Advancements in Diagnostics and Therapeutics for Cancer of Unknown Primary in the Era of Precision Medicine

Cancer of unknown primary (CUP), a set of histologically confirmed metastases that cannot be identified or traced back to its primary despite comprehensive investigations, accounts for 2–5% of all malignancies. CUP is the fourth leading cause of cancer-related deaths worldwide, with a median overall survival (OS) of 3–16 months. CUP has long been challenging to diagnose principally due to the occult properties of primary site. In the current era of molecular diagnostics, advancements in methodologies based on cytology, histology, gene expression profiling (GEP), and genomic and epigenomic analysis have greatly improved the diagnostic accuracy of CUP, surpassing 90%. Our center conducted the world's first phase III trial and demonstrated improved progression-free survival and favorable OS by GEP-guided site-specific treatment of CUP, setting the foundation of site-specific treatment in first-line management for CUP. In this review, we detailed the epidemiology, etiology, pathogenesis, as well as the histologic, genetic, and clinical characteristics of CUP. We also provided an overview of the advancements in the diagnostics and therapeutics of CUP over the past 50 years. Moving forward, we propose optimizing diagnostic modalities and exploring further-line treatment regimens as two focus areas for future studies on CUP.