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

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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 anti-angiogenic drugs.

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