Rethinking cancer of unknown primary: from diagnostic challenge to targeted treatment.

Journal: Nature reviews. Clinical oncology
Published Date: Aug 4, 2025

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.

Authors

  • Maria Pouyiourou
    Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
  • Tilmann Bochtler
    Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
  • Chantal Pauli
    Department of Pathology and Molecular Pathology, University and University Hospital Zürich, Zürich, Switzerland.
  • Holger Moch
    Institute of Surgical Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • Alexander Brobeil
    Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Klaus Pantel
    Institute of Tumour Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Albrecht Stenzinger
    From the Division of Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany (P.S., J.P.R., P.K., H.P.S., D.B.); Medical Image Computing, German Cancer Research Center (DKFZ), Heidelberg, Germany (S.K., K.H.M.H.); Department of Urology, University of Heidelberg Medical Center, Heidelberg, Germany (J.P.R., M.H.); Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany (M.W.); Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany (P.K.); Junior Group Medical Imaging and Radiology-Cancer Prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany (S.B.); Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany (T.A.K.); Institute of Pathology, University of Heidelberg Medical Center, Heidelberg, Germany (A.S.); and German Cancer Consortium (DKTK), Heidelberg, Germany (H.P.S., K.H.M.H., D.B.).
  • Alwin Krämer
    Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. a.kraemer@dkfz.de.

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