Cancer Without a Map: Navigating Cancer of Unknown Primary Through Molecular Profiling

Area of Science:

• Oncology
• Genomics
• Personalized Medicine

Background:

• Cancer of unknown primary (CUP) represents a heterogeneous group of rare metastatic cancers lacking a clear origin.
• Accurate diagnosis and targeted treatment are challenging in CUP management.

Purpose of the Study:

• To review the role of molecular profiling in improving diagnostic accuracy for CUP.
• To assess the impact of molecular data on predicting treatment response and guiding therapy selection.
• To synthesize evidence on tissue-of-origin (TOO) prediction, targeted therapy, and immunotherapy in CUP.

Main Methods:

• Literature search of PubMed, Scopus, and Web of Science.
• Synthesis of findings from clinical trials, meta-analyses, and cohort studies.
• Focus on multi-omics analyses (genomics, transcriptomics, proteomics, epigenomics) for TOO determination and alteration detection.

Main Results:

• Molecular profiling enhances tissue-of-origin determination and identifies actionable DNA alterations (e.g., MSI-high, TMB-high, BRAFV600E, NTRK, RET fusions).
• Tissue-of-origin directed therapy shows variable survival benefits; integration with clinicopathological data improves outcomes.
• Comprehensive genomic profiling facilitates targeted therapies and immunotherapy in selected CUP subgroups.

Conclusions:

• Molecular profiling is crucial for diagnostic clarification and individualized treatment in CUP.
• Molecularly guided therapy, combined with clinicopathological data, improves survival and expands treatment options.
• Future research should focus on optimizing biomarker strategies and standardizing predictive assays for CUP management.