值得注意的是，与观察组相比，ctDNA阳性的患者在atezolizumab组中的无病生存期和总生存期有所改善（无病生存风险比=0.58（95% 置信区间：0.43–0.79）；P=0.0024，总体生存风险比=0.59（95% 置信区间：0.41–0.86））。对于 ctDNA阴性的患者，治疗组之间的无病生存期或总生存期没有差异。atezolizumab组第6周的ctDNA清除率（18%）高于观察组（4%）（P=0.0204）。对 ctDNA阳性患者肿瘤的转录组学分析显示，细胞周期和角蛋白基因的表达水平较高。对于ctDNA阳性并接受atezolizumab治疗的患者，未复发与免疫反应特征和基底鳞状细胞基因特征相关，而复发与血管生成和成纤维细胞TGFβ特征相关。
Title: ctDNA guiding adjuvant immunotherapy in urothelial carcinoma
Author: Thomas Powles, Zoe June Assaf, Nicole Davarpanah, Romain Banchereau, Bernadett E. Szabados, Kobe C. Yuen, Petros Grivas, Maha Hussain, Stephane Oudard, Jrgen E. Gschwend, Peter Albers, Daniel Castellano, Hiroyuki Nishiyama, Siamak Daneshmand, Shruti Sharma, Bernhard G. Zimmermann, Himanshu Sethi, Alexey Aleshin, Maurizio Perdicchio, Jingbin Zhang, David S. Shames, Viraj Degaonkar, Xiaodong Shen, Corey Carter, Carlos Bais, Joaquim Bellmunt, Sanjeev Mariathasan
Abstract: Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45–8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43–0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41–0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal–squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.