Renin‐angiotensin system inhibitors, angiotensin I‐converting enzyme gene insertion/deletion polymorphism, and cancer

Abstract

BACKGROUND. Angiotensin I‐converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current epidemiologic study was to investigate whether renin‐angiotensin system inhibitors and/or ACE genotypes were associated with an altered risk of colorectal, lung, breast, and prostate cancer. METHODS. Data were obtained from the Rotterdam Study, a population‐based, prospective cohort study with 7983 participants. Participants who had a history of 1 of the cancers of interest (n = 216) or who had a medication history <6 months (n = 88) were excluded, leaving 7679 participants, of whom the ACE genotypes could be assessed in 6670 individuals. The mean follow‐up was 9.6 years, during which 730 incident cancers occurred. The effect of medication, ACE I/D genotypes, and their interaction on cancer risk and progression was studied by using Cox proportional hazard models. RESULTS. Carriers of the high‐activity genotype DD had an increased risk of breast cancer compared with low‐activity II/ID genotype carriers (hazard ratio [HR], 1.47; 95% confidence interval [95% CI], 1.05–2.04), but no association was demonstrated for other cancers. DD carriers who were exposed to long‐term and high‐dose medication were at lower risk for cancer (HR, 0.28; 95% CI, 0.10–0.79). Short‐term, high‐dose users were at risk for colorectal cancer progression in the II/ID stratum (HR, 3.83; 95% CI, 1.67–8.79). CONCLUSIONS. Renin‐angiotensin system‐inhibiting drugs seemed to protect against cancer in individuals with the DD genotype, which was associated with high levels of ACE. Cancer 2008. © 2008 American Cancer Society.

Angiotensin inhibition and malignancies: a review

“…RAS-inhibiting drugs seemed to protect against cancer in individuals with the DD genotype, which was associated with high levels of ACE. 59 Breast cancer An epidemiological study conducted in Chinese women in Singapore observed lower breast-cancer incidence in users of ACE inhibitors relative to nonusers with comparable cardiovascular conditions, 60,61 consistent with experimental data implicating ACE and Ang II in breast cancer.…”

The renin-angiotensin system meets the hallmarks of cancer

“…The authors observed a dose-dependent, protective association between RAS inhibitor use and cancer risk in individuals with the ACE DD genotype (HR, 0.28; 95% confidence interval (CI), 0.10-0.79), while short-term, high-dose users were at risk for colorectal cancer progression in the II/ID stratum (HR, 3.83; 95% CI, 1.67-8.79). 41 On the other hand, in a meta-analysis reported by Sipahi et al with 61,590 patients enrolled in five trials with an ARB randomly given in at least one group, a modest risk to develop cancer was found in the ARB-receiving group (7.2% vs 6.0%, relative risk (RR) 1.08, 95% CI 1.01-1.15; p = 0.016). The clinical relevance of an RR of 1.08 needs to be further evaluated in trials with the development of malignancy as a primary outcome measure.…”

“…They found that carriers of the high-activity genotype DD had an increased risk of breast cancer compared with low-activity II/ID genotype, but DD carriers who were exposed to long-term and high-dose medication were at a lower risk for other types of cancer. 41 All these results suggest that pre-clinical and clinical studies suggested that the blockade of the renin-angiotensin pathway with angiotensin system inhibitors might inhibit tumour growth in several cancer types. 35 …”

Use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers and cancer risk: a meta-analysis of observational studies

“…A beneficial effect was also found when the analysis was limited to the 11 studies with long-term follow-up (RR 0.89, 95% CI 0.83-0.96). 4,6,13,15,18,[22][23][24]27,31,33 When the analyses were restricted to studies that investigated the effect of only ACE inhibitors on cancer risk, the 12 cohort and nested case-control studies showed a nonsignificant protective effect (RR 0.93, 95% CI 0.86-1.01), 4,12,15,16,19,21,23,29−33 and the 8 studies with longterm follow-up showed a significant protective effect (RR 0.89, 95% CI 0.80-0.98). 4,13,15,18,22,23,31,33 No significant change was observed when we excluded two studies with crude estimates.…”