Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study
Por:
Conde, E, Earl, J, Crespo-Toro, L, Blanco-Agudo, C, Ramos-Munoz, E, Rodriguez-Serrano, E, Avila, J, Salinas-Munoz, L, Serrano-Huertas, S, Ferreiro, R, Rodriguez-Garrote, M, Sainz, B, Massuti, B, Alfonso, P, Benavides, M, Aranda, E, Garcia-Bermejo, M and Carrato, A
Publicada:
1 abr 2021
Ahead of Print:
4 abr 2021
Resumen:
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.
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.
Filiaciones:
Conde, E:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Earl, J:
Univ Alcala De Henares, Mol Epidemiol & Predict Tumor Markers Grp, Ramon y Cajal Hlth Res Inst IRYCIS, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Crespo-Toro, L:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Blanco-Agudo, C:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Ramos-Munoz, E:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Rodriguez-Serrano, E:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Avila, J:
Univ San Pablo CEU, Fac Ciencias Econ & Empresariales, Dept Matemat Aplicada & Estadist, C Julian Romea 23, Madrid 28003, Spain
Salinas-Munoz, L:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Serrano-Huertas, S:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Ferreiro, R:
Univ Alcala De Henares, Mol Epidemiol & Predict Tumor Markers Grp, Ramon y Cajal Hlth Res Inst IRYCIS, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Rodriguez-Garrote, M:
Univ Alcala De Henares, Mol Epidemiol & Predict Tumor Markers Grp, Ramon y Cajal Hlth Res Inst IRYCIS, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Sainz, B:
Univ Autonoma Madrid UAM, CSIC UAM, Dept Biochem, Ramon y Cajal Hlth Res Inst IRYCIS, C Arzobispo Morcillo 4, Madrid 28029, Spain
Univ Autonoma Madrid UAM, CSIC UAM, Inst Invest Biomed Alberto Sols IIBM, C Arzobispo Morcillo 4, Madrid 28029, Spain
Chron Dis & Canc Area 3 IRYCIS, Canc Stem Cells & Fibroinflammatory Microenvironm, Madrid 28034, Spain
:
Univ Miguel Hernandez, Dept Oncol, Inst Invest Sanitaria & Biomed Alicante ISABIAL, Hosp Gen Univ Alicante, Pintor Baeza 11, Alicante 03010, Spain
Alfonso, P:
Hosp Univ Gregorio Maranon, Dept Oncol, Inst Invest Sanitaria Gregorio Maranon, Doctor Esquerdo 46, Madrid 28028, Spain
Benavides, M:
Hosp Univ Reg & Virgen de la Victoria, Dept Oncol, IBIMA, Malaga 29010, Spain
Aranda, E:
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Univ Cordoba, Dept Oncol, Inst Maimonides Invest Biomed Cordoba, Hosp Univ Reina Sofia,IMIBIC, Ave Menendez Pidal S-N, Cordoba 14004, Spain
Garcia-Bermejo, M:
Ramon y Cajal Hlth Res Inst IRYCIS, Biomarkers & Therapeut Targets Grp, RedinRen, Madrid 28034, Spain
Ramon y Cajal Hlth Res Inst IRYCIS, Core Facil, RedinRen, Madrid 28034, Spain
Carrato, A:
Univ Alcala De Henares, Mol Epidemiol & Predict Tumor Markers Grp, Ramon y Cajal Hlth Res Inst IRYCIS, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Gold, Green Published
|