{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T02:56:59Z","timestamp":1770519419412,"version":"3.49.0"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,4,4]],"date-time":"2021-04-04T00:00:00Z","timestamp":1617494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers13071710","type":"journal-article","created":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T11:48:29Z","timestamp":1617623309000},"page":"1710","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3751-9602","authenticated-orcid":false,"given":"Elisa","family":"Conde","sequence":"first","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9360-4716","authenticated-orcid":false,"given":"Julie","family":"Earl","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology and Predictive Tumor Markers Group, Alcal\u00e1 University, Ram\u00f3n y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain"},{"name":"Biomedical Research Network in Cancer (CIBERONC), C\/Monforte de Lemos 3-5, Pabell\u00f3n 11, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorena","family":"Crespo-Toro","sequence":"additional","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Blanco-Agudo","sequence":"additional","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edurne","family":"Ramos-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E. Macarena","family":"Rodr\u00edguez-Serrano","sequence":"additional","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Carlos","family":"Mart\u00ednez \u00c1vila","sequence":"additional","affiliation":[{"name":"Departamento de Matem\u00e1tica Aplicada y Estad\u00edstica, Facultad de Ciencias Econ\u00f3micas y Empresariales, Universidad San Pablo CEU, C\/Juli\u00e1n Romea, 23, 28003 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Salinas-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Serrano-Huertas","sequence":"additional","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reyes","family":"Ferreiro","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology and Predictive Tumor Markers Group, Alcal\u00e1 University, Ram\u00f3n y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain"},{"name":"Biomedical Research Network in Cancer (CIBERONC), C\/Monforte de Lemos 3-5, Pabell\u00f3n 11, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Rodriguez-Garrote","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology and Predictive Tumor Markers Group, Alcal\u00e1 University, Ram\u00f3n y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain"},{"name":"Biomedical Research Network in Cancer (CIBERONC), C\/Monforte de Lemos 3-5, Pabell\u00f3n 11, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Bruno","family":"Sainz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ram\u00f3n y Cajal Health Research Institute (IRYCIS) and Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d (IIBM), Universidad Aut\u00f3noma de Madrid (UAM), CSIC-UAM, C\/Arzobispo Morcillo, 4, 28029 Madrid, Spain"},{"name":"Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer Area 3-IRYCIS, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bartomeu","family":"Massuti","sequence":"additional","affiliation":[{"name":"Oncology Department, Instituto de Investigaci\u00f3n Sanitaria y Biom\u00e9dica de Alicante (ISABIAL), Hospital General Universitario de Alicante, Universidad Miguel Hern\u00e1ndez, Pintor Baeza, 11, 03010 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4373-9978","authenticated-orcid":false,"given":"Pilar Garc\u00eda","family":"Alfonso","sequence":"additional","affiliation":[{"name":"Oncology Department, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Hospital Universitario Gregorio Mara\u00f1\u00f3n, Doctor Esquerdo 46, 28028 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9817-1291","authenticated-orcid":false,"given":"Manuel","family":"Benavides","sequence":"additional","affiliation":[{"name":"Oncology Department, Hospital Universitario Regional y Virgen de la Victoria, IBIMA, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Aranda","sequence":"additional","affiliation":[{"name":"Biomedical Research Network in Cancer (CIBERONC), C\/Monforte de Lemos 3-5, Pabell\u00f3n 11, 28029 Madrid, Spain"},{"name":"Oncology Department, Instituto Maimonides de Investigaci\u00f3n Biom\u00e9dica de C\u00f3rdoba, Hospital Universitario Reina Sofia, University of C\u00f3rdoba, IMIBIC, Av. Men\u00e9ndez Pidal, s\/n, 14004 C\u00f3rdoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8167-2276","authenticated-orcid":false,"given":"Mar\u00eda Laura","family":"Garc\u00eda-Bermejo","sequence":"additional","affiliation":[{"name":"Biomarkers and Therapeutic Targets Group and Core Facility, Ram\u00f3n y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7749-8140","authenticated-orcid":false,"given":"Alfredo","family":"Carrato","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology and Predictive Tumor Markers Group, Alcal\u00e1 University, Ram\u00f3n y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain"},{"name":"Biomedical Research Network in Cancer (CIBERONC), C\/Monforte de Lemos 3-5, Pabell\u00f3n 11, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14740\/wjon1166","article-title":"Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. 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