Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study

Cancers

Carolina Blanco-Agudo¹  Elisa Conde¹  Lorena Crespo-Toro¹  E.Macarena Rodríguez-Serrano¹  Laura Salinas-Muñoz¹  MaríaLaura García-Bermejo¹  Silvia Serrano-Huertas¹  Edurne Ramos-Muñoz¹  Enrique Aranda²  JoseCarlos Martínez Ávila³  Bruno Sainz⁴  Alfredo Carrato⁵  Julie Earl⁵  Reyes Ferreiro⁵  Mercedes Rodriguez-Garrote⁵  Manuel Benavides⁶  PilarGarcía Alfonso⁷  Bartomeu Massuti⁸ 

[1] Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain;Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain;Departamento de Matemática Aplicada y Estadística, Facultad de Ciencias Económicas y Empresariales, Universidad San Pablo CEU, C/Julián Romea, 23, 28003 Madrid, Spain;Department of Biochemistry, Ramón y Cajal Health Research Institute (IRYCIS) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Universidad Autónoma de Madrid (UAM), CSIC-UAM, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain;Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain;Oncology Department, Hospital Universitario Regional y Virgen de la Victoria, IBIMA, 29010 Málaga, Spain;Oncology Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Universitario Gregorio Marañón, Doctor Esquerdo 46, 28028 Madrid, Spain;Oncology Department, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario de Alicante, Universidad Miguel Hernández, Pintor Baeza, 11, 03010 Alicante, Spain;

关键词: miRNAs;    colorectal cancer;    regorafenib;    biomarkers;    treatment response;    toxicity;   

DOI  :  10.3390/cancers13071710

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown