Aspirin Reduces CRC Incidence in Individuals at Greatest Risk

John Burn, MD

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, according to a new analysis from the CAPP2 trial published in the Journal of Clinical Oncology.¹

In obese Lynch syndrome carriers, the risk of developing CRC was 134% higher compared with a reference group of normal and underweight participants (HR, 2.34; 95% CI, 1.17-4.67; P = .02). In the placebo arm, the risk of developing CRC increased by 175% when BMI was >30 kg/m² (HR, 2.75; 95% CI, 1.12-6.57; P = .03). However, in the aspirin arm, the increase CRC risk associated with obesity was not statistically significant (HR, 2.00; 95% CI, 0.61-6.70).

“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," said co-author John Burn, MD, professor of Clinical Genetics at Newcastle University, who led the international research collaboration. "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.”

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 <18.5, normal weight as 18.5 to 24.99, overweight as 25 to 29.99, and obese as ≥30 kg/m². For the analysis, those who were underweight (n = 14) were combined with normal weight individuals (n = 418) to create a reference group.

In patients with evaluable BMI (n = 719), 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 (HR, 1.28; 95% CI, 0.77-2.12). 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 (HR, 1.09). When BMI was measured as a continuous variable, each 1 kg/m² gained increased the risk of developing CRC by 7%.

For those with the MLH1 gene mutation, the risk of developing CRC was significantly higher in obese individuals (HR, 3.72; 95% CI, 1.41-9.81; P = .008). In individuals with the MSH2 mutation, obesity was not found to significantly impact the risk of developing CRC (HR, 1.59; 95% CI, 0.47-5.44).

“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," Burn said. “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."

According to earlier findings published in The Lancet,² across the full population of the study there was a 37% reduction in the risk of developing CRC with aspirin (HR, 0.63; 95% CI, 0.35-1.13; P = .12). When taking several factors into consideration, the incidence rate ratio (IRR) was 0.56 (95% CI, 0.32-0.99; P = .05).

Patients who took aspirin for at least 2 years experienced a more dramatic reduction in CRC risk (n = 258). In these patients, there was a 59% reduction in risk (HR, 0.41; P = .02) and an IRR of 0.37 (P = .008) compared with placebo (n = 250).

“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, PhD, 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 5139 individuals,³ the overall reduction in risk was 26% (HR, 0.74, P = .02). However, those who took aspirin for more than 5 years saw a 63% reduction in risk (HR, 0.37; P = .002).

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% at 20 years (HR, 0.78; P = .02).⁴ In those who received aspirin for greater than 5 years, there was a 65% reduction in the risk of colon cancer (HR, 0.35; P <.0001) and a 42% reduction in the risk of rectal cancer (HR, 0.58; P = .01).

Based on the growing body of long-term evidence demonstrating the benefits of aspirin for CRC prevention and risk reduction, the US Preventive Services Task Force (USPSTF) has recently issued a draft guideline recommending the use of low-dose aspirin for certain individuals.⁵ 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%. The draft also includes a Grade C recommendation for aspirin in individuals aged 60 to 69 years. This draft recommendation is open for public comment until October 12, 2015.

“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 said. “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. 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. Lancet. 2011;378(9809):2081-2087.
3. 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.
4. 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.
5. 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.