Aspirin a potential chemopreventive agent for cholangiocarcinoma

Aspirin has been investigated as a cancer chemopreventive agent for more than 50 years. In that time, at least as many published studies have looked at the association between aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer risk. Based on data from these studies, aspirin and non-aspirin NSAIDs are thought to exert anti-cancer effects through cyclooxygenase-2 (COX-2) inhibition. A majority of observational studies suggest that NSAIDs do, indeed, reduce the incidence of colorectal adenomas, cancers and cancer deaths. Clinical trials have been encouraging but less convincing.

One high-quality randomized controlled trial published in The New England Journal of Medicine in 2006 found a significant reduction in premalignant adenomas with celecoxib, a selective COX-2 inhibitor. Despite an associated increase in adverse cardiovascular events, COX-2 inhibitors continue to be investigated as potential chemopreventive agents because of the documented association between COX-2 overexpression and cancer risk at many organ sites.

In colorectal cancer, COX-2 is increasingly overexpressed from adenoma to carcinoma; higher expression is observed in more-aggressive and refractory forms of the disease. In a study published in The New England Journal of Medicine in 2007, regular aspirin use appeared to reduce the risk of colorectal cancers that overexpress COX-2 but not those having lower COX-2 expression.

In 2015, researchers at the University of Minnesota's Hormel Institute, using tissue supplied by Mayo Clinic, reported an intriguing association between COX-2 and epidermal growth factor receptor (EGFR) during development of colorectal cancer. They theorized that COX-2 may drive the formation of tumors through the upregulation of EGFR and that daily low-dose aspirin might normalize EGFR expression. Their research was published in EBioMedicine.

Then, in June 2016, Yin Cao, Sc.D, and colleagues reported in JAMA Oncology the results of a large-scale analysis of nearly 136,000 health professionals who underwent follow-up for as long as 32 years. Among participants enrolled in two prospectively followed cohorts — the Nurses' Health Study and the Health Professionals Follow-up Study — regular aspirin use was associated with a 19 percent reduction in colorectal cancer. The benefit was seen at relatively low doses with increasing benefits at higher doses and durations, leading the authors to conclude that regular aspirin use might reduce a significant proportion of colorectal cancers above and beyond those prevented by screening.

Aspirin and cholangiocarcinoma

Given the growing evidence associating regular, long-term aspirin use with reduced risk of gastrointestinal cancers, researchers at Mayo Clinic's campus in Rochester, Minnesota, investigated aspirin as a candidate chemopreventive for cholangiocarcinoma. In one of the largest hospital-based, case-control studies in Western populations, a team led by Jonggi Choi, M.D., and Lewis R. Roberts, M.B., Ch.B., Ph.D., looked at nearly 2,400 patients with cholangiocarcinoma (1,169 intrahepatic, 995 perihilar and 231 distal) seen at Mayo Clinic from 2000 through 2014. Controls from the Mayo Clinic Biobank were matched in a 2-to-1 ratio with cases by age, sex, race and residence. Of these, 2,129 controls and 591 cholangiocarcinoma patients used aspirin.

The results, published in 2016 in Hepatology, demonstrated that aspirin use was associated with a 2.7- to 3.6-fold reduced cholangiocarcinoma risk for intrahepatic, perihilar and distal disease. The study also showed that primary sclerosing cholangitis (PSC) biliary tract disease, cirrhosis, hepatitis B virus infection, diabetes and smoking conferred risks of different magnitude for the three subtypes, supporting the idea that each is a distinct disease with its own risk factors. PSC was more strongly associated with perihilar cholangiocarcinoma, for instance, whereas diabetes was more closely associated with the distal subtype.

Each of these risk factors is known to induce chronic bile duct inflammation, and the investigators speculate that aspirin may reduce the risk of cholangiocarcinoma by inhibiting COX-2 as well as by blocking other biological pathways that promote cancer development.

Paul J. Limburg, M.D., is a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, where he serves as the medical director of the Healthy Living Research Program and is principal investigator for the NCI-funded, multicenter Cancer Prevention Network. Dr. Limburg's group has been actively engaged in investigating and reporting novel approaches to cancer prevention, including evaluations of aspirin and non-aspirin NSAIDs as potential chemopreventive interventions for colorectal cancer and esophageal adenocarcinoma risks. The group has also developed a population pharmacokinetic model for the NSAID sulindac, which has been studied extensively as a cancer chemopreventive agent. The article was published in the Journal of Clinical Pharmacology in 2013.

With respect to the study published by Choi, Roberts and colleagues, Dr. Limburg observes that although the results are intriguing, the findings should be interpreted in the context of limitations that apply to any epidemiological study. "This is a large study, and the observed risk reduction was fairly impressive, but additional confirmatory results and clinical trial data should be obtained before aspirin can broadly be recommended as a chemopreventive agent for bile duct cancer," he says.

Dr. Roberts agrees, saying the next steps include population-based studies examining the association of aspirin use with the risk of bile duct cancer as well as clinical studies in high-risk populations.

For more information

Bertagnolli MM, et al. Celecoixib for the prevention of sporadic colorectal adenomas. The New England Journal of Medicine. 2006;355:873.

Chan AT, et al. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. The New England Journal of Medicine. 2007;356:2131.

Li H, et al. Aspirin prevents colorectal cancer by normalizing EGFR expression. EBioMedicine. 2015;2:247.

Cao Y, et al. Population-wide impact of long-term use of aspirin and the risk for cancer. JAMA Oncology. 2016;2:762.

Choi J, et al. Risk factors for cholangiocarcinoma: Aspirin use and the risk of cholangiocarcinoma. Hepatology. In press.

Berg AK, et al. Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. The Journal of Clinical Pharmacology. 2013;53:403.