Cancer of unknown primary: the hunt for its elusive tissue-of-origin - is it time to call off the search?

Cancer of Unknown Primary (CUP) is an heterogenous group of metastatic cancers, for which the primary site cannot be identified despite thorough diagnostic work-up. Whilst it is a relatively rare entity, its aggressive nature, together with the paucity of effective treatments, mean it has a disproportionately high mortality rate. Advances in genomic profiling have driven research in the area, but despite this, therapeutic options and prognosis remain poor. For many years, the primary focus in CUP has been improving identification of the tissue-of-origin (TOO), with the hope that site-specific therapy will improve survival outcomes. However, the lack of conclusive evidence to support this, as well as an emerging paradigm shift in how cancers should be classified, has reignited the debate surrounding the importance of TOO. Here, we provide a comprehensive review of the ongoing relevance of TOO, within both the CUP and wider oncology landscape.