BERLIN — The perseverance of researchers has led to the preliminary finding that aspirin helps prevent cancers in Lynch syndrome, a genetic condition that accounts for about 5% of all colon cancers.
A daily 600-mg dose of aspirin reduces the cancer burden in this high-risk group by about half, with the effect becoming apparent after about 3 years, Dr. John Burn said at a joint congress of the European Cancer Organization and European Society for Medical Oncology.
This preliminary finding is surprising, given that a report last year of the main trial results showed no difference in the number of colonic adenomas, after a mean of 29 months, between those taking aspirin and those taking 30 g of the resistant maize starch Novelose and placebo (N. Engl. J. Med. 2008;359:2567-78).
“The results were profoundly disappointing,” Dr. Burn said of the original trial. “There was absolutely no effect. If anything, the aspirin group had slightly more adenomas.”
The results were, however, in line with a series of randomized trials that have not found a convincing benefit with aspirin use. The difference with the current analysis is that follow-up extended up to 10 years after randomization, and it focused directly on cancers rather than on using adenomas as a surrogate for cancer prevention, said Dr. Burn, head of the Institute of Human Genetics at Newcastle University, Newcastle upon Tyne, England.
“We are working hard to fill in some of the missing data,” Dr. Burn said in an interview. “We can then begin to explore making treatment of Lynch syndrome a new official indication for aspirin.”
The follow-up analysis almost didn't happen: The original negative results dashed two attempts to secure funding for it, the study manager retired, and the statistician went on maternity leave. Dr. Burn and his coinvestigators D. Timothy Bishop, Ph.D., of Leeds (England) University and John Mathers, Ph.D., of Newcastle University pressed on, buoyed by a systematic review of the original cardiovascular trials showing that regular use of at least 300 mg of aspirin reduced the incidence of colorectal cancer, but only after a latency of about 10 years (Lancet 2007;369:1603-13).
With the help of a visiting fellow, the team tracked down and analyzed 711 of the original 937 patients for whom follow-up extended beyond the end of the trial.
An analysis of the still-blinded data revealed 17 colorectal cancers in the aspirin group vs. 29 in the placebo group, Dr. Burn reported. The difference between the aspirin and placebo groups did not achieve statistical significance (P = .08), but did so when the two groups were compared at least 24 months after randomization (P = .03). Six patients among a small group randomized to the starch limb also developed colorectal cancers.
The number of endometrial cancers was significantly reduced, with only 5 occurring in the aspirin group and 13 in the placebo group (P = .05). There was no impact of aspirin on breast (seven vs. five cases), ovarian (five vs. three), or pancreatic (two vs. two) cancers.
The benefit of aspirin was most obvious in those who used it for more than 2 years, and was seen about 3 years after randomization when most or all patients would have discontinued their aspirin, Dr. Burn said. “The effect takes 3 years to begin, but persists for 5 more years,” he said at a press briefing held during the meeting.
Surprisingly, the study did not demonstrate an effect of aspirin on adenoma formation, despite the decrease in cancers. Of the 100 participants with adenomas who were identified during long-term follow-up, 48% were in the aspirin group and 52% were in the placebo group.
Dr. Burn said that these data are still preliminary, and hypothesized that salicylate could induce apoptosis in aberrant stem cells, much as it does in plants as a defense against infection. Thus, adenomas may still form in patients on aspirin, but the reduced number of aberrant stem cells makes them less likely to progress to cancer.
The regular use of aspirin reduced cardiovascular events, but did not significantly increase bleeding events. This is likely because the cohort was relatively young (mean age, 45 years), said Dr. Burn, who noted that 600 mg is actually a subanalgesic dose.
The investigators are keen to initiate a large-scale, dose-inferiority study to determine if similar levels of protection can be achieved with a lower dose.
“We need large-scale international collaboration, but it can be done,” Dr. Burn said. “If we can reduce the hereditary cancer burden with an over-the-counter cheap drug, the long-term benefits will be wonderful.”