With the help of modern, highly sensitive analysis methods (NGS), such as ultra-low high-throughput sequencing, even the smallest amounts of circulating cell-free nucleic acids in the blood can be detected. In the individual course of therapy, the changes in concentration of the tumor-specific variants can thus be continuously monitored and appropriate therapy decisions can be made. The presence of minimal residual diseases and the development of resistance mutations can also be examined using this technique.

Molecular genetic diagnostic

Christopher Schroeder, Dr.

Julian Broche, Dr.

Stephan Ossowski, Prof. Dr.

In cooperation with the molecular tumor board of the University Hospital Tübingen (UKT), a prospective collection of blood samples during the course of therapy is planned. It is a pilot study in which the technical feasibility of the approach (Highly Sensitive Next-Generation Sequencing (NGS) methods) initially should to be evaluated and further developed.

In this study, we would like to use and further develop Highly Sensitive Next-Generation Sequencing (NGS) methods. For this purpose, circulating cell-free nucleic acids (cell free desoxyribonucleic acid (cfDNA) or cell free ribonucleic acid (cfRNA)) are first isolated from the blood plasma. The circulating tumor desoxyribonucleic acid (ctDNA) and circulating tumor ribonucleic acid (ctRNA) fractions contained therein arise from the tumor tissue and can provide information about the existing tumor burden and the original tissue of the tumor. Somatic Single Nucleotide Variants (SNVs) and insertions and deletions (indels) serve as biomarkers within the ctDNA and ctRNA. The ctDNA also contains epigenetic information in the form of DNA methylation, which shows a characteristic pattern for each tissue. Informative regions of the genome can be specifically enriched using personalized or fixed NGS panels. In this way, an ultra-deep sequencing of defined regions can be carried out and even the smallest concentrations of ctDNA and ctRNA in liquid biopsies can be detected.

CIRculating Cell-free nUcLeic Acids in Cancer Therapy Monitoring -01

The CIRCULATION-01 study will provide data in a pseudonymized manner to national and international databases set up to increase the diagnostic yield through advanced analysis tools.

Ratio of cfDNA/cfRNA at recurrence or disease progression

German Consortium for Translational Cancer Research

University Hospital Tuebingen

Phil Stephens, PhD

Foundation Medicine Inc. (FMI) is interested in studying the concordance of genomic alterations between primary and/or metastatic surgical biopsies, and circulating tumor DNA (ctDNA) within different solid tumor types and has been developing an assay in order to do so.

The purpose of this study is to assess whether a new ctDNA assay developed by Foundation Medicine is able to detect genomic alterations in peripheral blood that are consistent with the genomic alterations detected in a patient's matched primary and/or metastatic tumor biopsy sample analyzed by the FoundationOne® test. Study sites will provide matched solid tumor and peripheral blood samples of cancer patients to FMI for the purpose of testing the concordance of the FMI ctDNA assay to the FoundationOne® test. Participation in this study is part of a broader 2000 patient study to determine which tumor types are most readily measured via ctDNA profiling, and to learn of the similarity between the alterations found in a patient's tumor biopsy and the ctDNA from their blood.

Concordance Between ctDNA Assay and FoundationOne

Study of Concordance Between Circulating Tumor DNA Assay and Foundation One Tissue Analysis For Genomic Alterations

Johns Hopkins University

Oncology Consultants

Comprehensive Blood and Cancer Center

Illinois CancerCare

Sanford Health

Eastchester Center for Cancer Care

Rutgers Cancer Institute of New Jersey

Cone Health

Nebraska Cancer Specialists

University of California, Davis

University of Chicago

Northeast Georgia Medical Center

Hematology Oncology Associates of Fredericksburg

Memorial Sloan Kettering Cancer Center

Oncology Hematology Care, Inc

Montefiore Medical Center

Quincy Medical Group

Prisma Health-Upstate

Mary Crowley Cancer Research Center

Texas Health

University of California, San Diego

Avera Cancer Institute

Foundation Medicine

Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Patients with unresectable HCC who have no curative option like tumour ablation, resection or transplantation and are being taken for locoregional therapy will be recruited

