The goal of this clinical trial is to improve diagnosis and treatment strategies for patients with Cancer of Unknown Primary (CUP) by using advanced molecular profiling to identify the likely tumor origin and guide therapy.

The main questions it aims to answer are:

Can comprehensive molecular profiling help determine the origin of CUP tumors? Does identifying the tumor origin improve treatment choices and survival outcomes compared to historical data?

Participants will:

• Undergo a new biopsy to collect tumor tissue for advanced analyses.
• Provide blood samples for circulating tumor DNA (cfDNA/ctDNA) analyses.
• Provide a fecal sample for microbiome analysis.
• Have their tumor tissue analyzed using:

Methylation profiling and comprehensive gene panel testing.

• Have the results reviewed in a specialized CUP molecular MDT meeting to determine the likely tumor origin and guide treatment.
• Have their tumor tissue samples biobanked for further exploratory whole genome sequencing (WGS) and RNA sequencing.

Inclusion Criteria:

• ECOG PS 0-2.
• Life expectancy minimum 3 months.
• Radiologically verified metastatic disease (CT thorax/abdomen/pelvis) with no radiological signs of primary tumor.
• Histologically verified metastatic disease of unknown primary. Morphological and immunohistochemical findings suggesting a possible, but not definitive, origo is eligible.
• Eligible histologies include adenocarcinoma, squamous cell carcinoma, poorly and undifferentiated carcinoma and undifferentiated neoplasms.
• Clinically relevant endoscopic examinations have been performed as indicated by clinical, radiological and pathological findings, without identification of a primary tumor.
• Clinically relevant supplementary radiological examinations have been performed as indicated by clinical, radiological and pathological findings, with no radiological signs of primary tumor (e.g. PET/CT, mammography/MR mammae).
• Metastatic lesion available for biopsy. Protocol deviation may be allowed if lesion is not technically available for biopsy. For patients with metastatic lesion technically available for biopsy, the patient must be deemed medically fit to undergo a metastatic biopsy, as assessed by the investigator.
• Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

• Patients with any clinically significant medical or psychiatric condition which, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or which could jeopardize compliance with study requirements.
• Psychological, familial, sociological or geographical condition(s) potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Patient not able to give an informed consent or comply with study regulations as deemed by study investigator.