原发灶不明的不利癌 (CUP) 患者的预后极差，约为 1 年或更短，这强调需要更有针对性的治疗，目前正在临床试验中进行测试。 CUPISCO (NCT03498521) 是一项 II 期随机研究，针对既往未经治疗、病情不利的 CUP 患者进行靶向治疗/癌症免疫治疗与铂类化疗的比较，根据欧洲肿瘤内科学会指南进行定义。我们对参加 CUPISCO 研究的 464 名经严格诊断、不利的 CUP 患者进行了初步的描述性分子分析。对福尔马林固定、石蜡包埋的组织进行了基因组分析，以检测基因组改变并评估肿瘤突变负荷和微卫星不稳定性。总体而言，约 32% 的患者携带潜在的可靶向基因组改变，包括 PIK3CA、FGFR2、ERBB2、BRAFV600E、EGFR、MET、NTRK1、ROS1 和 ALK。使用共突变谱的层次聚类，鉴定出 10 个具有特定基因组改变共现的簇，其中一些镜像定义的肿瘤实体。结果揭示了具有不利 CUP 的患者的分子异质性，并表明基因组谱分析可用作知情的一部分确定潜在原发肿瘤和靶向治疗方案的决策。严格诊断的患有不利 CUP 的患者是否能够以与匹配已知原发的患者类似的方式从靶向治疗中受益，将是 CUPISCO 的一个关键知识。版权所有 © 2023 作者。由爱思唯尔有限公司出版。保留所有权利。

Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study.Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability.Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities.Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.