Pre and post procedure plasma cell free DNA will be assessed for response to locoregional therapy

Cell Free DNA

Madhumita Premkumar, MD DM

Harman Dhaliwal, MSc

Madhumita Premkumar

Radhika Srinivasan, MD PhD

Circulating tumor DNA (ctDNA) carrying tumor-specific sequence alterations has been found in the cell-free fraction of blood. Hepatocellular carcinoma (HCC) specimens are difficult to obtain, and noninvasive methods are required to assess cancer progression and characterize underlying genomic features. Use of 'liquid biopsy' by assessing circulating cell free DNA enables the clinician to offer targeted immunotherapy or signaling pathway inhibitors. It also offers a model to prove response to locoregional or immunotherapy therapy and predict tumor recurrence non-invasively.

Novelty:

Mutation analysis may not only help identify cancer drivers, but they can also provide useful data to predict response to other treatment modalities such as immunotherapies, particularly immune checkpoint blockade. There is published data on liquid biopsy in India from oncology in the field of pulmonary and renal cancers, but these studies have not been done in cirrhosis or in HCC patients.

Objectives In this project we hope to develop a biomarker panel which helps us prognosticate patients and tailor targeted therapy as per their genetic mutation landscape. The treatment options for advanced HCC are limited, and tissue biopsy is not routinely performed.

Methods In this pilot project, we will analyze 30 patients with unresectable hepatocellular carcinoma, ineligible for liver transplantation, who will undergo locoregional therapy in the form of transarterial chemoembolization (TACE) or radioembolization (TARE) for tissue diagnosis of tumor tissue DNA and circulating tumor DNA. We will design personalized assays targeting somatic rearrangements of each tumor to quantify serum ctDNA. Exome sequencing will be performed using cell-free DNA and paired primary tumor tissue DNA in order to create a non-invasive liquid biopsy for diagnosis and prognostication of HCC.

Liquid Biopsy in Hepatocellular Carcinoma

Assessment of Response to Locoregional Therapy Using Liquid Biopsy in Patients With Hepatocellular Carcinoma

Post Graduate Institute of Medical Education and Research, Chandigarh

Assistant Professor, Department of Hepatology

Symptoms and General Pathology

Rare Diseases

Stomach Neoplasms

Neoplastic Cells, Circulating

Stomach Diseases

Stomach Cancer

Histologically HER2 positive gastric cancer patients treated with HER2 targeted therapy. Interventions: peripheral blood samples of 12.5 mL for CTC and cfDNA analysis will be collected before targeted therapy, at the time that they achieve the optimal response and when they suffer progressive disease.

Histologically HER2 negative gastric cancer patients treated with chemotherapy. Interventions: peripheral blood samples of 12.5 mL for CTC and cfDNA analysis will be collected before targeted therapy, at the time that they achieve the optimal response and when they suffer progressive disease.

The enumeration of CTCs as well as the detection of HER2 expression will be achieved via the integrated subtraction enrichment (SET) and immunostaining-fluorescence in situ hybridization (iFISH) platform. Further, for the geneomic analysis, the enriched single CTC will be isolated for single-cell targeted sequencing. While for cfDNA analysis, extracted DNA from plasma will be directly subjected to targeted sequencing. Tumor response evaluation will be performed after two cycles of chemotherapy by CT/MRI based on RECIST. Clinical data, including tumor stage, metastastic organ, chemotherapy regimen, objective response, progression free survival, overall survival, etc, will be collected according to study protocol.

CTC and cfDNA analysis

To evaluate the clinical significance of cell free DNA (cfDNA) and circulating tumor cells (CTCs) in real-time monitoring the therapeutic response during HER2-targeted therapy in histologically confirmed HER2 positive advanced/metastatic gastric cancer.

