Di Salvatore Mariantonietta, Pietrantonio Filippo, Orlandi Armando, Del Re Marzia, Berenato Rosa, Rossi Ernesto, Caporale Marta, Guarino Donatella, Martinetti Antonia, Basso Michele, Mennitto Roberta, Santonocito Concetta, Mennitto Alessia, Schinzari Giovanni, Bossi Ilaria, Capoluongo Ettore, Danesi Romano, de Braud Filippo, Barone Carlo
Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Oncotarget. 2017 Mar 7;8(10):16887-16898. doi: 10.18632/oncotarget.14810.
Predictive biomarkers of efficacy and toxicity of bevacizumab have not yet been validated. This study assessed the influence of IL-8, eNOS and VEGF-A polymorphisms in RAS mutated metastatic colorectal cancer patients receiving bevacizumab-based chemotherapy.
120 patients treated with first-line combination FOLFOX6 plus bevacizumab were included. A historical cohort of 112 RAS mutated colorectal cancer patients treated with FOLFOX6 alone served as control group. The following SNPs were analyzed: IL-8 c.-251T>A; eNOS c.-786T>C and c.-894G>T; VEGF-A c.936C>T, c.958T>C, c.1154A>G and c.2578C>A. Correlation of SNPs, baseline IL-8 serum levels and bevacizumab-efficacy was done.
In the bevacizumab group, carriers of the IL-8 alleles c.-251TA+AA showed a shorter PFS (P=0.002) and OS (P=0.03) compared to TT alleles. Patients with pre-treatment IL-8 < 18.25 pg/ml showed significantly longer median PFS and OS (PFS: 10.9 vs 7.6 months, P=0.005; OS: 30.7 vs 18.2 months, P<0.001) compared to patients with IL-8 higher levels (>18,25 pg/ml). IL-8 c.-251TA+AA carriers had significantly higher IL-8 levels (P<0.0001). Multivariate analysis confirmed association of IL-8 polymorphism with PFS, and of IL-8 baseline levels with both PFS and OS. IL-8 SNP did not affect the outcome in the control group. The eNOS polymorphism c.-894G>T was found associated with higher severe toxicity (P=0.0002) in patients carrying the c.-894TT genotype.
Although our data need prospective validation, IL-8 and eNOS SNPs may be have a role as predictive biomarkers for bevacizumab efficacy and toxicity.
贝伐单抗疗效和毒性的预测生物标志物尚未得到验证。本研究评估了白细胞介素-8（IL-8）、内皮型一氧化氮合酶（eNOS）和血管内皮生长因子A（VEGF-A）基因多态性对接受基于贝伐单抗化疗的RAS突变转移性结直肠癌患者的影响。
纳入120例接受一线FOLFOX6联合贝伐单抗治疗的患者。选取112例仅接受FOLFOX6治疗的RAS突变结直肠癌患者作为历史队列作为对照组。分析以下单核苷酸多态性（SNP）：IL-8 c.-251T>A；eNOS c.-786T>C和c.-894G>T；VEGF-A c.936C>T、c.958T>C、c.1154A>G和c.2578C>A。对SNP、基线IL-8血清水平与贝伐单抗疗效之间的相关性进行了分析。
在贝伐单抗组中，与携带IL-8等位基因TT的患者相比，携带IL-8等位基因c.-251TA+AA的患者无进展生存期（PFS）较短（P=0.002），总生存期（OS）也较短（P=0.03）。与IL-8水平较高（>18.25 pg/ml）的患者相比，治疗前IL-8<18.25 pg/ml的患者中位PFS和OS显著更长（PFS：10.9个月对7.6个月，P=0.005；OS：30.7个月对18.2个月，P<0.001）。携带IL-8 c.-251TA+AA的患者IL-8水平显著更高（P<0.0001）。多因素分析证实IL-8基因多态性与PFS相关，IL-8基线水平与PFS和OS均相关。IL-8 SNP在对照组中不影响预后。发现eNOS基因多态性c.-894G>T与携带c.-894TT基因型的患者更高的严重毒性相关（P=0.0002）。
尽管我们的数据需要前瞻性验证，但IL-8和eNOS SNP可能作为贝伐单抗疗效和毒性的预测生物标志物。
