Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama; Translational Research Support Section, National Cancer Center Hospital East, Kashiwa; Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa; Cancer Treatment Center, Hiroshima University Hospital, Hiroshima.
Department of Genome Biology, Kindai University Faculty of Medicine, Osakasayama.
ESMO Open. 2022 Dec;7(6):100592. doi: 10.1016/j.esmoop.2022.100592. Epub 2022 Dec 8.
The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV).
Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value.
The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6).
The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further.
本前瞻性研究旨在评估血浆血管内皮生长因子 A 短亚型（pVEGF-Asi）预测贝伐珠单抗（BV）疗效的能力，并探讨转移性结直肠癌（mCRC）患者接受改良 FOLFOX6/XELOX+BV（mFOLFOX6/XELOX+BV）治疗时其他循环生物标志物的情况。
收集 100 例接受 mFOLFOX6/XELOX+BV 一线化疗的 mCRC 患者的预处理血浆样本。分析了包括 pVEGF-Asi 在内的 11 种与血管生成相关的分子和循环肿瘤 DNA 中 22 种癌症相关基因突变的血浆水平。对于主要终点，我们假设使用 Cox 比例风险模型计算的无进展生存期（PFS）的风险比（HR）<1.15，比较根据中位 pVEGF-Asi 值将高 pVEGF-Asi 水平与低 pVEGF-Asi 水平的患者进行分组。
pVEGF-Asi 的中位数为 37（范围 6.5-262）pg/ml。高 pVEGF-Asi 组与低 pVEGF-Asi 组的 PFS HR 为 1.3[95%置信区间（CI）0.8-2.1；对数秩检验，P=0.25]，大于预设的 1.15 阈值。多变量分析表明，PFS 与血浆细胞间黏附分子-1（pICAM-1）显著相关（≥190.0 与<190.0ng/ml；HR 2.1；95%CI 1.3-3.5）、RAS（突变与野生；HR 2.5；95%CI 1.5-4.3）和 FBXW7（突变与野生；HR 2.8；95%CI 1.2-6.8），而总生存期与 pICAM-1（HR 2.0；95%CI 1.1-3.7）和 RAS（HR 2.6；95%CI 1.5-4.6）显著相关。
BV 的加入并不能弥补高 pVEGF-Asi 水平与 PFS 较差相关的情况，这表明 pVEGF-Asi 不太可能成为 mFOLFOX6/XELOX+BV 治疗疗效的良好预测生物标志物。循环 ICAM-1、突变型 RAS 和突变型 FBXW7 水平的临床意义有待进一步研究。
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