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Abstract：
Background: Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. Methods: A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting. Results: We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving TP53 (41.88%), KRAS (18.81%), CDKN2A (8.8%), and PIK3CA (9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS. Conclusions: NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology.
摘要：
背景：不明原发癌（CUP）占所有恶性肿瘤的3-5％，尽管发病率有所下降，在过去的十年中，总生存率没有改善。化疗方案没有提供令人鼓舞的结果。新的诊断技术,例如下一代测序（NGS），可能代表一个机会来鉴定潜在的可靶向基因组改变，以便个性化CUP的治疗并提供对肿瘤生物学的见解。方法：对CUP患者的研究进行系统回顾，他们的肿瘤样本是通过NGS小组评估的，已经在6月10日演出了，2019年根据PubMed的PRISMA标准，ASCO会议图书馆和诊所试验.gov.我们已经确定了可获得批准/标签外/临床试验药物的潜在可靶向改变。此外，我们纳入了由NGS结果驱动进行靶向治疗的CUP患者的病例报告,以探讨NGS在这种情况下的临床作用.结果：我们评估了15篇出版物，其中11篇研究（9篇全文文章和2篇摘要）通过NGS技术分析了CUP的基因组概况，不同的平台和不同的患者队列，范围从16到1,806名患者。在所有这些研究中,85%的患者表现出至少一种分子改变，最常见的涉及TP53（41.88%），KRAS（18.81%），CDKN2A（8.8%），和PIK3CA（9.3%）。平均47.3％的患者具有潜在的可靶向改变，可获得批准/标签外/临床试验药物。此外，我们确定了4例病例报告,以评估通过NGS确定的特定靶向治疗的临床相关性.结论：NGS可能是一种工具，通过鉴定治疗上可行的改变并提供对肿瘤生物学的见解来改善CUP的诊断和治疗。
