Title: The SChISM study: Cell-free DNA size profiles as predictors of progression in advanced carcinoma treated with immune-checkpoint inhibitors Show Chinese title

Title: SChISM研究：无细胞DNA片段大小谱型作为晚期癌瘤接受免疫检查点抑制剂治疗进展的预测因子

Abstract: Background: Many advanced cancer patients experience progression under immune-checkpoint inhibitors (ICIs). Circulating cell-free DNA (cfDNA) size profiles offer a promising noninvasive multi-cancer approach to monitor and predict immunotherapy response. Methods: In the SChISM (Size CfDNA Immunotherapy Signature Monitoring) study (NCT05083494), pre-treatment plasmatic cfDNA size profiles from 126 ICI-treated advanced carcinomas were quantified using the BIABooster device. Fragmentomederived variables (concentration, peaks' position, and fragment size ranges) at baseline were analyzed for associations with early progression (EP, progression at first imaging) and progression-free survival (PFS), using logistic and Cox regression models. Bootstrap analysis validated robustness. Additional analyses were performed in homogeneous subpopulations: first-line lung cancer patients (n = 60) and head-andneck patients treated with Nivolumab (n = 25). Results: Higher cfDNA concentration and high quantities of short fragments (111-240 base pairs (bp)) were associated with poor response, unlike long fragments (> 300 bp). The proportion of fragments longer than 1650 bp demonstrated highest discriminatory power (AUC = 0.73, C-index = 0.69). It was significantly associated with non-EP (odds ratio = 0.39 [95% CI: 0.25-0.62]) and longer PFS (hazard ratio: 0.54 [95% CI: 0.42-0.68]). These associations remained significant when adjusted for confounders (age, sex, Eastern Cooperative Oncology Group performance status, tumor type, and neutrophil-to-lymphocyte ratio) and across both subpopulations. Bootstrap analysis confirmed robustness with mean accuracy of 70.1 $\pm$ 4.17% and positive predictive value of 55.6 $\pm$ 7.37%, in test sets. Conclusion: cfDNA size profiles significantly predicted ICI response and anticipate relapse, outperforming the routinely used marker programmed death-ligand 1 immunohistochemistry and reflecting enhanced immune system activation. Trial registration: (NCT05083494), date of registration: 2021-10-19. Show Chinese abstract

Abstract: 背景：许多晚期癌症患者在使用免疫检查点抑制剂（ICIs）时会出现病情进展。循环游离DNA（cfDNA）大小谱型提供了一种有前景的非侵入性多癌症方法，用于监测和预测免疫治疗反应。方法：在SChISM（Size CfDNA Immunotherapy Signature Monitoring）研究（NCT05083494）中，使用BIABooster设备量化了126例接受ICIs治疗的晚期癌患者的治疗前血浆cfDNA大小谱型。分析基线时由片段衍生的变量（浓度、峰的位置和片段大小范围）与早期进展（EP，首次影像学检查时的进展）和无进展生存期（PFS）之间的关联，使用逻辑回归和Cox回归模型。自举分析验证了稳健性。在同质亚人群中进行了额外分析：一线肺癌患者（n = 60）和接受纳武利尤单抗治疗的头颈癌患者（n = 25）。结果：较高的cfDNA浓度和大量短片段（111-240个碱基对（bp））与较差的反应相关，而长片段（> 300 bp）则不相关。大于1650 bp的片段比例表现出最高的区分能力（AUC = 0.73，C-index = 0.69）。它与非EP显著相关（比值比 = 0.39 [95% CI: 0.25-0.62]）和更长的PFS（风险比：0.54 [95% CI: 0.42-0.68]）。这些关联在调整混杂因素（年龄、性别、东部合作肿瘤学组表现状态、肿瘤类型和中性粒细胞与淋巴细胞比率）后以及在两个亚人群中仍然显著。自举分析在测试集中的平均准确率为70.1$\pm$4.17%，阳性预测值为55.6$\pm$7.37%，证实了稳健性。结论：cfDNA大小谱型显著预测ICIs反应并可预见复发，优于常用的程序性死亡配体1免疫组织化学标记，并反映了增强的免疫系统激活。试验注册：（NCT05083494），注册日期：2021-10-19。