Max Ma Xiaoju, Bendell Johanna C, Hurwitz Herbert I, Ju Christine, Lee John J, Lovejoy Alex, Mancao Christoph, Nicholas Alan, Price Richard, Sommer Nicolas, Tikoo Nalin, Yao Lijing, Yaung Stephanie J, Palma John F
Medical Scientific Affairs, Roche Sequencing Solutions, Inc., Pleasanton, California.
Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
Clin Cancer Res. 2020 Aug 1;26(15):4010-4017. doi: 10.1158/1078-0432.CCR-19-1209. Epub 2020 Mar 27.
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.
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.
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 , and . 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 ( = 0.987, < 0.0001).
ctDNA quantification in post-induction plasma may serve as a prognostic biomarker for mCRC post-treatment outcomes.
我们评估了血浆循环肿瘤DNA（ctDNA）水平作为一线转移性结直肠癌（mCRC）治疗后无进展生存期（PFS）的预后标志物。
阿瓦斯汀与维持治疗三联测序（STEAM）是一项随机II期试验，研究贝伐单抗（BEV）联合5-氟尿嘧啶/亚叶酸钙/奥沙利铂（FOLFOX）和5-氟尿嘧啶/亚叶酸钙/伊立替康（FOLFIRI）同时或序贯给药与FOLFOX-BEV用于一线mCRC的疗效。评估与治疗结果相关的生物标志物是一个探索性终点。生物标志物可评估人群（BEP）中的患者在距最后一次用药日期诱导≤60天内采集了1份组织样本、1份诱导前血浆样本和1份诱导后血浆样本。
在STEAM研究入组的280例患者中，183例有测序且可评估的肿瘤组织，118例有匹配的诱导前血浆，54例（BEP）有诱导前和诱导后血浆的ctDNA可评估测序数据。肿瘤组织和诱导前血浆中最常见的体细胞变异分别为 ，以及 。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，其PFS中位数更长（17.7个月对7.5个月，HR为0.33；95%置信区间为0.17 - 0.63）。诱导后mAF和每毫升诱导后平均突变分子数（mMMPM）水平较高，以及ctDNA的变化（根据诱导前和诱导后血浆中mAF降低10倍或100倍分层）与较短的PFS相关。诱导后mAF和mMMPM通常相互关联（ = 0.987， < 0.0001）。
诱导后血浆中的ctDNA定量可作为mCRC治疗后预后的生物标志物。
