The European Society for Medical Oncology (ESMO) strongly recommends to develop multigene sequencing in the framework of molecular screening programmes, in order to improve access to innovative drugs and to accelerate clinical research in cancers.

• Accordingly, this project aims to study the contribution of early systematic multigene sequencing (NGS) discussed in Molecular Tumour Board for poor prognosis cancers, with no current indication for early sequencing.
• The investigators teams propose to perform a randomized study in tumours in which actionable therapeutic targets according to the ESMO ESCAT scale are known (ESCAT II/IV) especially in pancreatic ductal adenocarcinoma, hepatocellular carcinoma or triple negative breast cancer.

Two approaches will be compared: a large multigenic early sequencing approach since the first line setting versus a Plan France Medecine Genomique 2025 approach since the second line setting.

The frequency of really initiated therapeutic proposals according to the molecular status will be compared in each group.

Part 1 sequential multi-gene sequencing (Simple NGS),

• Multi-gene DNA sequencing (43 genes panel corresponding to the most frequently targeted molecular alterations)
• And if no contributive:

Part 2: randomized study between two sequential approaches

- Experimental arm: early Multi-gene DNA sequencing (638 genes panel) Multi-gene RNA sequencing (ARCHER panel)

1. MMR status in molecular biology

2. - Tumour Mutational Burden

   • Control arm: after 1st line escape, according to Plan France Medecine Genomique 2025 In the Part 2, a new biopsy could be proposed if necessary

Inclusion Criteria:

• - Age >18 years.

• Advanced disease status ("unresectable" or "metastatic").

• Patient included either at the time of diagnostic investigation or during first line of treatment.

• Good general conditions, still compatible with a therapeutic proposal, WHO 0-1.

• The following tumour sites, with poor prognosis and for which ESCAT II/IV treatment targets can be found according to ESMO:

  • pancreatic adenocarcinoma
  • hepatocellular carcinomas,
  • triple negative breast cancer.

• Tumour tissue a priori available in sufficient quantity: at least one biopsy from a visceral metastatic site or surgical specimen (if available) for eligible cancers.

• Patient covered by a social sercurity scheme

Exclusion Criteria:

• - General condition WHO >1 and/or nutritional status not compatible with a therapeutic proposal
• Limiting systemic cardiovascular, renal, bronchopulmonary or endocrinological comorbidities with the initiation of a therapeutic proposal
• Active infection or active chronic disease (diabetes, liver dysfunction, immune disease) making the patient's condition incompatible with a therapeutic proposal.
• A priori unavailable, in insufficient quantity or of suboptimal quality tumour material.
• Administrative reasons: inability to receive informed information, inability to participate in the entire study, lack of social security coverage, refusal to sign consent.