Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Kezhong Chen, M.D.

Jun Wang, M.D.

To investigate the evolutionary genomic landscape, explore the genetic tumor heterogeneity and microenvironment of multiple primary lung cancer (MPLC) by using tissue genetic analysis and circulating tumor DNA detection, in order to provide robust evidence for the diagnosis, treatment, and surveillance of MPLC.

Multiple primary lung cancer (MPLC) has become a worldwide problem due to the difficulty in diagnosis, treatment and surveillance. Although exploring tumour clonal heterogeneity and microenvironment can help understand cancer evolution and impact therapeutic outcome, study is still lacking in this field on MPLC. Circulating tumor DNA (ctDNA) are short DNA fragments, which can be obtained conveniently and non-invasively, providing comprehensive views of the tumor as were shed by tumor cells from multiple tumor regions. Therefore, we design a prospective study of patients with surgically treated MPLC, aiming to use ctDNA technique to define the evolutionary landscape of MPLC through inter-tumor and intra-tumor heterogeneity by multi-region sampling and genetic analysis. We will also explore the the microenvironment by RNA sequencing and T cell receptor sequencing. This study may help understand the genetic evolution and microenvironment of MPLC, and provide evidence for the diagnosis, treatment and surveillance of these patients.

Fresh tumor tissue and blood samples were collected from each patient. Time for blood sample collection: 1) Preoperation. 2) The 1st to 3rd day of postoperation.

Evolution of Multiple Primary Lung Cancer (Evolution)

The Genetic Evolution and Microenvironment of Multiple Primary Lung Cancer

Explore the intra-tumor and inter-tumor genetic heterogeneity by analysis of clonal and subclonal mutations detected by ctDNA.

Using RNA sequencing and T cell receptor (TCR) sequencing to evaluate the microenvironment of each lesion of multiple primary lung cancer, including T cell receptpr clonality ,diversity , evenness, and richness.

Explore the correlation between the detection rate of ctDNA and subclonal mutations of different tumor sites detected by genetic analysis.

Explore the correlation between the detection rate of ctDNA and tumor burden.

Guangzhou Burning Rock Medical Examination Institute Co., Ltd.

Peking University People's Hospital

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

For Operable (stages I-IIIA) NSCLC Patients, blood sampling and tissue samples of the primary tumor as well as the regional involved lymph nodes and, in selected patients, from biopsies from metastasis

Patients' peripheral blood will be obtained before the surgical excision of the primary tumor as well as 1-month post-op and every 3-6 months thereafter until disease progression and upon disease relapse for the evaluation of ctDNA and CTCs. Different sites of the primary tumor as well as the regional involved lymph nodes and, in selected patients, biopsies from metastatic sites will be genotyped by NGS as well.

blood sampling

Vassilis Georgoulias, MD, PhD

Efthimios Prinarakis, PhD

Aggeliki Rapti, MD

Mina Gaga, MD

Evaggelos Sepsas, MD

Kosmas Iliadis, MD

Konstantinos Syrigos, MD,PhD,FCCP

Athanasios Kotsakis, MD, PhD

The purpose of his study is to investigate the intra tumor heterogeneity of the primary tumor and the involved lymph nodes from patients with resectable NSCLC, to detect primary tumor genetic alternations using "liquid biopsy" during the patients' clinical follow up and to correlate the "liquid biopsy" information with the disease recurrence.

Lung cancer is the most common cancer in the world. In operable early stage patients NSCLS can be curable, but even after complete primary tumor resection, about 45% of early stage patients develop local or distant recurrence within 8-18 months. Recent studies have established that targeted therapies may fail to cure the disease because of tumor heterogeneity. The presence of genetic heterogeneity in different portions of a tumor have demonstrated its importance in tumor biology suggesting that pre-existing genetically different sub clones may be selected by therapy or differentially involved in the metastatic process, leading to treatment failure.

