(Un-)Known Chances: Emerging Hope for Cancer of Unknown Primary - Highlights from ESMO 2025 and the First International Cancer of Unknown Primary Meeting.

Abstract

Background: Cancer of unknown primary (CUP) accounts for 1-3% of newly diagnosed cancers and remains a biologically heterogeneous and clinically challenging entity. For decades, management has relied on empirical platinum-based chemotherapy, which offers a poor prognosis with a median overall survival typically below 1 year. Recent advances in comprehensive genomic profiling, liquid biopsy, functional imaging, and tumour-agnostic drug development may transform diagnostic and therapeutic paradigms for the management of CUP.

Summary: This review synthesises current and upcoming data presented at ESMO 2025 and the first International Cancer of Unknown Primary Meeting (ICUPM), integrated with recent peer-reviewed literature. We highlight emerging diagnostic strategies, including whole-genome and transcriptome sequencing, ctDNA-based tissue-of-origin and cancer signal origin assays, and novel imaging modalities applied to CUP. We further discuss the clinical impact of multimodal molecular tumour boards, early detection approaches, and tumour-agnostic treatment strategies, including KRAS-directed and T-cell receptor-engineered cellular therapies.

Key messages: (i) Whole-genome and transcriptome sequencing, particularly when integrated within multidisciplinary tumour boards, may substantially improve diagnostic precision and tissue-of-origin prediction and may further be associated with improved survival in CUP patients. (ii) Liquid biopsy-based assays provide complementary, minimally invasive approaches for molecular stratification and tissue-of-origin prediction, with faster turnaround times than classical tissue sequencing. (iii) Fibroblast activation protein inhibitor PET-CT shows promise in improving primary tumour and metastasis detection beyond FDG-PET-CT. (iv) Tumour-agnostic treatment strategies, e.g., KRAS-selective inhibitors and T-cell receptor-engineered T-cell therapy, may advance the groundwork for molecularly driven treatment for CUP.