The study is a single-center, prospective study undertaken in anticipated 124 patients with both histologically HER2 positive and negative advanced/metastatic gastric cancer. Peripheral blood samples of 12.5 mL were collected from the patients for cfDNA and CTCs analysis. The blood samples will be respectively drawn before therapy, at the time that the patients achieve the optimal response and when they suffer progressive disease. The enumeration of CTCs as well as the detection of HER2 expression will be achieved via the integrated subtraction enrichment (SET) and immunostaining-fluorescence in situ hybridization (iFISH) platform. Further, for the geneomic analysis, the enriched single CTC will be isolated for single-cell targeted sequencing. While for cfDNA analysis, extracted DNA from plasma will be directly subjected to targeted sequencing. The correlation of the HER2 status on CTCs and the HER2 amplification in cfDNA to the therapeutic response will be evaluated. Moreover, gene variations associated with resistance in HER2-targeted therapy will be also studied based on the genomic data from sequencing of CTC and cfDNA.

Peripheral blood samples of 12.5 mL were collected from the patients for cfDNA and CTCs analysis

Liquid Biopsy in Monitoring the Therapeutic Efficacy of Targeted Therapy in Advanced/Metastatic Gastric Cancer

To evaluate the correlation of CTCs and their HER2 expression status to the clinical outcomes

To study the gene variations associated with resistance in HER2-targeted therapy based on the genomic data from sequencing of CTC and cfDNA

Peking University

Director of GI oncology

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Osimertinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Patients with metastatic adenocarcinoma of the lung for whom a 3rd generation TKI therapy is proposed and a search for resistance mutation by blood analysis as part of the usual management.

Description of the molecular alterations detected in blood samples of patients treated by osimertinib. This test is usualyy performed routinely to detect conventional mutations including EGFR T790M. We performed panel of genes screeining based on next generation sequencing. Thius, iIn some cases, new mutations can be detected by this assay.

Description of the molecular alterations detected in blood samples of patients treated by osimertinib

Jerome Solassol

In the management of non-small cell lung cancer of the adenocarcinoma type, different therapeutic strategies can be proposed. These strategies are defined according to the results of a biological analysis of blood and/or tissue samples from the lung tumor. Mutations in the tumor DNA are sought. Thus, patients with sensitizing mutations can benefit from a treatment with a 3rd generation tyroine kinase inhibitor (TKI) whose efficacy has been widely demonstrated. Patients without tumor mutations will not benefit. However, resistance to TKIs appears after a certain time, often linked to the appearance of new mutations in the tumor. For this reason, blood biologic analyses are regularly performed to search for the emergence of resistance mutations and to propose a therapeutic alternative as soon as possible.

These analyses are performed routinely in the laboratory. In the course of these analyses, the investigators have identified conventional mutations but also new mutations not previously described in the literature.

Our objective is to list all the molecular abnormalities revealed during blood biological analyses, to determine their frequency and to study whether certain abnormalities can be linked to resistance to TKI.

Resistance to Oral Therapy in Lung Cancer

Mechanisms of Resistance to 3rd Generation Thyrosine Kinase Inhibitors in Lung Cancer

This retrospective study will collate the molecular alterations detected during routine analysis. The elements extracted from the file will be age, sex, type of tumor and clinical-histological characteristics, dates of diagnosis and start of treatment. In addition, information on the dates of appearance of resistances (radiographic or clinical) will also be provided.

No additional analysis will be performed since the study will consist of the analysis of data generated by the analyses performed in the context of patient management and biological monitoring.

This research does not aim to modify your care. There will be no additional consultation or examination, nor will there be any changes in the treatment prescribed by your doctor.

Frequency of detected molecular alterations

University Hospital, Montpellier

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Antibodies

Immunoglobulins

Immunoglobulins, Intravenous

18 years of age or older with new diagnosis of non-Hodgkin lymphoma with FFPE specimen demonstrating enough tissue for elucidation of lymphoma specific variant and immunoglobulin clonotype, willing to provide baseline and follow up bloodwork to look for presence of variant and clonotype.

Etienne Mahe, MD, FRCPC

1. Develop a Next-Generation Sequencing (NGS) workflow for mutation profiling of formalin-fixed paraffin-embedded (FFPE) tissue and cell-free DNA (cfDNA) specimens.
2. Calculate the proportion of cases in a test series of B-cell non-Hodgkin Lymphomas (BNHL) with somatic mutations or immunoglobulin heavy chain (IGH) gene rearrangements common to both FPPE and cfDNA specimens.
3. Determine if certain types of BNHL are more likely to have mutation profiles common to both FFPE \& corresponding cfDNA ("FFPE-cfDNA dyads")
4. Determine if specific mutations or mutation profiles in FFPE or cfDNA specimens (or both) are of prognostic value after a clinical follow-up of 2 years from the time of diagnosis.