The relationship of tumor heterogeneity with the poor clinical outcome suggests that its assessment could provide interesting and useful clinical information, especially, in terms of prognosis and treatment selection. It is now, well established that during the evolution of tumor new cellular clones could be emerged which differ genetically from the molecular signature of tumor cells evaluated at the time of initial diagnosis. This molecular evolution may further contribute to the tumor heterogeneity during the disease progression. The evaluation of the real-time molecular tumor heterogeneity requires repeated re-biopsies during the different clinical phases of NSCLC which, however, are invasive and not, always, feasible. This problem can be by-passed by the use of tumor-originating elements in the plasma and among these cellular products the isolation and analysis of cell tumor DNA (ctDNA) and the characterization of Circulating Tumor Cells (CTCs) represent important tools for identification and monitoring of molecular tumor alterations in cancer patients, representing what the investigators call "liquid biopsy". ctDNA is originated from cellular necrosis due to increased tumoral cellular turnover and cellular ischemia as well as from apoptosis of tumor cells or lysis of Circulating Tumor Cells (CTCs). On the other hand, the CTCs, which designate the cells circulating in the blood, can be detected in several tumor types, irrespectively of the clinical phase, and their detection has been correlated with disease progression and treatment resistance. Therefore, the concomitant analysis of both ctDNA and CTCs could permit to better evaluate the genetic heterogeneity of the tumor since they continuously released from tumor cells throughout the clinical course of the disease and is considered to be proportional to tumor burden and tumor progression at each time-point.

This is a multicenter, single arm, non-randomized translational research study. Patients with operable NSCLC will be enrolled in the study. Patients' peripheral blood will be obtained before the surgical excision of the primary tumor as well as 1-month post-op and every 3-6 months thereafter until disease progression and upon disease relapse for the evaluation of ctDNA and CTCs. Different sites of the primary tumor as well as the regional involved lymph nodes and, in selected patients, biopsies from metastatic sites will be genotyped by NGS as well.

NSCLC Heterogeneity in Early Stage Patients and Prediction of Relapse Using a Personalized "Liquid Biopsy"

Evaluation of Non-small Cell Lung Carcinoma Genetic Heterogeneity in Patients With Operable Early Stage Disease and Prediction of Clinical Relapse Using a Personalized "Liquid Biopsy"

The initial tumor of all patients will be submitted to Next Generation Sequencing (NGS) in order to detect mutations and copy-number variations to the following set of genes: AKT1, KRAS, NRAS, BRAF, DDR2, EGFR, FGFR1, ERBB2 (HER2), MEK1, MET, PIK3CA, PTEN, TP53, MDM2, SOX2 and P63. Detected mutations will be monitored longitudinally in ctDNA from patient's blood samples by ddPCR, for a 2-year period or until PD. For each subject, molecular analysis results will be correlated with its clinical outcome in terms of time to disease progression (PFS). CTCs will be isolated based on the cell's size. CTCs isolated by ISET will be phenotypically characterized to define their proliferative, apoptotic, EMT status as well as their immune profile using antibodies and immunofluorescent staining. CTCs isolated by PARSORTIX will be analyzed for the detection of specific genetic changes present in the primary tumor (see NGS analysis of primary tumor) using either qRT-PCR or FISH analysis.

The initial tumor of all patients will be submitted to Next Generation Sequencing (NGS) in order to detect mutations and copy-number variations to the following set of genes: AKT1, KRAS, NRAS, BRAF, DDR2, EGFR, FGFR1, ERBB2 (HER2), MEK1, MET, PIK3CA, PTEN, TP53, MDM2, SOX2 and P63.

The initial tumor of all patients will be submitted to Next Generation Sequencing (NGS) in order to detect mutations and copy-number variations to the following set of genes: AKT1, KRAS, NRAS, BRAF, DDR2, EGFR, FGFR1, ERBB2 (HER2), MEK1, MET, PIK3CA, PTEN, TP53, MDM2, SOX2 and P63. Detected mutations will be monitored longitudinally in ctDNA from patient's blood samples by droplet digital Polymerase Chain Reaction (ddPCR), for a 2-year period or until PD.

The initial tumor of all patients will be submitted to Next Generation Sequencing (NGS) in order to detect mutations and copy-number variations to the following set of genes: AKT1, KRAS, NRAS, BRAF, DDR2, EGFR, FGFR1, ERBB2 (HER2), MEK1, MET, PIK3CA, PTEN, TP53, MDM2, SOX2 and P63. Detected mutations will be monitored longitudinally in ctDNA from patient's blood samples by droplet digital Polymerase Chain Reaction (ddPCR), for a 2-year period or until PD. Moreover, in patients where metastasis re-biopsy is feasible the metastasis tumor will be submitted to Next Generation Sequencing (NGS) in order to detect mutations and copy-number variations to the set of genes mentioned above. Correlation between the molecular analysis of the primary tumor, the ctDNA and the metastasis tumor will reveal whether longitudinal liquid biopsy can predict the metastasis genetic profile.

