Purpose: We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy. Experimental Design: The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially, versus FOLFOX-BEV in first-line mCRC. Evaluation of biomarkers associated with treatment outcomes was an exploratory endpoint. Patients in the biomarker-evaluable population (BEP) had 1 tissue sample, 1 pre-induction plasma sample, and 1 post-induction plasma sample collected ≤60 days of induction from last drug date. Results: Among the 280 patients enrolled in STEAM, 183 had sequenced and evaluable tumor tissue, 118 had matched pre-induction plasma, and 54 (BEP) had ctDNA-evaluable sequencing data for pre- and post-induction plasma. The most common somatic variants in tumor tissue and pre-induction plasma were TP53, APC , and KRAS . Patients with lower-than-median versus higher-than-median post-induction mean allele fraction (mAF) levels had longer median PFS (17.7 vs. 7.5 months, HR, 0.33; 95% confidence interval, 0.17–0.63). Higher levels of post-induction mAF and post-induction mean mutant molecules per milliliter (mMMPM), and changes in ctDNA (stratified by a 10-fold or 100-fold reduction in mAF between pre- and post-induction plasma), were associated with shorter PFS. Post-induction mAF and mMMPM generally correlated with each other ( ρ = 0.987, P < 0.0001). Conclusions: ctDNA quantification in post-induction plasma may serve as a prognostic biomarker for mCRC post-treatment outcomes.

中文翻译：

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转移性结直肠癌患者一线治疗后使用诱导后循环肿瘤 DNA 分析进行疾病监测。

目的：我们评估血浆循环肿瘤 DNA (ctDNA) 水平作为一线转移性结直肠癌 (mCRC) 治疗后无进展生存 (PFS) 的预后标志物。实验设计：阿瓦斯汀和维持测序三联体 (STEAM) 是一项随机 II 期试验，研究贝伐单抗 (BEV) 加 5-氟尿嘧啶/亚叶酸/奥沙利铂 (FOLFOX) 和 5-氟尿嘧啶/亚叶酸/伊立替康 (FOLFIRI) 的疗效，与一线 mCRC 中的 FOLFOX-BEV 相比，同时或顺序给药。与治疗结果相关的生物标志物的评估是一个探索性终点。生物标志物可评估人群 (BEP) 中的患者收集了 1 个组织样本、1 个诱导前血浆样本和 1 个诱导后血浆样本，这些样本是从上次用药日期起≤60 天的诱导期。结果：在纳入 STEAM 的 280 名患者中，183 名已测序和可评估的肿瘤组织，118 名具有匹配的诱导前血浆，54 名（BEP）具有诱导前和诱导后血浆的 ctDNA 可评估的测序数据。肿瘤组织和诱导前血浆中最常见的体细胞变异是 TP53、APC 和 KRAS。诱导后平均等位基因分数 (mAF) 水平低于中位数与高于中位数的患者具有更长的中位 PFS（17.7 与 7.5 个月，HR，0.33；95% 置信区间，0.17-0.63）。较高水平的诱导后 mAF 和诱导后平均每毫升突变分子 (mMMPM)，以及 ctDNA 的变化（由诱导前和诱导后血浆之间的 mAF 减少 10 倍或 100 倍分层）相关具有较短的 PFS。诱导后 mAF 和 mmMMPM 通常相互关联 (ρ = 0.987, P < 0.0001)。