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@ARTICLE{Pouyiourou:303375,
      author       = {M. Pouyiourou$^*$ and T. Bochtler$^*$ and C. Pauli and H.
                      Moch and A. Brobeil and K. Pantel and A. Stenzinger and A.
                      Krämer$^*$},
      title        = {{R}ethinking cancer of unknown primary: from diagnostic
                      challenge to targeted treatment.},
      journal      = {Nature reviews / Clinical oncology},
      volume       = {nn},
      issn         = {1759-4774},
      address      = {New York, NY},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2025-01624},
      pages        = {nn},
      year         = {2025},
      note         = {#EA:A360#LA:A360# / epub},
      abstract     = {Cancer 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.},
      subtyp        = {Review Article},
      cin          = {A360},
      ddc          = {610},
      cid          = {I:(DE-He78)A360-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40759731},
      doi          = {10.1038/s41571-025-01060-8},
      url          = {https://inrepo02.dkfz.de/record/303375},
}