Sammy Shaya, Okezie Uche-Ikonne, Bedirhan Kilerci, Julie Stevenson, Alastair Greystoke, Natalie Cook, Fiona C Thistlethwaite, Louise Carter, Donna M Graham, Matthew G Krebs
{"title":"Circulating Tumor DNA as a Prognostic Biomarker for Selecting Participants to Early Phase Clinical Trials.","authors":"Sammy Shaya, Okezie Uche-Ikonne, Bedirhan Kilerci, Julie Stevenson, Alastair Greystoke, Natalie Cook, Fiona C Thistlethwaite, Louise Carter, Donna M Graham, Matthew G Krebs","doi":"10.36401/JIPO-25-11","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Patients with advanced solid tumors may be considered for early phase clinical trials investigating the safety, tolerability, and dosing of experimental therapies. Optimizing participant selection is critical to maximize clinical benefit and meet trial endpoints with fewer participants. One in six participants does not meet routine life expectancy requirements (>3 months), highlighting the need for improved prognostication. Variant allele frequency (VAF) in circulating tumor DNA (ctDNA) correlates with overall survival (OS) in advanced solid tumors. We aimed to derive an optimal VAF threshold as a prognostic biomarker to enhance participant selection.</p><p><strong>Methods: </strong>ctDNA testing was performed as part of the TARGET (NIHR Clinical Research Network CPMS ID 39172) and TARGET National (NCT04723316) prospective cohort studies, in patients with advanced solid tumors referred for early phase clinical trials. Maximum (maxVAF) and mean VAF (meanVAF) were compared in their association with OS and ability to delineate favorable and poor outcomes at set threshold points using hazard ratios (HRs). Optimal thresholds of VAF were explored using receiver operating characteristic curve analysis to predict 3-month landmark OS. Univariable and multivariable analysis was performed to determine whether VAF was an independent prognostic marker.</p><p><strong>Results: </strong>Of 631 patients, 587 had evaluable ctDNA results. MeanVAF and maxVAF exhibited similar correlation with OS (r<sub>s</sub> = -0.32 vs -0.35, respectively) and similar prognostic utility at matched threshold points. A maxVAF value of 4% was selected as optimal for prognostic subgrouping (area under curve 0.77). OS was 5.9 versus 12.1 months (<i>p</i> < 0.0001) for patients with more than 4% and 4% or less maxVAF, respectively. Multivariable analysis confirmed more than 4% maxVAF as independently associated with reduced 3-month landmark OS (HR 2.17 [1.76-2.70], <i>p</i> < 0.001).</p><p><strong>Conclusion: </strong>VAF is an independent prognostic marker in patients with advanced solid tumors, with 4% maxVAF deemed optimal for delineating favorable and poorer prognostic subgroups in this patient cohort. Further validation and integration into existing prognostic scores are warranted.</p>","PeriodicalId":16081,"journal":{"name":"Journal of Immunotherapy and Precision Oncology","volume":"8 3","pages":"222-232"},"PeriodicalIF":3.2000,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416488/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Immunotherapy and Precision Oncology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.36401/JIPO-25-11","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: Patients with advanced solid tumors may be considered for early phase clinical trials investigating the safety, tolerability, and dosing of experimental therapies. Optimizing participant selection is critical to maximize clinical benefit and meet trial endpoints with fewer participants. One in six participants does not meet routine life expectancy requirements (>3 months), highlighting the need for improved prognostication. Variant allele frequency (VAF) in circulating tumor DNA (ctDNA) correlates with overall survival (OS) in advanced solid tumors. We aimed to derive an optimal VAF threshold as a prognostic biomarker to enhance participant selection.
Methods: ctDNA testing was performed as part of the TARGET (NIHR Clinical Research Network CPMS ID 39172) and TARGET National (NCT04723316) prospective cohort studies, in patients with advanced solid tumors referred for early phase clinical trials. Maximum (maxVAF) and mean VAF (meanVAF) were compared in their association with OS and ability to delineate favorable and poor outcomes at set threshold points using hazard ratios (HRs). Optimal thresholds of VAF were explored using receiver operating characteristic curve analysis to predict 3-month landmark OS. Univariable and multivariable analysis was performed to determine whether VAF was an independent prognostic marker.
Results: Of 631 patients, 587 had evaluable ctDNA results. MeanVAF and maxVAF exhibited similar correlation with OS (rs = -0.32 vs -0.35, respectively) and similar prognostic utility at matched threshold points. A maxVAF value of 4% was selected as optimal for prognostic subgrouping (area under curve 0.77). OS was 5.9 versus 12.1 months (p < 0.0001) for patients with more than 4% and 4% or less maxVAF, respectively. Multivariable analysis confirmed more than 4% maxVAF as independently associated with reduced 3-month landmark OS (HR 2.17 [1.76-2.70], p < 0.001).
Conclusion: VAF is an independent prognostic marker in patients with advanced solid tumors, with 4% maxVAF deemed optimal for delineating favorable and poorer prognostic subgroups in this patient cohort. Further validation and integration into existing prognostic scores are warranted.
导读:晚期实体瘤患者可以考虑进行早期临床试验,研究实验疗法的安全性、耐受性和剂量。优化参与者选择对于最大化临床效益和满足较少参与者的试验终点至关重要。六分之一的参与者未达到常规预期寿命要求(3个月),突出了改善预后的必要性。循环肿瘤DNA (ctDNA)中的变异等位基因频率(VAF)与晚期实体肿瘤的总生存期(OS)相关。我们的目标是得出一个最佳的VAF阈值作为预后生物标志物,以加强参与者的选择。方法:ctDNA检测作为TARGET (NIHR临床研究网络CPMS ID 39172)和TARGET National (NCT04723316)前瞻性队列研究的一部分,在转入早期临床试验的晚期实体肿瘤患者中进行。比较最大(maxVAF)和平均VAF (meanVAF)与OS的关系,以及使用风险比(hr)在设定阈值点描述有利和不良结局的能力。采用受试者工作特征曲线分析,探讨VAF的最佳阈值,预测3个月里程碑OS。单变量和多变量分析确定VAF是否是一个独立的预后指标。结果:在631例患者中,587例具有可评估的ctDNA结果。MeanVAF和maxVAF与OS具有相似的相关性(rs分别为-0.32 vs -0.35),并且在匹配的阈值点具有相似的预后效用。选择4%的maxVAF值作为预后亚组的最佳值(曲线下面积0.77)。对于maxVAF大于4%和小于4%的患者,OS分别为5.9和12.1个月(p < 0.0001)。多变量分析证实,超过4%的maxVAF与3个月里程碑OS降低独立相关(HR 2.17 [1.76-2.70], p < 0.001)。结论:VAF是晚期实体瘤患者的独立预后指标,在该患者队列中,4%的maxVAF被认为是描绘预后良好和较差亚组的最佳指标。进一步的验证和整合到现有的预后评分是必要的。