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000303375 1001_ $$0P:(DE-He78)d62d536fb73eb7644201ddaac56cf68f$$aPouyiourou, Maria$$b0$$eFirst author$$udkfz
000303375 245__ $$aRethinking cancer of unknown primary: from diagnostic challenge to targeted treatment.
000303375 260__ $$aNew York, NY$$bNature Publ. Group$$c2025
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000303375 520__ $$aCancer of unknown primary (CUP) is a metastatic malignancy for which a primary site of origin cannot be identified despite a thorough and standardized diagnostic work-up, and accounts for 1-3% of all malignancies. An unfavourable subgroup of CUP has a poor prognosis, with a median overall survival of <1 year when treated with current standard-of-care platinum-based chemotherapy. Virtually no progress in elucidating the disease biology and improving outcomes for patients with unfavourable CUP has been made over the past several decades, including a failure of initial randomized clinical trials to demonstrate the superiority of tissue-of-origin (ToO) identification by gene-expression profiling and subsequent primary-site-directed treatment over standard chemotherapy. However, large-cohort randomized trials have now shown that molecularly guided therapy improves outcomes for patients with CUP harbouring an actionable target, both in a tissue-agnostic as well as a primary tumour site-specific context. Moreover, data from non-randomized phase II trials suggest that immunotherapy using immune-checkpoint inhibitors can be beneficial even in patients with CUP that has relapsed after, or is refractory to, standard chemotherapy. In addition, a plethora of refined and novel strategies, including DNA and RNA sequencing, DNA-methylation profiling, circulating tumour DNA analysis, and artificial intelligence-based pathology, have been leveraged to facilitate ToO identification. In light of these developments, we review current ToO methodologies and compare the evidence supporting the use of a primary tumour site-guided approach versus a histology-agnostic approach to the management of CUP. We also discuss whether CUP can be viewed as a model disease for the development of histology-agnostic precision oncology treatment strategies.
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000303375 7001_ $$0P:(DE-He78)c741dc7f974390ad4310349f29aac40b$$aBochtler, Tilmann$$b1$$udkfz
000303375 7001_ $$aPauli, Chantal$$b2
000303375 7001_ $$00000-0002-7986-2839$$aMoch, Holger$$b3
000303375 7001_ $$aBrobeil, Alexander$$b4
000303375 7001_ $$00000-0001-5736-2772$$aPantel, Klaus$$b5
000303375 7001_ $$00000-0003-1001-103X$$aStenzinger, Albrecht$$b6
000303375 7001_ $$0P:(DE-He78)493c5fbf69f1b20df6f048712f3ad4a0$$aKrämer, Alwin$$b7$$eLast author$$udkfz
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