Aspirin Prevents Only COX-2-Positive Colorectal Cancer

May 23, 2007 — The effect of aspirin (acetylsalicylic acid) in preventing colorectal cancer is restricted only to tumors that are COX-2-postive, a new analysis concludes. Taking aspirin significantly reduced the risk of developing COX-2-positive colorectal cancer, but not COX-1-positive colorectal cancer, researchers conclude in the May 24 issue of the New England Journal of Medicine.

"Our research suggest that aspirin is effective primarily against colorectal cancer that has COX-2 expression, but at this point in time we don't have any real good predictors as to which type of patients will develop these tumors," lead researcher Andrew Chan, MD, from Massachusetts General Hospital and Harvard Medical School, in Boston, told Medscape in an interview. "That is a key question for future research — are there factors that will influence who will develop a COX-2-positive tumor, and are there any tests that we can use to identify these patients?"

One aspect of this that needs investigation in the near future, Dr. Chan continued, is whether aspirin can prevent a recurrence in patients who have already had colorectal cancer that is COX-2-positive and in individuals who have had polyps that were COX-2-positive. That is a substantial number of people, he pointed out, as between 30% and 40% of people over the age of 50 years of age develop polyps. "If we could provide information for this subset of people, that would be a huge step forward," he said.

"The other take-home message from our study is that it provides proof of principle that the COX-2 pathway is the critical pathway for cancer progression and that this pathway can be interrupted by medication like aspirin," Dr. Chan told Medscape. Further research may eventually lead to new drugs for cancer chemoprevention that have the benefits of aspirin without the drawbacks (eg, gastrointestinal bleeding).

Aspirin Cannot Be Recommended for Chemoprevention

At present, aspirin cannot be recommended for colorectal cancer prevention for the general public because of its adverse-effect profile and because aspirin does not entirely eliminate the risk for colorectal cancer, Dr. Chan told Medscape. There may be individual cases in which a physician may decide that for a particular patient it may be useful, but "as we don't have firm data at this point, it will be more of a judgment."

From a public health point of view, however, it is too premature to make any recommendation on the use of aspirin in colorectal cancer prevention, he said. Physicians who are faced with patients who are asking about this should emphasize the effectiveness of screening for colorectal cancer, usually with colonoscopy, but there are also other options, Dr. Chan continued. "The other point to raise is lifestyle issues — we know that maintaining a good body weight, eating a balanced diet with not too much red meat, and exercise are all important in reducing the risk for cancer. Where aspirin as a chemopreventive agent fits in to all of this is not clear yet."

These same points were laid out by Dr. Chan recently in a Lancet editorial that accompanied a new analysis of data from 2 large aspirin trials from the United Kingdom, which he said provided "convincing evidence" that aspirin does prevent colorectal cancer (Flossman E et al. Lancet. 2007;369:1603-1613; Chan A. Lancet. 2007: 369: 1577-1578), as reported by Medscape.

The latest results, which show that the preventive effect is confined only to colorectal cancer expressing COX-2, comes from a new analysis of data from 2 large aspirin studies conducted in the United States. One was the Nurses Health Study, which began in 1976 and involved 121,701 females; the other was the Health Professionals Follow-up Study, established in 1986 with 51,529 male participants. Together, these studies provided 2,446,4431 person-years of follow-up.

Dr. Chan and colleagues identified 636 incident cases of colorectal cancer that were available for COX-2 expression and found that about two thirds (423 tumors, 67%) were COX-2 positive, while the remaining third (213 tumors, 33%) were COX-2 negative.

The researchers then estimated the age-standardized incidence rate of colorectal cancer in relation to aspirin use for the entire cohort and found it to be:

Thirty-seven per 100,000 person-years for regular aspirin users vs 56 per 100,000 person-years for nonusers for COX-2–positive tumors (multivariate relative risk, 0.64; 95% CI, 0.52 – 0.78).
Twenty-seven per 100,000 person years for regular aspirin users vs 28 per 100,000 for nonusers for COX-2–negative tumors (multivariate relative risk, 0.96; 95% CI, 0.73 – 1.26).

The difference between aspirin users and nonusers was significant for COX-2-positive tumors, but not for COX-1-negative tumors, the researchers point out. In total in the 2 studies, aspirin had a significant effect in reducing the risk for colorectal cancer, but this reduction in risk "was due almost entirely to a reduction in the number of COX-2–positive colorectal cancers in regular aspirin users," they comment.

Several Challenges Ahead

In their paper, the researchers say these results suggest that COX-2 could be used as a molecular marker to tailor the use of aspirin as a chemopreventive agent in patients with a history of colorectal cancer. However, such an "individualized-medicine" approach poses several challenges, comments an accompanying editorial.

First, the individuals who would be most likely to benefit need to be identified, writes editorialist Sanford Markowitz, MD, PhD, from Case Western Reserve University, in Cleveland, Ohio. Then, it needs to be shown that certain persons reproducibly demonstrate high COX-2 expression in independent adenomas or cancers, because of genetic predisposition or environmental exposures. And third, the work of Dr. Chan and colleagues needs to be extended by demonstrating that prevention of colon adenomas by aspirin or COX-2 inhibitors also involves blocking the development of the highest COX-2–expressing lesions, he says.

The editorial concludes that the findings of Dr. Chan and colleagues "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."

N Eng J Med 2007;356:2131-2142, 2195-2198.

Source: http://www.medscape.com/viewarticle/557150?src=mp