The proposal is to conduct a prospective, multi-cohort study aiming to decipher molecular profiles/biological characteristics of advanced cancer patients during the course of their disease with longitudinal and sequential analyses of tumor and liquid biopsies. This approach will allow i) to develop a model in order to predict tumor response / resistance in real life conditions and to better understand adaptive mechanisms and ii) to potentially propose therapeutic options to enrolled patients following the review of the biological/molecular data generated during this study and during a Molecular Tumor Board in case of disease progression. This study will include 12 cohorts according to tumor type and standard treatment received (See Inclusion criteria I1). Patient will be enrolled before the initiation of standard anti-cancer treatment.

Most of the molecular screening programs have allowed to successfully guide patients to personalized therapy only for a minority of patients (10-20%) and few patients have actually benefit from these programs with low objective response under personalized therapy.

During the course of disease and / or of treatment, tumors become more heterogeneous and include a collection of cells harboring distinct molecular signatures with differential levels of sensitivity to treatment. Assessment of tumor heterogeneity and plasticity are essential for the development of effective therapies. Longitudinal analysis of biopsy samples is of considerable interest to assess the complex clonal architecture of cancers and potentially adapt cancer treatment to tumor profile/characteristics overtime. In this context, profiling of circulating tumor DNA using non-invasive liquid biopsies is also an interesting approach to assess cancer evolution by showing the contribution of clonal heterogeneity to chemotherapy resistance and metastasis in high-risk patients.

The proposal is to conduct a prospective, multi-cohort study aiming to decipher molecular profiles/biological characteristics of advanced cancer patients during the course of their disease with longitudinal and sequential analyses of tumor and liquid biopsies. This approach will allow i) to develop a model in order to predict tumor response / resistance in real life conditions and to better understand adaptive mechanisms and ii) to potentially propose therapeutic options to enrolled patients following the review of the biological/molecular data generated during this study and during a Molecular Tumor Board in case of disease progression. This study will include 12 cohorts according to tumor type and standard treatment received (See Inclusion criteria I1). Patient will be enrolled before the initiation of standard anti-cancer treatment.

Inclusion Criteria:

I1. Adult male or female patient with confirmed diagnosis of advanced/metastatic cancer to be treated with standard anti-cancer treatment according to :

• For metastatic Small cell lung cancer (SLCC) : treatment by Immunotherapy ± chemotherapy
• For Recurrent/Metastatic Head and Neck squamous cell carcinoma (HNSCC) : treatment by Immunotherapy (all lines) ± chemotherapy if in agreement with SmPC
• For Metastatic Urothelial carcinoma : treatment by 1st line chemotherapy with avelumab as maintenance treatment (patients will be enrolled following 4 to 6 cycles of CT, only patient initiating avelumab maintenance are eligible (i.e. patients with SD or PR after CT)
• For MSI-High, any tumor types : treatment by Immunotherapy
• For HPV-related cancers, any tumor types : treatment by Immunotherapy
• Metastatic GIST : treatment by Imatinib
• BRAF- V600E tumors (lung and thyroid cancer) : treatment by Dabrafenib + trametinib
• BRAF- mutated tumors (CRC, lung and thyroid cancer) :

Lung (V600E only) and thyroid (all BRAF mutation with known sensitivity to Dabrafenib): treatment by Dabrafenib + trametinib CRC (BRAF V600E): treatment by Encorafenib + cetuximab

• All solid tumor types with ret fusion / mutation : treatment by Selpercatinib
• Metastatic Triple negative breast cancer (TNBC) : treatment by 1st line chemotherapy
• Glioblastoma : treatment by Radiochemotherapy
• Advanced high grade epithelial ovarian cancer : treatment by 1st line Chemotherapy
• Chronic Lymphocytic Leukemia (CLL) in the relapsed setting : treatment by Bruton Kinase Inhibitors

I2. All solid tumor cohorts: Availability of an archival representative formalin-fixed paraffin-embedded (FFPE) tumor sample [...]

I3. All solid tumor cohorts: Disease evaluable as per RECIST V1.1

I4. All solid tumor cohorts excluding Glioblastoma: Tumor lesion visible by medical imaging and accessible to repeatable percutaneous or endoscopic mandatory de novo tumor sampling [...]

I5. Performance status (PS) ECOG 0 or 1.

I6. Patient should understand, sign, and date the written ICF prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures including sequential tumor biopsies as per protocol.

I7. Patient must be covered by a medical insurance.

Exclusion Criteria:

NI1. All solid tumor cohorts - Patient with non-acceptable tumor sample at screening.

NI2. Any condition contraindicated with blood/tumor sampling procedures required by the protocol.

NI3. Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure.

NI4. Pregnant or breast-feeding woman.