Analysis of circulating tumor DNA during checkpoint inhibition in metastatic melanoma using a tumor-agnostic panel.

IF 1.5 4区 医学 Q3 DERMATOLOGY
Melanoma Research Pub Date : 2023-10-01 Epub Date: 2023-06-12 DOI:10.1097/CMR.0000000000000903
Judit Kisistók, Ditte Sigaard Christensen, Mads Heilskov Rasmussen, Lone Duval, Ninna Aggerholm-Pedersen, Adam Andrzej Luczak, Boe Sandahl Sorensen, Martin Roelsgaard Jakobsen, Trine Heide Oellegaard, Nicolai Juul Birkbak
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Abstract

Immunotherapy has revolutionized treatment of patients diagnosed with metastatic melanoma, where nearly half of patients receive clinical benefit. However, immunotherapy is also associated with immune-related adverse events, which may be severe and persistent. It is therefore important to identify patients that do not benefit from therapy early. Currently, regularly scheduled CT scans are used to investigate size changes in target lesions to evaluate progression and therapy response. This study aims to explore if panel-based analysis of circulating tumor DNA (ctDNA) taken at 3-week intervals may provide a window into the growing cancer, can be used to identify nonresponding patients early, and determine genomic alterations associated with acquired resistance to checkpoint immunotherapy without analysis of tumor tissue biopsies. We designed a gene panel for ctDNA analysis and sequenced 4-6 serial plasma samples from 24 patients with unresectable stage III or IV melanoma and treated with first-line checkpoint inhibitors enrolled at the Department of Oncology at Aarhus University Hospital, Denmark. TERT was the most mutated gene found in ctDNA and associated with a poor prognosis. We detected more ctDNA in patients with high metastatic load, which indicates that more aggressive tumors release more ctDNA into the bloodstream. Although we did not find evidence of specific mutations associated with acquired resistance, we did demonstrate in this limited cohort of 24 patients that untargeted, panel-based ctDNA analysis has the potential to be used as a minimally invasive tool in clinical practice to identify patients where the benefits of immunotherapy outweigh the drawbacks.

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使用肿瘤不可知小组分析转移性黑色素瘤检查点抑制期间的循环肿瘤DNA。
免疫疗法彻底改变了被诊断为转移性黑色素瘤患者的治疗,近一半的患者从中受益。然而,免疫疗法也与免疫相关的不良事件有关,这些不良事件可能是严重和持续的。因此,尽早识别那些没有从治疗中受益的患者是很重要的。目前,定期安排的CT扫描用于研究靶病变的大小变化,以评估进展和治疗反应。本研究旨在探索以3周为间隔对循环肿瘤DNA(ctDNA)进行的基于面板的分析是否可以提供一个了解癌症生长的窗口,是否可以用于早期识别无反应的患者,并在不分析肿瘤组织活组织检查的情况下确定与检查点免疫疗法获得性耐药性相关的基因组改变。我们设计了一个用于ctDNA分析的基因小组,并对来自丹麦奥胡斯大学医院肿瘤科的24名不可切除的III期或IV期黑色素瘤患者的4-6个系列血浆样本进行了测序,这些患者接受了一线检查点抑制剂的治疗。TERT是ctDNA中发现的突变最多的基因,与预后不良有关。我们在高转移负荷的患者中检测到更多的ctDNA,这表明更具侵袭性的肿瘤会向血液中释放更多的ctDNA。尽管我们没有发现与获得性耐药性相关的特定突变的证据,但我们确实在这个由24名患者组成的有限队列中证明,非靶向的、基于面板的ctDNA分析有潜力在临床实践中用作微创工具,以识别免疫疗法利大于弊的患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Melanoma Research
Melanoma Research 医学-皮肤病学
CiteScore
3.40
自引率
4.50%
发文量
139
审稿时长
6-12 weeks
期刊介绍: ​​​​​​Melanoma Research is a well established international forum for the dissemination of new findings relating to melanoma. The aim of the Journal is to promote the level of informational exchange between those engaged in the field. Melanoma Research aims to encourage an informed and balanced view of experimental and clinical research and extend and stimulate communication and exchange of knowledge between investigators with differing areas of expertise. This will foster the development of translational research. The reporting of new clinical results and the effect and toxicity of new therapeutic agents and immunotherapy will be given emphasis by rapid publication of Short Communications. ​Thus, Melanoma Research seeks to present a coherent and up-to-date account of all aspects of investigations pertinent to melanoma. Consequently the scope of the Journal is broad, embracing the entire range of studies from fundamental and applied research in such subject areas as genetics, molecular biology, biochemistry, cell biology, photobiology, pathology, immunology, and advances in clinical oncology influencing the prevention, diagnosis and treatment of melanoma.
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