residual disease in the given patients.

Sign in / Sign up

Export Citation Format

Share Document