Study: Daily high-dose aspirin taken for at least 2 years reduces the risk of colorectal cancer but not other cancers in people with Lynch syndrome

IN-DEPTH REVIEW OF RESEARCH

Study background

Lynch syndrome is a hereditary cancer syndrome that is caused by an inherited mutation in one of five genes: MLH1, MSH2, MSH6, PMS2 or EPCAM.  People with Lynch syndrome are at increased risk of colon and other cancers, especially endometrial cancer.

Many studies have consistently shown a link between daily aspirin use and reduced cancer risk, especially the risk for colorectal cancer. In fact, the United States Preventive Services Task Force recommends daily low-dose aspirin to help prevent colorectal cancer in adults who are age 50 to 59 years with a 10% or greater risk of cardiovascular disease in 10 years.

Daily aspirin use has also been linked to reduced colorectal and ovarian cancers in some people who do not have Lynch syndrome (see our XRAY review). While daily aspirin use has been studied as a preventive measure against the onset of cancers such as prostate, ovarian, endometrial, and breast cancers, the findings do not consistently show that aspirin protects against these cancer types.

The CAPP2 trial was the first large-scale trial involving patients with Lynch syndrome to test a drug that may reduce cancer risk. Participants were randomly assigned to receive 600 mg/day of aspirin or a placebo for at least two years (some took aspirin for up to 4 years, the average participant to aspirin for 25 months). Two years after participants stopped taking aspirin or placebo, no significant difference was found in the rate of colorectal cancer between the two groups. When the first participants reached their 10-year follow-up, the researchers found that those who were assigned to the aspirin group had significantly fewer colon and other Lynch syndrome-related cancers.

The results presented here reflect the 10-year follow-up milestone for all participants, and some patients reached a 20-year follow-up.

Researchers of this study wanted to know:

Researchers wanted to know whether daily aspirin can be used to reduce cancer risk among patients with Lynch syndrome. This latest analysis allowed researchers to test the long-term effects of taking regular aspirin among patients in this population.

Populations looked at in this study:

All participants had Lynch syndrome.  At the time of enrollment, the mean age of participants was 45 years. Most participants were from Europe (82%), while others were from Australia (13%) and Africa (4%); less than one percent were from the Americas.

Study design:

Between January 1999 and March 2005, 861 participants were randomly assigned to the aspirin group or the placebo group. The aspirin group consisted of 427 participants who received 600 mg of aspirin daily for two years while the placebo group consisted of 434 participants who received a sugar pill daily for two years. Researchers monitored for at least 10 years whether participants were diagnosed with cancer; some participants were monitored through national registries of some countries for up to 20 years.

Study findings:

• When the first participants reached their 10-year follow-up researchers found that those who took aspirin had substantial protection against colorectal cancer and other Lynch syndrome cancers. (The average follow-up time for all the participants at this time was almost 5 years.)
  • 30 (7%) people in the placebo group developed colorectal cancer compared to 18 (4.2%) people in the aspirin group.
  • 24 (5.5%) people in the placebo group developed other (non-colorectal) Lynch syndrome cancers compared to 16 (3.7%) people in the aspirin group. Of these:
    • 13 women in the placebo group developed endometrial cancer compared to 5 in the aspirin group.
• When all participants reached their 10-year follow-up researchers found that those who took aspirin had substantial protection against colorectal cancer, confirming their earlier results.
  • 58 (13%) people in the placebo group developed colorectal cancer compared to 40 (9%) people in the aspirin group.
  • While earlier results showed protection by aspirin for some non-colorectal Lynch syndrome cancers this finding was not statistically significant in the final analysis.
    • 36 (8.3%) people in the placebo group and 36 (8.5%) people in the aspirin group developed other (non-colorectal) Lynch syndrome cancers. Of these:
      • 17 women in the placebo group developed endometrial cancer compared to 7 women in the aspirin group but this was not statistically significant.

Lynch syndrome patients who took a daily aspirin for up to four years had fewer cases of colorectal cancer. 
 

Strengths and Limitations

Strengths:

• This was a large study with long-term follow-up of participants.
• The long-term follow-up supports that aspirin likely decreases the risk of colorectal cancer.

Limitations:

• This was an international study, which made it difficult to collect frequent colonoscopy data on all participants.
• Aspirin is a widely available, over-the-counter medication. Participants may have chosen to continue aspirin (or take aspirin, in the case of people in the placebo arm) without the knowledge of the study researchers. This was not reported.
• This study had participants taking aspirin for two years. A longer period of aspirin use may show different results.
• Future studies are needed to identify the best dose of aspirin and how long it should be taken to provide the highest level of risk reduction for colorectal cancer among patients with Lynch syndrome.
• The age of the patients were relatively young (45 years on average). Older patients may have different side effects (example, stomach ulcers and gastrointestinal bleeding).
• The researchers were not able to comment on how aspirin affects mortality in patients with Lynch syndrome. This requires a much larger study.
• The specific Lynch syndrome gene mutations of the participants were not known. It is also unknown whether people with certain gene mutations had different outcomes than all Lynch syndrome patients combined.
• Because study participants were mostly Caucasian, these results may not apply to other racial groups.

Context

In 1998 researchers of a colorectal case-control study reported that aspirin may have a protective effect. Since then, over 100 studies have confirmed that aspirin can reduce cancer risk. The large Women’s Health Study (WHS) showed no effect of aspirin on cancer at 10 years but concluded that at 18 years participants who were randomly assigned to receive aspirin had significantly lower rates of colon cancer.

The CAPP2 study results are similar. It also showed that the preventive effect of aspirin, particularly on the risk of colon cancer, is delayed and continues for up to 10 years in patients with Lynch syndrome. The ongoing Cancer Prevention Project 3 (CaPP3) trial will compare three different doses of aspirin to find the dose that most effectively reduces cancer risk in people with Lynch syndrome. 

While aspirin has been linked to reduced risk of cancers, such as breast, prostate and colorectal cancers, the evidence for a similar reduction of endometrial cancer risk is conflicting. Whether an association exists remains unclear. A recent meta-analysis of the literature suggests that aspirin is associated with a reduced risk of endometrial cancer, and the reduced risk is closely linked to the frequency of use. Further randomized controlled trials are needed to confirm these findings.

Conclusions

The results of the CAPP2 study support the recommendation that adults with Lynch syndrome take up to 600 mg of aspirin daily for at least two years to reduce their risk of colorectal cancer. It is important to understand that the benefit of aspirin may not be apparent for several years after treatment. This is called a legacy effect.

While it is currently unknown exactly how aspirin works to prevent cancer, these results support other studies that indicate the benefit of aspirin in cancer prevention. You can see our review of another study of how cancer risk factors such as obesity, smoking, physical inactivity or a family history of cancer can modify the risk-reducing benefits of daily aspirin here.

Share your thoughts on this XRAYS article by taking our brief survey.
posted 5/17/21