Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study
Introduction
Colorectal cancer (CRC) is one of the most common forms of cancer worldwide with approximately 450,000 new cases detected in Europe in 2012 (Arnold et al., 2015, Ferlay et al., 2013). In the last decades, the field of chemoprevention has experimented a rising interest, with the use of certain drugs to reduce the individual risk of cancer. Nowadays, the role of aspirin therapy in the reduction of colorectal cancer risk and precancerous adenomas (Flossmann and Rothwell, 2007, Cole et al., 2009) is well known and there is increasing evidence of the chemopreventive effect of many others drugs used for cardiovascular diseases such as statins (Bardou et al., 2010) and renin-angiotensin system (RAS) inhibitors (Mansouri et al., 2013). In addition, recent observational studies and one meta-analysis have shown a protective effect of RAS therapy against CRC (Azoulay et al., 2012, Kedika et al., 2011, Makar et al., 2014, Dai et al., 2015). Despite these encouraging findings, other studies have yielded conflicting results (Hallas et al., 2012, Sipahi et al., 2010, Yoon et al., 2011), calling for additional studies before recommending the clinical use of RAS inhibitors for CRC chemoprevention. The mechanism of action of the RAS-inhibitors combines both pro and antitumor effects, probably explain the controversial results obtained in observational studies. Moreover, the potential interaction with lifestyle factors (eg, diet) warrants more investigation (Song and Giovannucci, 2014). Finally, it is important to identify whether there is a differential effect regarding the tumor anatomic subsite, given that, to the best of our knowledge, no previous studies have analyzed these aspects.
Therefore, the purpose of this work is to evaluate the effects of angiotensin-converting-enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) on overall colorectal cancer risk, and on its different anatomic locations, in a large population-based case-control study conducted in Spain, the MCC-Spain study.
Section snippets
Study design and population
We conducted a multi-region case-control study “the Spanish multicase-control study” (MCC-Spain). This study was designed with the main objective of investigating lifetime environmental, infectious, medical and occupational exposures, as well as genetic factors associated with five cancer sites. Briefly, the MCC-Spain is a population-based case-control study of common tumors in Spain; the recruitment includes histologically confirmed incident cases of colorectal cancer diagnosed between January
Results
During the study period, data from 2165 colorectal cancer cases and 3912 population controls were collected. The characteristics of cases and controls are shown in Table 1. The main differences between cases and controls were found at educational level, family history of colon cancer and diet. Controls had higher educational level and less often had a first-degree relative with colorectal cancer. Finally, regarding eating habits, controls had lower ethanol, energy and red meat intake and higher
Discussion
In this study, we analyzed a population-based case control study for evaluating the potential effect of RAS inhibitors on CRC. Our study shows a relevant protective effect against CRC for the ACEis limited to the under-65 group and to men, but no effect for the ARBs. The stronger association was observed in the under 65-year men where the ACEis show a protective effect in short term treatments. However, in men over 65, only the length of consumption greater than five years showed a protective
Conclusions
Our study found a protective effect on the CRC risk of the ACEis limited to the under-65 group and less markedly in men. In those aged under 65 years, this protection shows a descending gradient across the colon and disappears in the rectum. Age and sex were modifiers of this association. We found no evidence of any effect on colorectal cancer risk among those exposed to the ARBs.
The potential protective effect of RAS inhibitors is a subject of increasing interest due to their possible role as
Funding
This work was supported by the “Accion Transversal del Cancer”, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613), PI15/00069, PI15/01032, PI15/00914, by the Fundación Marqués de Valdecilla (API
Ethical approval
The study was carried out according to Spanish laws on biomedical research. The ethics committees of participant hospitals approved the protocol. Informed consent was obtained from all individual participants included in the study. All procedures were performed with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Conflict of interest
None.
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