食管鳞状细胞癌（ESCC）是一种具有频繁复发的致命疾病。目前还没有满足临床需求的预后生物标志物，以便动态监测疾病进展并检测最小残留病灶。本单中心、基于人群的队列研究纳入了香港玛丽医院外科和临床肿瘤科的连续147例患者，从2016年8月1日到2021年9月31日，接受根治性治疗（n=74）或姑息性治疗（n=73）。随访了2年。收集了不同纵向时间点的血浆样本，进行77个有操作性的基因的前瞻性循环肿瘤DNA（ctDNA）下一代测序研究。患者接受了直接手术、新辅助化疗放疗加手术或不加辅助治疗的手术，或姑息性化疗（CT）。检测循环肿瘤DNA（ctDNA）的存在，无进展生存期（PFS）和总生存期（OS）。对147例局部和转移性ESCC患者的478个连续血浆样本进行了前瞻性分析。在治愈组的74例患者中（中位[范围]年龄，66 [46-85]岁，男性56人[76.0%]），44人（59.5%）复发，36人（48.6%）死亡。对于接受根治性手术治疗的患者，术后6个月高ctDNA水平（危险比[HR]，7.84; 95%置信区间[CI]，1.87-32.97；P=0.005）和ctDNA改变（HR，5.71; 95% CI，1.81-17.97；P=0.003）与较差的总生存期独立相关。接受新辅助化疗放疗的患者中，新辅助化疗后ctDNA改变与较差的无进展生存期相关（HR，3.16；95% CI，1.17-8.52；P=0.02）。在姑息组的73例患者中（中位[范围]年龄，63 [45-82]岁；男性63人[86.0%]），71人（97.3%）复发，68人（93.2%）死亡。可检测的化疗前NFE2L2改变与无进展生存期（HR，2.99；95% CI，1.35-6.61；P=0.007）和总生存期（HR，28.39；95% CI，7.26-111.03；P=1.52x10^-6）独立相关，而高ctDNA水平（HR，2.41；95% CI，1.18-4.95；P=0.02）和化疗前三个周期ctDNA改变（HR，1.99；95% CI，1.03-3.85；P=0.04）与无进展生存期的关联较弱。化疗前ctDNA的改变与总生存期（HR，4.46；95% CI，1.86-10.69；P=7.97x10^-4）独立相关。本队列研究的结果表明，包含ctDNA特征的预后模型对ESCC具有实用价值。在姑息组中，化疗前ctDNA水平和NFE2L2改变以及化疗前三个周期后的ctDNA改变被发现是重要的预后因子，而根治组术后6个月的ctDNA改变可能定义了复发高风险组。高风险患者可以通过及时切换到下一个治疗方案获益。

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with frequent recurrence. There are unmet needs for prognostic biomarkers for dynamically monitoring disease progression and detecting minimal residual disease.To examine whether circulating tumor DNA is clinically useful as a prognostic biomarker for ESCC recurrence and patient survival.This single-center, population-based cohort study consecutively enrolled 147 patients receiving curative (n = 74) or palliative (n = 73) treatment at the surgery and clinical oncology departments of Queen Mary Hospital in Hong Kong from August 1, 2016, to September 31, 2021. Patients were followed up for 2 years. Plasma samples were collected at different longitudinal time points for a prospective circulating tumor DNA (ctDNA) next-generation sequencing profiling study of 77 actionable genes.Patients were treated with up-front surgery, neoadjuvant chemoradiotherapy plus surgery with or without adjuvant therapy, or palliative chemotherapy (CT).Detection of circulating tumor DNA (ctDNA), progression-free survival (PFS), and overall survival (OS).A total of 478 serial plasma samples from 147 patients with locoregional or metastatic ESCC were prospectively analyzed. Among the 74 patients in the curative group (median [range] age, 66 [46-85] years; 56 [76.0%] male), 44 (59.5%) relapsed and 36 (48.6%) died. For patients receiving curative surgical treatment, a high ctDNA level (hazard ratio [HR], 7.84; 95% CI, 1.87-32.97; P = .005) and ctDNA alterations (HR, 5.71; 95% CI, 1.81-17.97; P = .003) at 6 months postoperation were independently associated with poor OS. Among patients receiving neoadjuvant chemoradiotherapy, postneoadjuvant ctDNA alterations were associated with poor PFS (HR, 3.16; 95% CI, 1.17-8.52; P = .02). In the 73 patients in the palliative group (median [range] age, 63 [45-82] years; 63 [86.0%] male), 71 (97.3%) had disease relapse and 68 (93.2%) died. Detectable pre-CT NFE2L2 alterations were independently associated with PFS (HR, 2.99; 95% CI, 1.35-6.61; P = .007) and OS (HR, 28.39; 95% CI, 7.26-111.03; P = 1.52 × 10-6), whereas high ctDNA levels (HR, 2.41; 95% CI, 1.18-4.95; P = .02) and alterations in pre-cycle III ctDNA (HR, 1.99; 95% CI, 1.03-3.85; P = .04) showed weaker associations with PFS. Alterations in pre-CT ctDNA were independently associated with OS (HR, 4.46; 95% CI, 1.86-10.69; P = 7.97 × 10-4).The findings of this cohort study indicate that prognostic models incorporating ctDNA features are useful in ESCC. Both ctDNA level and NFE2L2 alterations pre-CT and before cycle III were found to be important prognostic factors in palliative groups, and ctDNA alterations after treatment and at 6 months after surgery may define high-risk groups for recurrence in the curative group. High-risk patients can benefit by a timely switch to the next therapeutic options.