This trial is a multicenter, prospective cohort study aiming to describe molecular profiles of soft tissue sarcoma (STS) with complex genomic profiles in particular to assess the incidence of NTRK1/2/3, ROS1 or ALK gene fusions to direct such patients through an ongoing clinical trial with entrectinib when appropriate. An exploratory translational program is also correlated to this trial in order to analyse immune gene expression.

Following inform consent form (ICF) signature, a formalin-fixed and paraffin-embedded (FFPE) tumor block (archival or a dedicated freshly collected tumor biopsy) will be collected for all enrolled patients and centralized at the biological resources platform of the Centre Léon Bérard.

At reception, a central pathological review will be performed to confirm if quality and quantity of material is acceptable: all tumor sample should present at least 20 % (ideally 30 %) of tumor cells and have a surface area > 5 mm2 (optimal condition is a surface area of 5-25 mm2). If the quality and quantity of tumor sample do not meet the standards, patients will be considered as "screening failure". If standards are met, inclusion will be confirmed and molecular screening will be initiated as well as the translational research program.

The molecular screening to detect NTRK1,2,3, ROS1 or ALK gene rearrangements will be a two-step process, consisting of :

1. First, immunohistochemistry (IHC) assay to detect protein expression of TRKA/B/C (encoded by NTRK1,2,3), ROS1 or ALK. Only positive IHC samples will continued the 2nd step of molecular screening. Negative IHC patients do not require further NTRK, ROS or ALK gene rearrangement testing; however tumor samples will be further used for additional translational research program presented in Section VII and data about the clinical evolution of these patients will be collected
2. Second, RNAseq analysis will be performed on positive IHC specimens to detect specific rearrangements in the NTRK1,NTRK2, NTRK3, ROS1 or ALK genes.
3. Following molecular analyses, screening results will be immediately (within 24 hours) communicated to investigators, GSF-GETO Network and Ignyta representatives in order to recommend patients with NTRK1, NTRK2, NTRK3, ROS1 or ALK rearrangement for formal eligibility determination for potential enrolment in a clinical trial in particular with entrectinib (STARTRK-2; NCT02568267).

Inclusion Criteria:

• I1. Male or female patients aged ≥ 12 years at time of informed consent form (ICF) signature.
• I2. Histologically confirmed diagnosis of advanced /metastatic disease STS with complex genomics (e.g., Leiomyosarcoma [LMS], Undifferentiated Pleomorphic Sarcoma [UPS], pleomorphic liposarcoma/rhabdomyosarcoma [P-LPS/P-RMS], angiosarcoma, malignant peripheral nerve sheath tumor [MPNST], myxofibrosarcoma, fibrosarcoma).
• I3. Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor sample, with the corresponding hematoxylin and eosin stained slide and a pathological report:

either a tumor archival block (less than 3 years old) or a dedicated freshly collected de novo biopsy performed from one accessible lesion visible by medical imaging and accessible to percutaneous sampling with a diameter of at least 10 mm.

• I4. Tumor sample meeting following quality/quantity control (QC) criteria confirmed by a central pathological review:

at least 20% (ideally 30%) of tumor cells and a sample size surface area > 5mm2 (ideally 5-25mm2).

• I5. Patient (and legal guardians if not-emancipated minor) should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study procedures as per protocol.
• I6. Patient must be covered by a medical insurance.

Non-inclusion criteria:

• NI1. Patients with non-assessable tumor sample.
• NI2. Prior treatment with approved or investigational TRK, ROS1, or ALK inhibitors. Any other prior anticancer therapy are allowed with no limit of prior number of treatment lines.
• NI3. Pregnant or breast-feeding patients.