Conde Elisa, Earl Julie, Crespo-Toro Lorena, Blanco-Agudo Carolina, Ramos-Muñoz Edurne, Rodríguez-Serrano E Macarena, Martínez Ávila Jose Carlos, Salinas-Muñoz Laura, Serrano-Huertas Silvia, Ferreiro Reyes, Rodriguez-Garrote Mercedes, Sainz Bruno, Massuti Bartomeu, Alfonso Pilar García, Benavides Manuel, Aranda Enrique, García-Bermejo María Laura, Carrato Alfredo
Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain.
Cancers (Basel). 2021 Apr 4;13(7):1710. doi: 10.3390/cancers13071710.
First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.
瑞戈非尼用于虚弱的转移性结直肠癌（mCRC）患者的一线治疗已显示出一定益处。为了在治疗前准确识别此类患者，我们研究了血液生物标志物和原发性肿瘤分子。我们发现血清微小RNA（miRNA）、血管生成相关基因中的单核苷酸多态性（SNP）以及Notch 1表达作为与反应或毒性相关的生物标志物。对接受瑞戈非尼治疗的虚弱mCRC患者的血液进行了miRNA阵列分析和选定SNP的基因分型。还分析了肿瘤中Notch 1和CRC相关miRNA的表达。血清中高水平的miR-185-5p、血管内皮生长因子受体1（VEGFR1）基因中的rs7993418以及活检中的Notch 1表达与治疗的良好反应相关。血清miR-126-3p和miR-152-3p水平以及miR-92a-1-5p的肿瘤表达与治疗毒性相关，这在患有合并症的患者中尤其有趣，而高水平的miR-362-3p与乏力相关。此外，几种miRNA与转移、局部复发和腹膜转移的存在相关。此外，在原发性肿瘤中测定的miRNA与肿瘤-淋巴结-转移（TNM）分期相关。VEGFR2和VEGFA中的rs2305948和rs699947 SNP分别是与局部区域复发、更高的N分期和转移脱落相关的不良预后标志物。总之，VEGF和VEGFR SNP、miRNA以及Notch 1水平是瑞戈非尼治疗晚期CRC管理中潜在有用的生物标志物。
