State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
J Pathol. 2023 Oct;261(2):198-209. doi: 10.1002/path.6166. Epub 2023 Aug 16.
Non-invasive biomarkers for immunotherapy response remain a compelling unmet medical need. POLARIS-03 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-programmed cell death 1) in refractory metastatic urothelial carcinoma (mUC). We assessed the predictive utility of longitudinal circulating tumor DNA (ctDNA) analysis from a single-institution biomarker cohort. Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled. Serial plasma specimens were obtained at baseline and then every two cycles during treatment. The 600-gene panel (PredicineATLAS™) liquid biopsy assay was applied to probe somatic variants and cancer cell fraction (CCF). Low-pass whole genome sequencing was used to determine the copy number abnormality (CNA) score. Across the entire cohort, we observed different degrees of concordance between somatic aberrations detected by ctDNA and those inferred by matched tumor samples. Although the baseline CCF or CNA had limited predictive value, early ctDNA response at week 8 was associated with toripalimab efficacy and prolonged patient survival. Integrating CCF and CNA decrease achieved a superior accuracy of 90.5% in classifying responders and non-responders and predicted long-term benefit from toripalimab. Dynamic changes in the CCF and CNA in blood exquisitely reflected radiographic assessment of malignant lesions, including those with FGFR3-TACC3 gene fusion or microsatellite instability. This study demonstrates the feasibility and effectiveness of integrated longitudinal ctDNA profiling as a potential biomarker in mUC patients undergoing immunotherapy and supports further clinical evaluation of minimally invasive liquid biopsy assays for treatment stratification and therapy monitoring. © 2023 The Pathological Society of Great Britain and Ireland.
免疫治疗反应的非侵入性生物标志物仍然是一个迫切需要解决的医学难题。POLARIS-03 是一项多中心 II 期临床试验，旨在评估 toripalimab（抗程序性细胞死亡 1 ）在难治性转移性尿路上皮癌（mUC）患者中的安全性和疗效。我们评估了来自单一机构生物标志物队列的纵向循环肿瘤 DNA（ctDNA）分析的预测效用。在仁济医院接受 toripalimab（3mg/kg，每 2 周 1 次）治疗的 27 例 mUC 患者入组本研究。在基线时和治疗期间每 2 个周期采集系列血浆标本。应用 600 基因panel（PredicineATLAS™）液体活检检测方法检测体细胞变异和肿瘤细胞分数（CCF）。采用低深度全基因组测序来确定拷贝数异常（CNA）评分。在整个队列中，我们观察到 ctDNA 检测到的体细胞异常与匹配肿瘤样本推断出的异常之间存在不同程度的一致性。尽管基线 CCF 或 CNA 预测价值有限，但在第 8 周时的早期 ctDNA 反应与 toripalimab 疗效和患者生存延长相关。整合 CCF 和 CNA 降低可将分类应答者和非应答者的准确性提高到 90.5%，并预测 toripalimab 的长期获益。血液中 CCF 和 CNA 的动态变化能够精确反映恶性病变的影像学评估，包括 FGFR3-TACC3 基因融合或微卫星不稳定的患者。这项研究证明了整合纵向 ctDNA 分析作为接受免疫治疗的 mUC 患者潜在生物标志物的可行性和有效性，并支持进一步临床评估微创液体活检检测在治疗分层和治疗监测中的应用。
