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.

需要采用微创方法来检测手术后残留的疾病，以识别有转移复发风险的癌症患者。循环肿瘤 DNA (ctDNA) 有望成为分子残留疾病和复发的生物标志物¹。我们评估了 581 名接受过手术且可评估 ctDNA 的患者的结局，这些患者来自一项辅助atezolizumab 与观察可手术尿路上皮癌的随机 III 期试验。该试验在意向治疗人群中未达到疗效终点。在这里，我们显示治疗开始时（第 1 周期第 1 天）的 ctDNA 检测确定了 214 名（37%）ctDNA 阳性且预后不良的患者（观察组风险比 = 6.3（95% 置信区间：4.45-8.92） ); P < 0.0001)。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提高（无病生存期风险比 = 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。在第 6 周时，atezolizumab 组 (18%) 的 ctDNA 清除率高于观察组 (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更高。对于 ctDNA 阳性并接受 atezolizumab 治疗的患者，非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。这些数据表明，与 ctDNA 阳性和复发高风险患者的观察相比，辅助atezolizumab 可能与改善结果相关。这些发现，如果在其他环境中得到验证，将改变术后癌症护理的方法。