LIquid BIopsies in Patients Presenting Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The goal of this project is to characterize the genetic profile of patients with advanced stage IIIB/IV non-small cell lung cancer (NSCLC) using liquid biopsies

Detailed Description
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Lung cancers are the first cause of death by cancer in the world. The majority of these patients are diagnosed at a late stage, non-eligible to a curative treatment. Due to tumoral genomic identification, it has been possible to classify NSCLC in molecular subtypes according to molecular abnormalities detection called drivers which can be targeted using an appropriate treatment. This change modifies the standard treatments from the very first line of treatment particularly for patients having an EGFR mutation or an ALK or ROS1 rearrangement, with a significant benefit of progression free survival. The French NCI (INCa) recommends to identify genomic alterations of a genes panel including EGFR, KRAS, BRAF, HER2, ALK and ROS1 as well as mutations in MET exon 14. However, all the patients who benefit from a targeted therapy develop resistance after a mean duration of 10-12 months after starting the treatment. In case of progression, the tumour genetic analysis through new biopsies, enables to identify these mechanisms and then to determine if the patient can benefit or not from a third generation molecule active on these mechanisms, and to have a better understanding of the disease evolution. The detection of these alterations is routinely performed using tissular biopsies but in 10 to 20% of the cases, it is not possible. The detection of these molecular abnormalities in the plasma, called  liquid biopsy  is a valuable non-invasive complementary approach for these patients. It is presently used in routine for detecting the EGFR mutations at diagnosis as well as for searching EGFR T790M mutation for resistant patients. The liquid biopsies enable to detect circulating tumoral DNA.

Official Title
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Liquid Biopsies in Patients With Advanced Non-small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Participation Criteria
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Eligibility Criteria
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COHORT 1 Inclusion Criteria: Patients with histologically confirmed advanced non-small-cell lung carcinoma (stage IIIB/IV) regardless of the mutation status Inclusion at the time of diagnostic Realization of tumor biopsy at the institution (Centre Léon Bérard) or outside the institution with an available histopathological report Age ≥ 18 years Covered by a health insurance Signed consent Exclusion Criteria: - Patients treated before their liquid biopsy COHORT 2 Inclusion criteria Patients with histologically confirmed advanced non-small-cell lung carcinoma (stage IIIB/IV) with one of the following molecular anomalies: Epidermal Growth Factor Receptor (EGFR), B-Raf proto oncogene (BRAF) or Human Epidermal Growth Factor Receptor-2 (HER2) mutations, Anaplatsic Lymphoma Kinase (ALK) or ROS porto-oncogene 1 (ROS1) translocation, Mesenchymal-epithelial transition factor (MET) amplification, RET rearrangement. Inclusion at the time of diagnosis Realization of tumor biopsy at the institution (Centre Léon Bérard) or outside the institution with an available histopathological report Age ≥ 18 years Covered by a health insurance Signed consent COHORT 3 Inclusion criteria Patients with histologically confirmed advanced non-small-cell lung carcinoma (stage IIIB/IV) whatever the mutational or PD-L1 status. Inclusion at the time of immunotherapy treatment initiation (1st or 2nd line) Realization of tumor biopsy at the institution (Centre Léon Bérard) or outside the institution with an available histopathological report Age ≥ 18 years Covered by a health insurance Signed consent Exclusion criteria - Initiation of immunotherpy before their liquid biopsy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1<br>Patients with advanced NSCLC and no druggable molecular alteration at time of diagnosis | |
| Cohort 2<br>Patients with advanced NSCLC harboring targetable molecular alterations at time of diagnosis | |
| Cohort 3<br>Patients with advanced NSCLC at time of immunotherapy introduction (1st or 2nd line) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of the genetic profile in advanced or metastatic NSCLC patients using liquid biopsies (circulating tumoral DNA) | Technique: ddPCR + targeted NGF, whole exome sequencing | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of genetic biomarkers (or molecular profiles) having a potential predictive value in the treatments response | Techniques: ddPCR + targeted NGF, whole exome sequencing | 5 years | 
| Detection of the ALK and ROS1 genes translocations in the circulating DNA | Techniques: ddPCR + targeted NGF, whole exome sequencing | 5 years | 
| Evaluation of the liquid biopsies role in the tumoral monitoring | Correlation between mutated allelic fractions or expression's modification with the treatment response. Techniques: ddPCR + targeted NGF, whole exome sequencing | 5 years | 
| Evaluation of genomic and transcriptomic factors detectable in the plasma, associated to the immunotherapy response | Correlation between transcriptomic and genomic factors and response to immunotherapy. Techniques: ddPCR + targeted NGF, whole exome sequencing | 5 years | 
| Evaluation of the spatial and temporal tumor heterogeneity under targeted therapy treatment | Techniques: ddPCR + targeted NGF, whole exome sequencing | 5 years | 
| Evaluation of the miRNAs' expression in plasma as an epigenetic factor associated to treatments response | Correlation between miRNAS expression in plasma and treatment's efficacy. Techniques: miRNAs profiling using HTG technology | 5 years | 
| Circulating tumoral cells isolation and analysis to determine the role of non-genomic and/or phenotypic factors in the treatments response. | Single cell isolation technology | 5 years | 
| Evaluation of the resistance mechanisms to targeted therapies | Technique: ddPCR + targeted NGF, whole exome sequencing | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematologic test, Liquid biopsy