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


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.
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.
Diana
D
Moreno-Muñoz
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.
Juan R
JR
de la Haba-Rodríguez
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.
Francisco
F
Conde
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.
Laura M
LM
López-Sánchez
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.
Araceli
A
Valverde
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.
Vanessa
V
Hernández
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.
Antonio
A
Martínez
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.
Carlos
C
Villar
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.
Auxiliadora
A
Gómez-España
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.
Ignacio
I
Porras
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.
Antonio
A
Rodríguez-Ariza
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.
Enrique
E
Aranda
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000068258:Bevacizumab / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D064593:Heterografts / Q000378:metabolism; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C544065:AGTR1 protein, human; D020533:Angiogenesis Inhibitors; D044140:Receptor, Angiotensin, Type 1; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D000068258:Bevacizumab; D007703:Peptidyl-Dipeptidase A
Angiogenesis; angiotensin; angiotensin II receptor 1; breast cancer; colorectal cancer; polymorphisms