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

Eur J Clin Invest. 2015 Dec;45(12):1325-32. doi: 10.1111/eci.12557. Epub 2015 Nov 20.

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.

Keywords: Angiogenesis; angiotensin; angiotensin II receptor 1; breast cancer; colorectal cancer; polymorphisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / therapeutic use*
  • Angiotensin II / metabolism
  • Animals
  • Bevacizumab / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genotype
  • Heterografts / metabolism
  • Humans
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Peptidyl-Dipeptidase A / metabolism
  • Polymorphism, Genetic
  • Prospective Studies
  • Receptor, Angiotensin, Type 1 / genetics
  • Renin-Angiotensin System / genetics*
  • Retrospective Studies
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • AGTR1 protein, human
  • Angiogenesis Inhibitors
  • Receptor, Angiotensin, Type 1
  • Vascular Endothelial Growth Factor A
  • Angiotensin II
  • Bevacizumab
  • Peptidyl-Dipeptidase A