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- Title
Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients.
- Authors
Moreno‐Muñoz, Diana; Haba‐Rodríguez, Juan R.; Conde, Francisco; López‐Sánchez, Laura M.; Valverde, Araceli; Hernández, Vanessa; Martínez, Antonio; Villar, Carlos; Gómez‐España, Auxiliadora; Porras, Ignacio; Rodríguez‐Ariza, Antonio; Aranda, Enrique
- Abstract
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 antiangiogenic drugs.
- Subjects
HUMAN genetic variation; RENIN-angiotensin system; BEVACIZUMAB; CANCER patients; BIOMARKERS; HYPERTENSION
- Publication
European Journal of Clinical Investigation, 2015, Vol 45, Issue 12, p1325
- ISSN
0014-2972
- Publication type
Article
- DOI
10.1111/eci.12557