深入评估接受免疫检查点抑制的黑色素瘤患者血液中游离DNA的BRAF、NRAS、KRAS、EGFR和PIK3CA突变

IF 12.8 1区 医学 Q1 ONCOLOGY
Isabel Heidrich, Charlotte Rautmann, Cedric Ly, Robin Khatri, Julian Kött, Glenn Geidel, Alessandra Rünger, Antje Andreas, Inga Hansen-Abeck, Finn Abeck, Anne Menz, Stefan Bonn, Stefan W Schneider, Daniel J Smit, Christoffer Gebhardt, Klaus Pantel
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引用次数: 0

摘要

循环肿瘤DNA (ctDNA)有望指导免疫检查点抑制剂(ICI)治疗,并将应答者与无应答者分层。虽然肿瘤知情ctDNA检测方法是敏感的和包含突变的,但它们需要肿瘤组织,这限制了在现实环境中的适用性。相反,肿瘤不可知论方法通常具有有限的基因组覆盖范围。在这项研究中,我们评估了一种肿瘤不可知论的、宽面板的ctDNA检测,用于晚期黑色素瘤患者的ICI治疗。方法:我们对来自39例不可切除的III/IV期黑色素瘤患者的241个纵向样本进行了前瞻性分析,使用SYSMEX靶向NGS面板,涵盖1,114个COSMIC突变。在基线和ICI治疗期间收集血浆样本。该检测的灵敏度达到7个突变分子,对应于0.07%的突变等位基因频率(MAF)。ctDNA谱与匹配的肿瘤组织进行比较,并与临床特征和生存率相关。结果:基线时,64.5%的患者检测到ctDNA。常见的突变包括BRAFV600E(43.8%)和NRASG12D(36.4%),其次是KRAS、EGFR和PIK3CA变体。总体组织-血浆一致性为51.6%,不一致性与更长的活检-血浆间隔相关(p = 0.0105)。值得注意的是,12.2%的病例表现出部分一致性,其特征是共有突变和额外的仅限血浆的改变,强调了基于血液的谱分析的补充价值。治疗后持续或再次出现的ctDNA阳性与较短的无进展生存期相关(PFS, p = 0.003),而ctDNA阴性患者的预后显着改善。与持续ctDNA阳性(中位3个月)或转化为阳性(中位7.5个月;p = 0.0073)。早期NRAS和KRAS ctDNA水平强烈预测不良反应(p = 0.0069和p = 0.028)。预后影响超出了典型驱动因素,因为非热点变异也与结果相关。值得注意的是,即使是低水平的ctDNA持久性(5-10 MM/mL)也会带来不良的预后影响(p = 0.0054)。对于较短的PFS, ctDNA阳性也与S100水平升高相关(p = 0.047)。器官特异性突变富集(例如,KRASG12D在脑,EGFRG719A在淋巴结)提示可能的转移性。结论:广泛的肿瘤不确定ctDNA分析有效地识别临床相关突变并预测ici治疗的黑色素瘤患者的预后。这种方法可以实现与组织无关的实时ctDNA监测,并可能在未来的介入性试验中为患者选择和治疗策略提供信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In-depth assessment of BRAF, NRAS, KRAS, EGFR, and PIK3CA mutations on cell-free DNA in the blood of melanoma patients receiving immune checkpoint inhibition.

Introduction: Circulating tumor DNA (ctDNA) holds promise for guiding immune checkpoint inhibitor (ICI) therapy and stratifying responders from non-responders. While tumor-informed ctDNA detection approaches are sensitive and mutation-inclusive, they require tumor tissue, which limits applicability in real-world settings. Conversely, tumor-agnostic methods often have limited genomic coverage. In this study, we evaluated a tumor-agnostic, broad-panel ctDNA assay in patients with advanced melanoma treated with ICI.

Methods: We conducted a prospective analysis of 241 longitudinal samples from 39 patients with unresectable stage III/IV melanoma using a SYSMEX targeted NGS panel covering 1,114 COSMIC mutations. Plasma samples were collected at baseline and during ICI therapy. The assay's sensitivity reached seven mutant molecules, corresponding to a 0.07% mutation allele frequency (MAF). ctDNA profiles were compared with matched tumor tissue and correlated with clinical features and survival.

Results: At baseline, ctDNA was detected in 64.5% of patients. Common mutations included BRAFV600E (43.8%) and NRASG12D (36.4%), followed by KRAS, EGFR, and PIK3CA variants. Overall tissue-plasma concordance was 51.6%, with more extended biopsy-plasma intervals associated with discordance (p = 0.0105). Notably, 12.2% of cases exhibited partial concordance, characterized by shared mutations and additional plasma-only alterations, underscoring the complementary value of blood-based profiling. Persistent or re-emerging ctDNA positivity post-therapy correlated with shorter progression-free survival (PFS, p = 0.003), while ctDNA-negative patients showed significantly improved outcomes. Patients that remained ctDNA-negative had significantly longer progression-free survival (median not reached) compared to those with persistent ctDNA positivity (median 3 months) or those converting to positive (median 7.5 months; p = 0.0073). Early NRAS and KRAS ctDNA levels strongly predicted poor response (p = 0.0069 and p = 0.028). The prognostic impact extended beyond canonical drivers, as non-hotspot variants also correlated with the outcome. Notably, even low-level ctDNA persistence (5-10 MM/mL) carried adverse prognostic implications (p = 0.0054). Concerning a shorter PFS, ctDNA positivity was also associated with elevated S100 levels (p = 0.047). Organ-specific mutation enrichment (e.g., KRASG12D in brain, EGFRG719A in lymph nodes) suggested possible metastatic tropism.

Conclusion: Broad tumor-agnostic ctDNA analysis effectively identified clinically relevant mutations and predicted outcomes in ICI-treated melanoma patients. This approach enables tissue-independent and real-time ctDNA monitoring and may inform patient selection and therapeutic strategies in future interventional trials.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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