Journal of the National Cancer Institute Advance Access published online on August 26, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn262
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© The Author 2008. Published by Oxford University Press.
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Association of ACE Inhibitors and Angiotensin Receptor Blockers with Keratinocyte Cancer Prevention in the Randomized VATTC Trial
Affiliations of authors: Department of Community Health, Brown University, Providence, RI (JBC); Department of Community Health, Brown University (KLL); School of Pharmacy, University of Rhode Island (ALH); Department of Family Medicine and Center for Primary Care and Prevention, Brown University (CBE); Dermatoepidemiology Unit, V A Medical Center Providence Department of Dermatology, Rhode Island Hospital Departments of Dermatology and Community Health, Brown University (MAW)
Correspondence to: Jennifer B. Christian, PharmD, MPH, PhD, Department of Community Health, Brown University, Box G-S121, Providence, RI 02912 (e-mail: JChristian111{at}gmail.com or maw{at}brown.edu).
Background: The observation that angiotensin II is a potent angiogenic and growth factor raises the possibility that blocking its effects could reduce the incidence of cancer. We evaluated associations between use of angiotensin-converting enzyme (ACE) inhibitors and of angiotensin receptor blockers (ARBs) and keratinocyte cancer incidence in a population at high risk of the disease.
Methods: A cohort study design was conducted using data on 1051 participants in the randomized Department of Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial, all of whom were at increased risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). We followed participants from enrollment (November 1998 through January 2003) until first BCC or SCC. Study participants were examined every 6 months by a study dermatologist; biopsies were taken on all suspicious lesions and centrally reviewed. Use of ACE inhibitors and ARBs was ascertained from VA pharmacy records. Cox proportional hazards models were used to estimate adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of BCC and SCC with use of ACE inhibitors or ARBs.
Results: During a median follow-up of 3.4 years, 472 incident BCCs, 309 SCCs, and 200 deaths from any cause were observed. Compared with nonusers, users of ACE inhibitors or ARBs had statistically significantly reduced risks of BCC (IRRBCC = 0.61, 95% CI = 0.50 to 0.76) and SCC (IRRSCC = 0.67, 95% CI = 0.52 to 0.87). The combined absolute incidence rates of BCC and SCC were 237 per 1000 person-years among users of ACE inhibitors or ARBs and 374 per 1000 person-years among nonusers. The greatest reduction in keratinocyte cancer was seen among people who initiated use of ACE inhibitors or ARBs during the study period (IRRBCC = 0.45 [95% CI = 0.34 to 0.59]; IRRSCC = 0.48 [95% CI = 0.35 to 0.67]).
Conclusion: Among a high-risk group of veterans, users of ACE inhibitors or ARBs had a lower incidence of keratinocyte cancers than nonusers. The more pronounced reduction among those who initiated use during the study may indicate an immediate effect.
| Context and Caveats Prior knowledge Antihypertensive agents that target angiotensin II (ie, angiotensin-converting enzyme, or ACE, inhibitors and angiotensin receptor blockers, or ARBs) have been suggested to have chemopreventive activity on the basis of animal, in vitro, and epidemiologic evidence. Study design The association between use of ACE inhibitors or ARBs and risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) was analyzed in a population at very high risk of these keratinocyte cancers. The study population comprised participants in a randomized trial of topical tretinoin for the prevention of skin cancer. Contributions Users of ACE inhibitors or ARBs had substantially lower risks of both BCC and SCC than nonusers, and the reductions were statistically significant. The association was not observed for other kinds of antihypertensive medications. No differences in overall or cancer-specific mortality were seen between users and nonusers. Implications The associations raise the possibility that ACE inhibitors and ARBs have chemopreventive activity against keratinocyte cancers in high-risk individuals. Limitations Because the study population was limited to individuals at very high risk of keratinocyte cancers, it is not possible to draw any conclusion about the association between use of ACE inhibitors or ARBs and incidence of BCC and SCC in people at normal risk. This epidemiologic analysis cannot establish causality. From the Editors
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Manuscript received December 20, 2007; revised June 13, 2008; accepted July 3, 2008.
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J Natl Cancer Inst 2008 100: 1191.
J Natl Cancer Inst 2008 100: 1191.
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