Tissue-Free Circulating Tumor DNA Assay and Patient Outcome in a Phase III Trial of FOLFOX-Based Adjuvant Chemotherapy (Alliance N0147).

We evaluated the prognostic value of a tissue-free, epigenomic ctDNA assay in patients with stage III colon cancer (CC) enrolled in a phase III adjuvant chemotherapy trial.

我们评估了一种无组织的表观基因组ctDNA检测在III期结肠癌（CC）患者中的预后价值，这些患者参与了一项III期辅助化疗试验。

Methods

Plasma samples were collected after surgery and before adjuvant infusional fluorouracil, leucovorin, and oxaliplatin alone or combined with cetuximab. ctDNA was analyzed using a tissue-free assay; in ctDNA-positive patients, tumor fraction (TF) was quantified and genotyping was performed with a 739-gene panel.

手术后及仅接受辅助性输注氟尿嘧啶、亚叶酸和奥沙利铂或联合西妥昔单抗治疗前收集了血浆样本。采用无组织检测法分析循环肿瘤DNA（ctDNA）；在ctDNA阳性的患者中，对肿瘤分数（TF）进行定量，并使用739基因组面板进行基因分型。

Associations with disease-free survival (DFS), time to recurrence (TTR), and overall survival(OS) were assessed using multivariable Cox models adjusted for covariates.

使用多变量Cox模型调整协变量后，评估了与无病生存期（DFS）、复发时间（TTR）和总生存期（OS）的关联。

Results

Among 2,260 evaluable patients, 461 (20.4%) were ctDNA-positive with significantly higher detection in advanced T-/N-stage, high-grade, obstruction/perforation, and BRAFV600E tumors.

在2260名可评估的患者中，有461名（20.4%）ctDNA阳性，特别是在晚期T/N分期、高级别、梗阻/穿孔以及BRAFV600E突变肿瘤中检测率显著更高。

At a median follow-up of 6.1 years, ctDNA positivity was independently associated with shorter TTR (hazard ratio[HR], 5.96 [95% CI, 5.11 to 6.96]), DFS (HR, 5.03 [95% CI, 4.36 to 5.81]), and OS (HR, 4.45 [95% CI, 3.76 to 5.27]; all P < .0001).

在中位随访6.1年时，ctDNA阳性与较短的治疗反应时间（风险比[HR]，5.96 [95% 置信区间，5.11至6.96]）、无病生存期（HR，5.03 [95% 置信区间，4.36至5.81]）和总生存期（HR，4.45 [95% 置信区间，3.76至5.27]；所有P < .0001）独立相关。

The 5-year DFS was 27.7% (95% CI, 23.8 to 32.2) v 77.1% (95% CI, 75.1 to 79.1) in ctDNA-positive versus ctDNA-negative patients, and adverse prognostic impact was greater in lower T/N stage, low-risk, and dMMR subsets (interaction P = .0012-.041).

在 ctDNA 阳性与 ctDNA 阴性患者中，5年无病生存率分别为27.7%（95% 置信区间，23.8至32.2）和77.1%（95% 置信区间，75.1至79.1），且在较低的T/N分期、低风险和dMMR亚组中，不良预后影响更大（交互作用P = .0012-.041）。

Among ctDNA-positive patients, TF was nearly double in those who recurred or died (P = .0002) and stratified patients for TTR, DFS, and OS (all adjusted P < .002).

在 ctDNA 阳性患者中，复发或死亡患者的TF几乎是其他患者的两倍（P = .0002），并且可以对患者的治疗反应时间（TTR）、无病生存（DFS）和总生存（OS）进行分层（所有调整后的P < .002）。

Genotyping identified mutations in FLT1 (OR, 8.99) and PREX2 (OR, 7.73) genes that were most strongly associated with recurrence (P < .03).

基因分型识别了与复发最强烈相关的FLT1（比值比，8.99）和PREX2（比值比，7.73）基因突变（P < .03）。

Conclusions

Evaluation of ctDNA in resected stage III CC using a tissue-free assay provided robust and independent prognostic value.

使用无组织检测法评估III期结肠癌切除术后循环肿瘤DNA（ctDNA）提供了强大且独立的预后价值。

Higher ctDNA burden, dMMR, and specific mutations defined poor prognostic groups among ctDNA-positive patients.

较高的循环肿瘤DNA负荷、dMMR以及特定的突变定义了ctDNA阳性患者中的预后不良群体。