Pouyiourou Maria, Bochtler Tilmann, Pauli Chantal, Moch Holger, Brobeil Alexander, Pantel Klaus, Stenzinger Albrecht, Krämer Alwin
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Nat Rev Clin Oncol. 2025 Aug 4. doi: 10.1038/s41571-025-01060-8.
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.
原发灶不明的癌症（CUP）是一种转移性恶性肿瘤，尽管经过全面且标准化的诊断检查，仍无法确定其原发部位，占所有恶性肿瘤的1%-3%。CUP的一个不良亚组预后较差，采用当前基于铂类的标准化疗方案治疗时，中位总生存期小于1年。在过去几十年里，在阐明该疾病生物学特性以及改善不良CUP患者的治疗结局方面几乎没有取得进展，包括最初的随机临床试验未能证明通过基因表达谱鉴定组织起源（ToO）并随后进行原发部位定向治疗优于标准化疗。然而，大型队列随机试验现已表明，分子导向治疗可改善具有可操作靶点的CUP患者的治疗结局，无论是在不考虑组织类型还是在原发性肿瘤部位特异性的情况下。此外，非随机II期试验的数据表明，即使在经标准化疗后复发或难治的CUP患者中，使用免疫检查点抑制剂进行免疫治疗也可能有益。此外，人们还利用了大量精细且新颖的策略，包括DNA和RNA测序、DNA甲基化分析、循环肿瘤DNA分析以及基于人工智能的病理学，以促进ToO的识别。鉴于这些进展，我们回顾了当前的ToO方法，并比较了支持采用原发性肿瘤部位导向方法与不考虑组织学类型的方法来管理CUP的证据。我们还讨论了CUP是否可被视为开发不考虑组织学类型的精准肿瘤治疗策略的模型疾病。