Patients with newly diagnosed B cell NHL will be identified. Samples will be cored from their diagnostic FFPE blocks and assayed to find lymphoma specific variants and immunoglobulin heavy chain gene rearrangements. Blood samples collected at baseline will be compared to see if variants and rearrangements can be detected in tumor specific DNA based on previous studies. Participant data will be collected, and clinical outcomes will be assessed to determine effect of mutation profiles on outcomes over 2 year follow up.

Blood samples will be prospectively collected at scheduled follow up and if primary objectives of this study are met, will be assessed for presence of cfDNA and impact of variation on clinical outcomes.

DNA library, RNA and formalin fixed paraffin embedded (FFPE) specimens will be banked with participants' prior permission.

Development of a Tissue-Based & Cell Free DNA Next-Generation Sequencing Workflow

Recorded in percentage. To determine impact of lymphoma specific mutation on outcome.

Proportion of cases of BNHL with somatic mutations or IgH gene rearrangements detectable in blood. Will be recorded in percentage, and determined at baseline.

Alberta Health Services, Calgary

Resident

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Daily collection of breath and blood before and after each of the 5 radiotherapy treatment sessions. Before and after daily cone beam CT image collection

Stereotactic Body Radiotherapy

Susan Forman

Duncan B McLaren, MBBS

Personalisation of radiotherapy dose based on real-time assessments of normal tissue and tumour response would maximise cure and minimise treatment related toxicity. During a 5 fraction course of prostate Stereotactic Body Radiotherapy (SBRT) this pilot study will assess whether a number of different biomarker approaches can predict for normal tissue and tumour response. Firstly the investigators will analyse volatile organic compounds released within the breath with each fraction of treatment. Secondly the investigators will analyse cell free normal tissue and tumour DNA released during treatment. Thirdly the investigators will develop imaging processing algorithms to look for imaging biomarkers predicting rectal wall toxicity using pre and post treatment cone beam CT verification images. Each of these approaches will be assessed against prostate specific antigen (PSA), Common Terminology Criteria for Adverse Events (CTCAE v4.0) criteria and Expanded Prostate Cancer Index Composite (EPIC-26) patient reported outcomes with a maximum of 24 months of follow up.

Radiotherapy scheduling and prescription dose does not take into account individual patient heterogeneity in normal tissue response or tumour response. Personalisation of radiotherapy dose based on real-time assessments of normal tissue and tumour response would maximise cure and minimise treatment related toxicity. During a 5 fraction course of prostate Stereotactic Body Radiotherapy (SBRT) this pilot study will assess whether a number of different biomarker approaches can predict for normal tissue and tumour response. Firstly the investigators will analyse volatile organic compounds released within the breath with each fraction of treatment using Gas Chromatography Ion Mobility Spectroscopy (GC-IMS). The investigators have extensive experience in this area within the TOXI-Triage research program (www.toxi-triage.eu/) including deep learning and machine learning techniques to interrogate the metabolomics data generated. Secondly the investigators will analyse cell free normal tissue and tumour DNA released during treatment to assess both tumour and normal tissue response. Radiotherapy releases large amounts in to the blood stream allowing easier quantitative analysis. Thirdly the investigators will look for imaging biomarkers of rectal wall toxicity using imaging analysis algorithms of on-treatment cone beam verification CT images taken before and after each radiotherapy treatment. The RayPilot® system made by Micropos Medical Ltd tracks prostate motion throughout the SBRT delivery to ensure that the treatment dose is delivered with great precision. The potential of each biomarker approach for predicting normal tissue and tumour response will be assessed against PSA and CTCAE v 4.0 toxicity criteria and EPIC-26 patient reported outcome measures after 24 months of patient follow up.

