Lambrechts Diether, Thienpont Bernard, Thuillier Vincent, Sagaert Xavier, Moisse Matthieu, Peuteman Gilian, Pericay Carles, Folprecht Gunnar, Zalcberg John, Zilocchi Chiara, Margherini Emmanuelle, Chiron Marielle, Van Cutsem Eric
Vesalius Research Center, VIB, Leuven, Belgium.
Department of Oncology, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
Br J Cancer. 2015 Sep 29;113(7):1027-34. doi: 10.1038/bjc.2015.329. Epub 2015 Sep 10.
Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC.
Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs).
Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs.
This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.
阿柏西普（ziv-阿柏西普）是一种抗血管生成药物，最近被批准与FOLFIRI联合用于治疗先前接受过奥沙利铂治疗的转移性结直肠癌（mCRC）患者。尽管对阿柏西普的反应存在异质性，但尚未确定疗效或不良反应的生物标志物。在此，我们展示了来自随机II期AFFIRM试验的生物标志物数据，该试验评估了阿柏西普与mFOLFOX6联合用于mCRC一线治疗的效果。
分析了mCRC关键致癌驱动基因中的96个体细胞突变以及血管内皮生长因子（VEGF）通路基因中的133个常见单核苷酸多态性（SNP），并在基线、治疗期间和治疗后测量了27种血浆标志物。我们评估了这三类生物标志物与无进展生存期（PFS）和不良事件（AE）的相关性。
在KRAS、BRAF、NRAS、PIK3CA和PIK3R1中鉴定出的体细胞突变与PFS无显著相关性（多重检验校正的错误发现率（FDR）或多重检验校正的FDR>0.3）。单个SNP均与PFS无相关性（多重检验校正的FDR>0.22），但在基因水平上，VEGFB的变异性与PFS显著相关（多重检验校正的FDR=0.0423）。尽管在基线时测量的血浆标志物均与PFS无显著相关性，但基线时循环IL8水平较高以及治疗期间IL8水平升高与PFS降低显著相关（多重检验校正的FDR=0.0478）。未发现生物标志物与AE之间存在关联。
这是第一项关于阿柏西普治疗mCRC的生物标志物研究。基线时IL8血浆水平较高以及随后IL8水平升高与较差的PFS相关，提示IL8可能作为阿柏西普治疗结果的潜在预测生物标志物。
