Progress in refining the clinical management of cancer of unknown primary in the molecular era

Abstract

Cancer of unknown primary (CUP) is an enigmatic disease entity encompassing heterogeneous malignancies without a detectable primary tumour, despite a thorough diagnostic workup. A minority of patients with CUP (15–20%) can be assigned a putative primary tissue of origin according to clinical and histopathological findings and typically have a more favourable prognosis with the use of corresponding tumour type-specific therapies. Thus, the majority of patients with CUP have disease that cannot be assigned to a culprit primary tumour, are treated with empirical chemotherapy and have a poor prognosis. In the molecular era, the use of (epi)genomic or transcriptomic CUP classifiers and DNA or RNA sequencing offers two, sometimes overlapping, therapeutic strategies: tumour type-specific therapy and biomarker-guided therapy. Published data reveal that the accuracy of site-of-origin predictions made using CUP classifiers ranges between 54% and 98% when compared with the assignment made according to the recommended clinicopathological criteria. These advances have led to promising results in non-randomized prospective studies evaluating the efficacy of tumour type-specific therapy; however, the favourable outcomes were not confirmed in randomized controlled studies comparing this approach with standard empirical chemotherapy. Currently, the evidence supporting the use of biomarker-guided therapies is limited to case reports and small case series. In this Review, we discuss the clinical management of CUP in the era of precision medicine. We focus on the advances in understanding the biology of CUP, the implications for the diagnosis and classification of CUP according to the tissue of origin and the shift away from empirical therapy towards tailored therapy.

Key points

  • Cancer of unknown primary (CUP) is a clinically well-recognized, but biologically enigmatic, disease entity that encompasses a heterogeneous group of metastatic cancers without an identifiable primary tumour, despite extensive investigations.

  • The current era is witnessing a decrease in the proportion of patients with cancer who are diagnosed with CUP to 1–2%, in comparison to 3–5% in the early 1990s.

  • The recommended diagnostic workup includes a thorough physical examination, basic blood analyses, evaluation of tumour biomarkers (guided by the clinical scenario) and CT scans of the thorax, abdomen and pelvis.

  • Multiple assays have been developed to predict the putative tissue of origin by alignment with prominent molecular profiles established for cancers with a known primary.

  • Together with the overall clinical picture and results of pathology investigations, molecular profiling of CUP can have therapeutic implications by guiding treatment decisions according to the putative primary tumour type and the detection of potential driver mutations.

  • The design of future prospective randomized trials should address the minority of patients that present with targetable mutations, especially driver mutations, based on the findings of molecular analyses and the predicted primary tumour type.

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Fig. 1: The development and dissemination of CUP.
Fig. 2: Proposed algorithm for the diagnosis and management of CUP.

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Rassy, E., Pavlidis, N. Progress in refining the clinical management of cancer of unknown primary in the molecular era. Nat Rev Clin Oncol (2020). https://doi.org/10.1038/s41571-020-0359-1

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