# Molecular-Guided Precision Oncology in Cancer of Unknown Primary: A State-of-the-Art Perspective

## TL;DR

This paper reviews how cancer of unknown primary is shifting from traditional chemotherapy to precision treatments based on molecular insights.

## Contribution

The paper highlights recent clinical trials and molecular technologies transforming CUP treatment into a precision oncology approach.

## Key findings

- Landmark trials like CUPISCO and Fudan CUP-001 show molecular therapies improve survival in CUP patients.
- Comprehensive genomic profiling and liquid biopsies are increasingly used for CUP diagnostics and treatment.
- Molecular tumor boards and tumor-agnostic therapies are key to advancing personalized CUP care.

## Abstract

Cancer of unknown primary (CUP) is evolving from a diagnosis of exclusion treated with empirical chemotherapy to a molecularly defined entity amenable to precision-based interventions. This heterogeneous entity, comprising 2–3% of all metastatic malignancies, encompasses diverse cancers with clinically occult primary sites at diagnosis after a thorough workup. Recent landmark trials including CUPISCO and Fudan CUP-001 have demonstrated significant survival improvements with molecularly guided therapies compared to empirical chemotherapy, fundamentally enhancing and complementing traditional organ-centric treatment paradigms. This review synthesizes the current evidence supporting molecular diagnostics, tumor-agnostic therapies, and precision-based approaches in CUP management. We examine the clinical utility of comprehensive genomic profiling, gene expression profiling, and liquid biopsy technologies, while addressing implementation challenges and future directions. The integration of molecular tumor boards and the emergence of tissue/tissue-of-origin agnostic therapies herald a new era where CUP transitions from therapeutic nihilism to personalized oncology. As molecular technologies advance and targeted therapies proliferate, CUP may no longer represent a diagnosis of exclusion but rather an opportunity for molecularly informed precision care.