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Good News and Bad News About Colonic Polyps and Prevention of Colon Cancer: The Good News

Aspirin prevents COX-2–overexpressing colorectal cancers.

Colorectal cancer is the third most commonly detected cancer and the second leading cause of cancer-related deaths in the U.S. Many agents have been studied as possible "cancer-protective" therapies — some have proven to be ineffective (Journal Watch Oncology and Hematology Jul 2 2007). However, the use of aspirin and other agents that inhibit prostaglandin-generating cyclooxygenase (COX) pathways reduces both the incidence of colorectal polyps and colorectal cancer. How these agents affect development of polyps and cancers is unclear, although we know that the COX-2 enzyme is overexpressed in some polyps and cancers. Recent trials indicate that specific COX-2 inhibitors reduce the incidence of colorectal adenomatous polyps but at the cost of increased risk for cardiovascular complications, including heart attack and stroke Journal Watch Oncology and Hematology Oct 16 2006). Large observational trials have indicated that long-term aspirin use can lower risk for colorectal cancer (e.g., Journal Watch Gastroenterology Sep 13 2005), but, currently, we are unable to identify particular patients who will benefit from aspirin therapy.

Researchers now report the results of a retrospective analysis of data from two large observational studies, the Nurses’ Health Study (NHS; >120,000 women) and the Health Professionals Follow-Up Study (HPFS; >50,000 men). Previous analyses in both these cohorts indicated that regular daily aspirin use lowered risk for colorectal cancer. The authors hypothesized that the influence of aspirin on risk for colorectal cancer would vary with the level of expression of COX-2 enzymes in the tumor. Tissue specimens from incident colorectal cancers were obtained from 648 cases (76% of the total number of cases) during 16 years of follow-up in the HPFS and from 662 cases (58% of the total) during 22 years of follow-up in the NHS. Pathologists who were blinded to any clinical data performed immunohistochemical staining to evaluate the expression of COX-2 in tumor specimens. A total of 636 specimens were of adequate quality for evaluation of COX-2 expression; 423 (67%) exhibited moderate or strong COX-2 expression, and 213 (33%) showed weak or absent COX-2 expression.

Statistical analysis showed that the benefit of regular aspirin use (>10 years) was confined to preventing cancers that expressed COX-2 (relative risk, 0.64; 95% confidence interval, 0.52–0.78). Aspirin use had no effect on risk for developing colorectal cancer with weak or absent COX-2 expression (RR, 0.96; 95% CI, 0.73–1.26). Higher weekly intakes of aspirin were associated with further risk reduction but, again, only for COX-2–expressing tumors. The adjusted incidence rate for COX-2–expressing tumors was 37 per 100,000 person-years for long-time aspirin users versus 56 per 100,000 person-years for nonusers, whereas the incidence of COX-2–negative tumors was the same among long-time users and nonusers (about 27 per 100,000 person-years).

Comment: Aspirin-associated reduction in colorectal cancer risk appears to be limited to COX-2–expressing cancers. This landmark observation validates COX-2 as a target for colorectal polyp and cancer prevention and identifies a subset of patients who potentially could benefit from aspirin or related agents. Of course, how to identify patients at specific risk for developing COX-2–positive tumors is unclear — such identification might require evaluation of surrogate markers. However, patients with histories of COX-2–expressing colorectal cancers might be ideal candidates in whom to evaluate COX-2–targeted agents for cancer prevention. Because we know that currently available COX-2–specific inhibitors impart cardiovascular toxicity, alternative agents will require clinical development and study. And we’ll need to find other strategies to target COX-2–negative tumors.

— David H. Ilson, MD, PhD

Published in Journal Watch Oncology and Hematology July 2, 2007

Citation(s):

Chan AT et al. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 2007 May 24; 356:2131-42.

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