Pathophysiological Mechanisms Involved in the Pronostic and Evolution of Non-Small Cell Lung Cancer (NSCLC) at All Stages of the Disease

Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Despite major therapeutic advances over the past two decades, including targeted therapies and immune checkpoint inhibitors, long-term survival remains limited for a substantial proportion of patients. Although five-year survival has improved compared to the early 2000s, prognosis remains heterogeneous and largely dependent on tumor biology, stage at diagnosis, molecular alterations, and host-related factors.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers and represents a biologically heterogeneous group of diseases. Tumor progression and resistance to therapy are driven by complex interactions between tumor cells, the tumor microenvironment, immune components, and host-related factors such as aging, smoking exposure, and chronic inflammatory lung diseases including chronic obstructive pulmonary disease (COPD).

A deeper understanding of these mechanisms is required to:

• Identify biomarkers associated with tumor progression and relapse
• Better predict therapeutic response and resistance
• Develop innovative diagnostic and therapeutic strategies

Bordeaux University Hospital is a regional referral center managing approximately 300-400 lung cancer patients annually. The institution hosts multiple academic research laboratories with expertise in tumor biology, immunology, thoracic diseases, and molecular oncology. This study aims to create a structured translational research continuum integrating clinical care and laboratory research.

Clinical data will be extracted from:

• The institutional clinical data warehouse
• Electronic medical records

Data collected will include:

• Demographics and smoking history
• Comorbidities (including COPD and other lung diseases)
• Tumor histology and molecular characteristics
• TNM staging
• Treatment modalities (surgery, radiotherapy, systemic therapies)
• Treatment response and toxicity
• Recurrence, progression, and survival outcomes Clinical data will be pseudonymized and recorded in a dedicated REDCap electronic case report form hosted at Bordeaux University Hospital.

Clinico-biological correlation analyses will make it possible to define :

• Response in study patients and evaluation of the impact of the different biological factors on treatment response, assessed according to RECIST 1.1 criteria
• Prognostic analyses may also be performed on overall survival (time between inclusion and death/loss to follow-up) and progression-free survival (time between inclusion and progression/loss to follow-up/death)
• Survival of patients in the cohort (overall survival, progression-free survival)
• Response rate of patients in the cohort according to treatment
• Factors statistically associated with survival using univariate then multivariate Cox analysis
• Treatment tolerance (descriptive analysis)
• List of pathways involved in resistance processes, and description of newly identified therapeutic targets for the different treatments
• Validation of the functional involvement of proteins/pathways in in vitro models

Biological Samples and Translational Analyses Tumor samples consist of formalin-fixed paraffin-embedded (FFPE) biopsy or surgical specimens stored at the institutional Biological Resource Center.

Samples will undergo translational analyses in partner academic laboratories, including:

• Molecular characterization of tumor cells
• Metabolic profiling
• Characterization of the tumor immune microenvironment
• Evaluation of immunosuppressive pathways
• Analysis of secretome-related functions
• Identification of aging-related biological signatures

After analysis, biological data will be securely transferred to the coordinating center and correlated with clinical variables.

All samples and associated data will be pseudonymized in accordance with applicable data protection regulations.

Inclusion criteria

• Adult patients
• NSCLC treated at the Bordeaux University Hospital.
• TNM stage between I to IV
• Patient affiliated with or beneficiary of a social security scheme.
• Non opposition

Exclusion criteria

• Patients with small cell lung cancer.
• History of any other malignancy other than NSCLC within 1 years prior to screening. except for non-melanoma skin cancers, in situ cancers, or low-risk prostate cancer
• Pregnant or breastfeeding women.
• Patients with a medical or psychiatric condition or illness that compromises their ability to understand the information or participate in the study.
• Individuals subject to legal protection measures (legal guardianship, trusteeship or curatorship).
• Individuals deprived of their liberty by judicial or administrative decision.
• Individuals who are unable to give their consent.
• Patients who are in a period of exclusion following another study or who have participated in another interventional study involving a medicinal product within 30 days prior to entry into the protocol or who are participating in another clinical study.