Cancer with Unknown Primary - CUP

CUP Tumors

Prof. Chantal Pauli

30. April 2026

Cancer with unknown primary tumor (CUP) is one of the most challenging oncological conditions. While metastases are visible, the origin remains concealed. A research project at the University Hospital Zurich demonstrates that even with this difficult-to-classify diagnosis, biological targets for more precise therapies can be identified.

When the Origin Remains in the Dark

In most cancer diagnoses, clinicians can identify the organ where the disease originated. This is not the case with CUP (Cancer of Unknown Primary). In CUP, metastases are found in one or more organs, but the primary tumor site remains unidentified.

CUP represents roughly 3% of all cancer diagnoses. For many patients, the outlook is poor: about 80–85% have an aggressive form of the disease and often survive less than a year after diagnosis. Because the site of origin is unknown, treatment typically relies on standard chemotherapy. This approach does not account for the tumor’s individual biological characteristics, limiting its effectiveness. In addition, many tumors quickly develop resistance to therapy.

Molecular Analyses Bring More Clarity

This is where part of the research project comes in: When the origin remains unknown, alternative methods must be found to better understand the tumor. Prof. Chantal Pauli and her team at the University Hospital Zurich analyzed genomic data from various CUP patients. This analysis confirmed that CUP is not a uniform disease. Instead, different subgroups can be distinguished, which resemble known tumor types in their genetic characteristics.

This means that even when the origin cannot be determined clinically, these genetic patterns provide important clues about how a tumor behaves and which therapies may be relevant.

Prof. Pauli is a pathologist and an expert in the diagnostic evaluation of the CUP syndrome, and her experiences have contributed to updated diagnostic recommendations (ESMO Clinical Practice Guideline, 2023, Oncopedia Guidelines).

Tumor Organoids: Testing Medications on Models

However, genetic data alone do not address the critical question of which medications are truly effective.

To enhance their evaluation, the research team developed tumor organoids from CUP patients. These three-dimensional cell models, cultivated from tumor tissue in the laboratory, serve as miniature replicas of the original tumors. They retain essential characteristics of the original tumors, enabling systematic testing of various medications.

The CUP tumor organoids were characterized at genomic, transcriptional, and protein levels and were compared with organoids from tumors of known origin. The analysis revealed that some CUP tumors share similarities with established cancer types, including comparable responses to certain medications. However, it also demonstrated that CUP tumors display significant heterogeneity, indicating the need for personalized treatment approaches. These insights facilitate a deeper understanding of the disease, encompassing both molecular analyses and actual medication responses. As a result, CUP emerges as a collection of distinct tumors rather than a singular diagnosis.

Additionally, Prof. Pauli and her team identified potential vulnerabilities in the DNA repair mechanisms of specific CUP tumors. When a critical repair process malfunctions, certain targeted therapies may become particularly effective. These strategies are already being employed in the treatment of other cancers and may prove beneficial for select CUP patients in the future.

Significance for Patients

This project enhances our understanding and classification of CUP, shifting the focus from standard therapies to the unique biological characteristics of each tumor.

The research team plans to test additional drug combinations and conduct more in-depth analyses as the next steps. In the long run, these efforts could lead to more precise therapy selection and better personalization of treatment for individual patients. While further studies are needed, the findings lay a crucial foundation for developing future treatment strategies.

Project Number: KFS-5270-02-2021

This project is supported by Swiss Cancer Research in collaboration with funding foundations. We would like to specifically mention Candriam, the Isaac Dreyfus-Bernheim Foundation, and the Fondation Marie & René.