Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study
by
, , , , and
Elisa Conde
1,†
,
Julie Earl
2,3,†
,
Lorena Crespo-Toro
1,
Carolina Blanco-Agudo
1,
Edurne Ramos-Muñoz
1,
E. Macarena Rodríguez-Serrano
1,
Jose Carlos Martínez Ávila
4,
Laura Salinas-Muñoz
1,
Silvia Serrano-Huertas
1,
Reyes Ferreiro
2,3,
Mercedes Rodriguez-Garrote
2,3,
Bruno Sainz, Jr.
5,6, 
Bartomeu Massuti
7,
Pilar García Alfonso
8,
Manuel Benavides
9,
Enrique Aranda
3,10,
María Laura García-Bermejo
1,*,‡ and
Alfredo Carrato
2,3,‡ 1
Biomarkers and Therapeutic Targets Group and Core Facility, Ramón y Cajal Health Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain
2
Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain
3
Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain
4
Departamento de Matemática Aplicada y Estadística, Facultad de Ciencias Económicas y Empresariales, Universidad San Pablo CEU, C/Julián Romea, 23, 28003 Madrid, Spain
5
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
6
Cancer Stem Cells and Fibroinflammatory Microenvironment Group, Chronic Diseases and Cancer Area 3-IRYCIS, 28034 Madrid, Spain
7
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
8
Oncology Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Universitario Gregorio Marañón, Doctor Esquerdo 46, 28028 Madrid, Spain
9
Oncology Department, Hospital Universitario Regional y Virgen de la Victoria, IBIMA, 29010 Málaga, Spain
10
Oncology Department, Instituto Maimonides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofia, University of Córdoba, IMIBIC, Av. Menéndez Pidal, s/n, 14004 Córdoba, Spain
*
Author to whom correspondence should be addressed.
†
Equal contribution as first author.
‡
Equal contribution as last author.
Cancers 2021, 13(7), 1710; https://doi.org/10.3390/cancers13071710
Submission received: 18 February 2021
/
Revised: 27 March 2021
/
Accepted: 30 March 2021
/
Published: 4 April 2021
(This article belongs to the Section Cancer Biomarkers)
Simple Summary
Biomarkers able to predict response and toxicity upon regorafenib therapy for colorectal cancer (CRC) are critical for treatment choice, particularly relevant in fragile patients. Here, we validated for the first time 18 distinct microRNAs (miRNAs) detected in serum and primary tumor samples, three germline single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) genes, and low levels of Notch 1 expression in the primary tumor as predictive biomarkers of different features. Specifically, these markers were associated with a favorable response to treatment, disease stage, and relapse, as well as the appearance of asthenia. Therefore, these markers can be potentially useful biomarkers for patient stratification and for providing a more personalized and effective therapeutic strategy in fragile patients, while limiting the appearance of adverse effects.
Abstract
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.
Keywords:
miRNAs; colorectal cancer; regorafenib; biomarkers; treatment response; toxicity
