New Insight Into Aspirin for Colorectal Cancer Prevention

Long-term aspirin use significantly lowered the risk of developing colorectal cancer (CRC) in Lynch syndrome carriers while ameliorating the added risk associated with obesity. These conclusions come from a new analysis from the CAPP2 trial published in the Journal of Clinical Oncology.¹

Further, the U.S. Preventive Services Task Force (USPSTF) issued a draft guideline today that would recommend the use of low-dose aspirin for the prevention of cardiovascular disease and CRC in certain individuals deemed to be at greater risk.² If it becomes a final recommendation statement, the USPSTF would be reversing their previous decision against the use of aspirin for CRC prevention.

In obese Lynch syndrome carriers, the risk of developing CRC was 134 percent higher compared with a reference group of normal and underweight participants. In the placebo arm, the risk of developing CRC increased by 175 percent when body mass index (BMI) was greater than 30 kg/m². However, in the aspirin arm, the increase CRC risk associated with obesity was not statistically significant.

“This is important for people with Lynch syndrome but affects the rest of us, too. Lots of people struggle with their weight and this suggests the extra cancer risk can be cancelled by taking an aspirin," says co-author John Burn, professor of Clinical Genetics at Newcastle University, who led the international research collaboration. “But, if there is a strong family history of cancer, then people may want to weigh up the cost-benefits particularly as these days drugs which block acid production in the stomach are available over the counter."

In the CAPP2 trial, Lynch syndrome carriers were randomized to aspirin at 600 mg per day or an aspirin placebo. Within these groups, patients also received resistant starch at 30 grams per day or a starch placebo. Individuals in the study had a history of a cured Lynch syndrome-related neoplasm and had an intact colon. The primary endpoint of the study was the development of CRC.

The mean duration of treatment was 25 months and the mean follow-up was 55.7 months. BMI was recorded according to WHO criteria, which defines underweight at less than 18.5, normal weight as 18.5 to 24.99, overweight as 25 to 29.99, and obese as ≥30 kg/m². In the analysis, those who were underweight (14 patients) were combined with normal weight individuals (418 patients) to create a reference group.

Among those with evaluable BMI (719 patients), 117 developed colorectal adenoma during the treatment phase of the trial. After adjusting for age, sex, aspirin use, and other factors, there was a nonsignificant increase in the risk of developing a colorectal adenoma in obese individuals compared with the reference group. This trend was observed across those with MLH1 and MSH2 mutations.

Across all individuals enrolled in the CAPP2 study, 55 developed CRC, with a trend toward a higher incidence in overweight individuals. When BMI was measured as a continuous variable, each 1 kg/m² gained increased the risk of developing CRC by 7 percent.

For those with the MLH1 gene mutation, the risk of developing CRC was significantly higher in obese individuals. In individuals with the MSH2 mutation, obesity was not found to significantly impact the risk of developing CRC.

“This research adds to the growing body of evidence which links an increased inflammatory process to an increased risk of cancer. Obesity increases the inflammatory response," Burn says. "One explanation for our findings is that the aspirin may be suppressing that inflammation which opens up new avenues of research into the cause of cancer.”

According to earlier findings published in The Lancet,³ across the full population of the study there was a 37 percent reduction in the risk of developing CRC with aspirin. When taking several factors into consideration, the incidence rate ratio was 0.56.

Patients who took aspirin for at least two years experienced a more dramatic reduction in CRC risk (258 patients). In these patients, there was a 59 percent reduction in risk and an incidence rate ratio of 0.37 compared with placebo (250 patients).

“The lesson for all of us is that everyone should try to maintain a healthy weight, and for those already obese, the best thing is to lose weight," lead author John C. Mathers, professor of Human Nutrition at Newcastle University, said in a statement. "However, for many patients this can be very difficult, so a simple aspirin may be able to help this group.”

Outside of Lynch syndrome carriers, evidence also supports the prophylactic use of aspirin for lowering CRC risk in a broader population. In a study with more than 20 years of follow-up that looked at aspirin use across 5,139 individuals,⁴ the overall reduction in risk was 26 percent. However, those who took aspirin for more than five years saw a 63 percent reduction in risk.

Subsequent studies found similar reductions in risk with aspirin at long-term follow-ups. In a pooled analysis of four clinical trials that assessed aspirin at varying doses compared with control, the absolute reduction in the risk of colon cancer was 24 percent at 20 years.⁵ In those who took aspirin for more than five years, there was a 65 percent reduction in the risk of colon cancer and a 42 percent reduction in the risk of rectal cancer.

Based on the growing body of long-term evidence demonstrating the benefits of aspirin for CRC prevention and risk reduction, the U.S. Preventive Services Task Force (USPSTF) issued a draft guideline today recommending the use of low-dose aspirin for certain individuals.² The current guideline recommends against the use of aspirin.

“Each person has only one decision to make — whether or not to take aspirin for prevention,” USPSTF member Douglas K. Owens, MD, MS, said in a statement. “To help individuals and their clinicians make this decision, the Task Force integrated the evidence about the use of aspirin to prevent cardiovascular disease and colorectal cancer into one recommendation on the use of aspirin.”

In the draft guideline, the USPSTF issued a Grade B recommended for low-dose aspirin in adults aged 50 to 59 years for prevention of CRC and cardiovascular disease in those with a 10-year risk of greater than 10 percent. The draft also includes a Grade C recommendation for aspirin in individuals aged 60 to 69 years.

A Grade B recommendation means “[t]here is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial,” according to the USPSTF website.Grade C status, however, means that the USPSTF recommends “selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small.”

This draft recommendation is open for public comment until October 12.

“Before anyone begins to take aspirin on a regular basis they should consult their doctor as aspirin is known to bring with it a risk of stomach complaints, including ulcers," Burn says. “We may be seeing a mechanism in humans whereby aspirin is encouraging genetically damaged stem cells to undergo programmed cell death, this would have an impact on cancer.”

References

1. Movahedi M, Bishop DT, Macrae F, et al. Obesity, Aspirin, and Risk of Colorectal Cancer in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2 Study [Published online ahead of print August 17, 2015]. J Clin Oncol. doi: 10.1200/JCO.2014.58.9952
2. Draft Recommendation Statement: Aspirin to Prevent Cardiovascular Disease and Cancer website http://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/aspirin-to-prevent-cardiovascular-disease-and-cancer. Updated September, 2015. Accessed September 15, 2015.
3. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.
4. Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007;369(9573):1603-1613.
5. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741-1750.