Background:Longitudinal genomic profiling through serial circulating tumor DNA (ctDNA) testing offers a noninvasive method to monitor clonal evolution in advanced prostate cancer. This study evaluated the frequency and nature of newly emergent and potentially actionable genomic alterations detected through serial testing in a real-world setting.Methods:We conducted a retrospective analysis of advanced prostate cancer patients who underwent multiple Guardant360 ctDNA tests between October 2020 and March 2023. The study focused on identifying new genomic alterations absent in the initial test, with particular attention to alterations relevant for on-label therapies, therapies approved in other oncologic indications (i.e., off-label), or a clinical trial.Results:Among 479 patients with at least two ctDNA tests, the median interval between the first and second evaluable tests was 207 days. New and potentially actionable alterations emerged in 57.8% of patients, including potential targets for on-label therapies (16.7%), off-label therapies (16.5%), and clinical trials (55.7%). Tumor mutational burden (TMB) increased from “low” to “high” in 11% of patients, although none had microsatellite instability or mismatch repair deficiency. In a Mayo Clinic subset, ten patients received olaparib based on treatment-emergent alterations, but none achieved a prostate-specific antigen (PSA) response. Two patients who transitioned from low to high TMB received pembrolizumab, both with progressive disease as best response.Conclusions:In a large real-world cohort, serial ctDNA testing frequently identified new alterations that were not detected at baseline and are potentially actionable therapeutic targets, highlighting the value of serial genomic profiling for capturing clonal dynamics. Additional research is needed to better establish a framework for retesting and to clarify how these results should influence subsequent treatment decisions.
背景：通过连续循环肿瘤DNA（ctDNA）检测进行纵向基因组分析，为监测晚期前列腺癌的克隆演化提供了一种无创方法。本研究评估了真实世界环境中通过连续检测新出现的、具有潜在可操作性的基因组变异的频率与特征。 方法：我们对2020年10月至2023年3月期间接受多次Guardant360 ctDNA检测的晚期前列腺癌患者进行了回顾性分析。研究重点在于识别首次检测中未出现的新基因组变异，特别关注与标签内疗法、其他肿瘤适应症已批准疗法（即标签外疗法）或临床试验相关的变异。 结果：在至少接受两次ctDNA检测的479例患者中，首次与第二次可评估检测的中位间隔时间为207天。57.8%的患者出现了新的潜在可操作变异，包括标签内疗法（16.7%）、标签外疗法（16.5%）和临床试验（55.7%）的潜在靶点。11%的患者肿瘤突变负荷（TMB）从“低”转为“高”，但均未出现微卫星不稳定性或错配修复缺陷。在梅奥诊所亚组中，10例患者基于治疗期间新出现的变异接受了奥拉帕利治疗，但均未达到前列腺特异性抗原（PSA）应答。2例从低TMB转为高TMB的患者接受了帕博利珠单抗治疗，最佳疗效均为疾病进展。 结论：在大型真实世界队列中，连续ctDNA检测常能发现基线未检出且具有潜在治疗靶点价值的新变异，凸显了连续基因组分析在捕捉克隆动态方面的重要价值。未来需要进一步研究以建立更完善的再检测框架，并明确这些结果应如何影响后续治疗决策。
肿瘤(癌症)患者之家