Berger Martin D, Yamauchi Shinichi, Cao Shu, Hanna Diana L, Sunakawa Yu, Schirripa Marta, Matsusaka Satoshi, Yang Dongyun, Groshen Susan, Zhang Wu, Ning Yan, Okazaki Satoshi, Miyamoto Yuji, Suenaga Mitsukuni, Lonardi Sara, Cremolini Chiara, Falcone Alfredo, Heinemann Volker, Loupakis Fotios, Stintzing Sebastian, Lenz Heinz-Josef
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Eur J Cancer. 2017 May;77:13-20. doi: 10.1016/j.ejca.2017.02.020. Epub 2017 Mar 26.
The most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF-associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC).
Patients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing.
The FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2-3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02-0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2-3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14-1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45-4.04; P = 0.60).
This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab.
贝伐单抗最常见的相关副作用是高血压、蛋白尿、出血和血栓栓塞。迄今为止，尚无生物标志物可预测抗血管内皮生长因子（VEGF）相关毒性。由于自噬抑制血管生成，我们推测自噬相关基因内的单核苷酸多态性（SNP）可能预测转移性结直肠癌（mCRC）患者中贝伐单抗介导的毒性。
本研究纳入了两项III期随机试验（即TRIBE试验，n = 219，发现队列；FIRE-3试验，n = 234，验证队列）中接受一线FOLFIRI和贝伐单抗治疗的mCRC患者。接受FOLFIRI和西妥昔单抗治疗的患者（FIRE-3，n = 204）作为阴性对照。通过基于聚合酶链反应（PCR）的直接测序分析了8个自噬相关基因（ATG3/5/8/13、贝克林1、FIP200、unc-51样激酶1、UVRAG）中的12个SNP。
在TRIBE队列中，FIP200基因的rs1129660变体与高血压显著相关。携带FIP200 rs1129660 SNP任何G等位基因的患者与A/A基因型患者相比，2-3级高血压发生率显著更低（3%对15%，比值比[OR] 0.17；95%置信区间[CI]，0.02 - 0.73；P = 0.009）。同样，在FIRE-3验证队列中，FIP200 rs1129660 SNP的G等位基因携带者发生2-3级高血压的可能性低于A/A基因型患者（9%对20%，OR 0.43；95% CI，0.14 - 1.11；P = 0.077），而在对照队列中未观察到这种关联（12%对9%，OR 1.40；95% CI，0.45 - 4.04；P = 0.60）。
这是首份表明自噬相关FIP200基因多态性可能预测接受FOLFIRI和贝伐单抗治疗的mCRC患者高血压的报告。
