Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients.

Autor: Moreno-Muñoz D; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., de la Haba-Rodríguez JR; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., Conde F; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., López-Sánchez LM; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., Valverde A; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., Hernández V; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., Martínez A; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain.; Clinical Analysis Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain., Villar C; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain.; Pathology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain., Gómez-España A; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., Porras I; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., Rodríguez-Ariza A; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain., Aranda E; Oncology Department, Maimonides Institute for Biomedical Research (IMIBIC), Hospital Reina Sofía, University of Córdoba, Córdoba, Spain.; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain.
Jazyk: angličtina
Zdroj: European journal of clinical investigation [Eur J Clin Invest] 2015 Dec; Vol. 45 (12), pp. 1325-32. Date of Electronic Publication: 2015 Nov 20.
DOI: 10.1111/eci.12557
Abstrakt: Background: Currently, there are no predictive biomarkers for anti-angiogenic strategies in cancer, but response to anti-angiogenic drugs is associated with development of hypertension secondary to treatment. Therefore, this study explored the clinical relevance of genetic polymorphisms in some components of the renin-angiotensin system (RAS).
Material and Methods: Genomic DNA was isolated from peripheral blood from 95 metastatic breast or colorectal cancer patients treated with bevacizumab, and AGTR1-A1166C (rs5186), AGT-M235T (rs699) SNPs and ACE I/D (rs4646994) polymorphisms were genotyped using RT-PCR. Circulating vascular endothelial grow factor and angiotensin converting enzyme (ACE) levels were analysed using ELISA kits. The antitumoral activity of bevacizumab was assayed in mice orthotopically xenografted with AGTR1-overexpressing breast cancer cells.
Results: The ACE IN/IN genotype was associated with a higher rate of disease progression compared to DEL/IN and DEL/DEL genotypes (36% vs. 11·1% P < 0·05). Similarly, AGTR1-1166A/A genotype was also associated with a higher rate of disease progression compared to AGTR1-1166A/C and AGTR1-1166C/C genotypes (24·4% vs. 2·7% P < 0·01). ACE IN/IN genotype was also found to be associated with shorter time to treatment failure compared to ACE IN/DEL and ACE DEL/DEL genotypes (14 weeks vs. 41·71, P = 0·033), whereas circulating ACE levels were found to be associated with a better response to bevacizumab treatment. Besides, in vivo experiments showed a significantly higher antitumoral activity of bevacizumab in tumours derived from AGTR1-overexpressing breast cancer cells.
Conclusions: A higher activity of ACE-angiotensin-II-AGTR1 axis is associated with a better response to bevacizumab, supporting that the RAS can be an important source of potential predictive markers of response to anti-angiogenic drugs.
(© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)
Databáze: MEDLINE
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