Hellenic Oncology Research Group

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Digestive System Diseases

Rare Diseases

Neoplasm Metastasis

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Peritoneal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Abdominal Neoplasms

Peritoneal Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Construction of a core database of genetic and epigenetic markers, in order to identify predictive biomarkers and potentially actionable targets for controlling the spread of peritoneal carcinomatosis.

construction of a database of genetic and epigenetic data on peritoneal carcinomatosis of colorectal or ovarian origin.

Olivier GLEHEN, MD

Sara CALATTINI, CRA

How epigenetic deregulation affects gene expression patterns in subclones of the same tumor is poorly known. Peritoneal Carcinomatosis (PC) is a condition in which multiple metastases of the same abdominal tumor develop in the peritoneal cavity and intra-peritoneal organs, thus defining different ecosystems of the same cancer. PITCHER addresses the variations in epigenetically regulated gene expression between different subclones of PC in relation with cell mechanoresponses, providing insights on how cancer epigenetic landscapes evolve under environmental pressures and on strategies used by cancer cells to adapt to the transition from one ecosystem to the other.

PITCHER is a network of 10 teams from Lyon, Grenoble and Marseille, based on data and specimen collection of patients who have undergone a surgery for a peritoneal carcinomatosis of ovarian or colorectal origin. PC lesions and eventually matched specimens of primary tumors will be collected in the same patients at the time of the surgery or eventually retrieved from already existing samples. Epigenetic landscapes will be analyzed by a bioinformatics pipeline combining exome sequencing, transcriptome and methylome to identify "epigenetic hotspots", and their variations across lesions will be evaluated. These analyses will be realized in fresh (when available) or pre-existing samples. When possible, organoid cultures and animal models will be derived from multicellular structures in peritoneal fluids and membrane, cytoskeletal and nucleoskeletal mechanoresponses will be characterized using Atomic Force Microscopy. The role of tumor axonogenesis, a process of neo-formation of axon fibers in tumors, will be addressed. Experimental studies of cell responses to therapy will be performed to derive mathematical predictive models. All components will be integrated in a systems biology map of PC.

tumor samples (peritoneal carcinomatosis, primary tumor, other tumor metastasis (when applicable)), healthy tissue

PITCHER (Peritoneal Carcinomatosis Heterogeneity)

The main endpoint is to implement a specific tissue collection of appropriate quality, assembling "multiplets" of biospecimens from the same patient, in order to construct a core database for research on mechanisms, biomarkers and actionable therapeutic targets in PC. This database will include molecular analysis by next-generation sequencing of whole-exome genetic, transcriptomic and epigenetic patterns of primary, peritoneal and metastatic lesions. "Omics" data are compiled using a data model also including anonymized information on histopathology and clinical history of treatments (when applicable)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Evolution of Multiple Primary Lung Cancer (Evolution)	NCT04326751	Multiple Primar... Lung Cancer Non Small Cell ...		18 Years - 80 Years	Peking University People's Hospital
NSCLC Heterogeneity in Early Stage Patients and Prediction of Relapse Using a Personalized "Liquid Biopsy"	NCT03771404	Non Small Cell ...	blood sampling	18 Years -	Hellenic Oncology Research Group
NSCLC Heterogeneity in Early Stage Patients and Prediction of Relapse Using a Personalized "Liquid Biopsy"	NCT03771404	Non Small Cell ...	blood sampling	18 Years -	Hellenic Oncology Research Group
NSCLC Heterogeneity in Early Stage Patients and Prediction of Relapse Using a Personalized "Liquid Biopsy"	NCT03771404	Non Small Cell ...	blood sampling	18 Years -	Hellenic Oncology Research Group
NSCLC Heterogeneity in Early Stage Patients and Prediction of Relapse Using a Personalized "Liquid Biopsy"	NCT03771404	Non Small Cell ...	blood sampling	18 Years -	Hellenic Oncology Research Group
PITCHER (Peritoneal Carcinomatosis Heterogeneity)	NCT04714957	Secondary Perit... Colorectal Canc... Ovarian Cancer	construction of...	18 Years -	Hospices Civils de Lyon

Spots Global Cancer Trial Database for tumor heterogeneity