Volatile Organic Compound Breath Analysis, Cell-Free DNA normal tissue and tumour DNA, Cone Beam CT pre and post each fraction of radiotherapy, Genomic saliva analysis.

Using Breath, Cell Free DNA and Image Analysis to PRedIct Normal TissUe and Tumour Response During Prostate Cancer SBRT

Using Breath,Cell Free DNA and Image Analysis to PRedIct Normal TissUe and Tumour Response During Prostate Cancer SBRT With RayPilot® Motion Management

The pilot data will be used to inform a larger study cohort and to establish the optimal methodology and time points for sample collection

Measurement of the change in the 3D chromatogram of volatile organic compound GC-IMS Spectra detected from baseline pre-treatment, to completion of SBRT at each time point, for each patient. Each 3D chromatogram GC-IMS printout is generated from the readings of each axis. The y axis is associated with GC separation of VOC's, the x axis measures the movement of the generated ions (IMS drift time) and the z axis ion detector response equating to concentration. These 3 values separate, identify and quantify the VOC compounds detected.

Change in the density of 90-150 base pair fragment size cfDNA from baseline pre-treatment to completion of SBRT for each time point, for each patient

Dose calculation in cGy between expected and observed actual dose to the rectal wall using pre and post each fraction radiotherapy linear accelerator treatment verification cone beam CT scans

Common Terminology Criteria for Adverse Events CTCAE v 4.0 scores for urinary and bowel treatment related toxicity. Scale runs form Grade 1 mild requiring no intervention to grade 5 death

Expanded Prostate Cancer Index Composite EPIC-26 patient reported outcomes questionnaire. A clinical tool to assess urinary, bowel, sexual and vitality health. The score from each of the 5 domains runs from 0 (none) to 12 (severe) impact on quality of life. Each domain score when added together gives an overall score of zero (unaffected) to 60 (severely affected)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CIRculating Cell-free nUcLeic Acids in Cancer Therapy Monitoring -01	NCT05871593	Next-Generation...	Molecular genet...	18 Years -	University Hospital Tuebingen
Concordance Between ctDNA Assay and FoundationOne	NCT02620527	Circulating Tum... Cancer Neoplasms Genomic Testing Genomic Alterat...		18 Years -	Foundation Medicine
Liquid Biopsy in Hepatocellular Carcinoma	NCT04111029	Hepatic Carcino...	Cell Free DNA	18 Years - 70 Years	PGIMER
Liquid Biopsy in Monitoring the Therapeutic Efficacy of Targeted Therapy in Advanced/Metastatic Gastric Cancer	NCT02610218	Gastric Cancer	CTC and cfDNA a...	18 Years -	Peking University
Resistance to Oral Therapy in Lung Cancer	NCT04546282	Non Small Cell ...	Description of ...	18 Years - 90 Years	University Hospital, Montpellier
Liquid Biopsy in Hepatocellular Carcinoma	NCT04111029	Hepatic Carcino...	Cell Free DNA	18 Years - 70 Years	PGIMER
Liquid Biopsy in Hepatocellular Carcinoma	NCT04111029	Hepatic Carcino...	Cell Free DNA	18 Years - 70 Years	PGIMER
CIRculating Cell-free nUcLeic Acids in Cancer Therapy Monitoring -01	NCT05871593	Next-Generation...	Molecular genet...	18 Years -	University Hospital Tuebingen
Development of a Tissue-Based & Cell Free DNA Next-Generation Sequencing Workflow	NCT02788084	Non-Hodgkin Lym...		18 Years -	Alberta Health Services, Calgary
Using Breath, Cell Free DNA and Image Analysis to PRedIct Normal TissUe and Tumour Response During Prostate Cancer SBRT	NCT04081428	Prostate Cancer Radiotherapy Si... Volatile Organi... DNA Damage	Stereotactic Bo...	18 Years - 80 Years	NHS Lothian
Liquid Biopsy in Monitoring the Therapeutic Efficacy of Targeted Therapy in Advanced/Metastatic Gastric Cancer	NCT02610218	Gastric Cancer	CTC and cfDNA a...	18 Years -	Peking University

Spots Global Cancer Trial Database for cell free dna