Daily Aspirin Cut Risk of Colon Cancers With Excess COX-2

BOSTON, May 23 -- Regular use of aspirin reduced the risk of colon cancer but only in tumors high in an enzyme that promotes cancer growth, researchers here reported.

Extended use of aspirin cut the risk of colorectal cancers that overexpress cyclooxygenase-2 (COX-2) by almost a third, but not the risk of cancers with weak or absent COX-2 expression, Andrew T. Chan, M.D., M.P.H., of Harvard, and colleagues reported in the May 24 issue of the New England Journal of Medicine.

The significance of the COX-2 target emerged from 2,446,431 person-years of follow-up of 82,911 women in the Nurses' Health Study and 47,363 men in the Health Professionals Follow-up Study. Assessments of Cox-2 expression came from a review of pathology reports.

The investigators identified 636 incident cases of colorectal cancer among users and nonusers of aspirin that were available for analysis of COX-2 expression. Of the tumors, 423 (67%) had moderate or strong COX-2 expression (P for heterogeneity = 0.02).

Aspirin users took at least two standard 325 mg tablets a week or used aspirin at least twice a week.

Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 (multivariate relative risk 0.64; 95% confidence interval, 0.52 to 0.78), the researchers found. It had no effect on tumors with weak or absent expression of Cox-2 (multivariate relative risk, 0.96, CI 0.73 to 1.26).

The age-standardized incidence rate for cancers that overexpressed COX-2 was 37 per 100,000 person-years among regular aspirin users, compared with 56 per 100,000 person-years among those who did not use aspirin regularly.

In contrast, with absent or weak COX-2 tumors, regular or nonregular use of aspirin made no difference. The rate for cancers with little or no COX-2 expression was 27 per 100,000 person-years among regular aspirin users compared with 28 per 100,000 person years among nonregular aspirin users.

Increasing duration of use and increased aspirin dose were also significant, the researchers said.

A reduction for the risk of COX-2-positive tumors was found with increasing duration of aspirin use (multivariate relative risk 0.59), becoming evident after 10 years, the researchers said. But they found was no statistically significant reduction for the Cox-2-negative tumors.

The fact that the reduction in cancer risk was found only after several years of aspirin use suggests an effect of aspirin on the early stages of colorectal adenoma or cancer, the researchers wrote.

A reduction in the relative risk became most apparent with an intake of more than five tablets a week and was further reduced as the number of tablets (six to 14 or more) increased, but again not for the COX-2-negative tumors.

COX-2 is progressively overexpressed during the stepwise sequence from adenoma to carcinoma, Dr. Chan said. Randomized controlled trials have shown that selective COX-2 inhibitors prevent recurrence of adenoma in patients with a history of adenoma or familial polyposis.

Our study suggests, he said, that the anticancer benefit of aspirin is mediated, at least in part, by inhibition of COX-2. Possibly through production of inflammatory prostaglandins or eicosanoids, COX-2 may regulate angiogenesis, apoptosis, or tumor-cell invasiveness.

Experimental studies have shown that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS), especially at high doses, have a range of other potentially antineoplastic actions, suggesting that further work is needed to clarify the effects of these agents and COX-2 (or its downstream effectors) on the development of colorectal cancer, the researchers said.

Study limitations acknowledged by the authors included the fact that the study was observational and aspirin use was self-selected. Thus, among users and nonusers there were small, but statistically significant differences in risk factors, including smoking history, physical activity, and use of multivitamins.

Another limitation, they noted, was the lack of a standardized classification system for COX-2 expression in colorectal cancer. However, in this study, in the overall population, the proportion of tumors that overexpressed COX-2 was similar to that found by other investigators, the researchers said.

These results support the importance of continued investigation into COX-2 and related pathways for the development of new treatments and the potential use of COX-2 as a molecular marker for tailoring chemoprevention in participants with a history of colorectal cancer, the investigators concluded.

In an accompanying editorial, Sanford D. Markowitz, M.D., Ph.D., of Case Western Reserve University in Cleveland, wrote that current thinking ascribes the cancer-preventive activity of aspirin and NSAIDS principally to the ability of COX-2 to block the generation of PGE₂, the most abundant colon prostaglandin.

The work of Dr. Chan and his colleagues, Dr. Markowitz said, raises a number of questions. How is the cancer-promoting activity of COX-2 mediated? Is it the only or the best target in the pathway to colon cancer? Can we identify the people who are most likely to benefit from COX-2? Are some established colon cancers responsive to inhibitors of this pathway?

He noted that, given the findings of this study, in which only one-third of colon cancers that are positive for COX-2 are prevented by regular aspirin use, it is necessary to ask whether there are alternative strategies for targeting the COX pathway that are more effective and have lower rates of adverse effects.

Furthermore, Dr. Markowitz said, the study's findings pose the challenge of whether we can identify persons in whom COX inhibitors would have the highest likelihood of conferring protection.

A final caveat, he said, is that the primacy of PGE₂ has been extrapolated from murine models. There may remain unexpected features unique to the pathogenesis of human colon cancers and particularly of cancers with the highest levels of COX-2.

The findings of this study, Dr. Markowitz said, "provide powerful support for the role of COX-2 as a key mediator in the development of colon cancer and now pose important questions about the biologic basis and clinical implications of discovering differences between colon cancers that express high or low levels of COX-2."