Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial

Abstract

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE₂, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8-12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (-4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; P = 0.018) or 325 mg/day (-28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

Figure 1.

ASPIRED recruitment and participant enrollment overview (CONSORT Diagram).

Figure 2.

Percent change in urinary PGE-M in individual ASPIRED participants according to treatment assignment in context of risk thresholds for advanced adenoma. Data from the Nurses’ Health Study (Bezawada et al.; Reference 8) suggested that individuals with the highest quartile (Q) of PGE-M at baseline (Q4, median = 9.44 ng/mg cr) were at significantly increased risk for developing advanced adenomas compared to those in lower quartiles (Q3, median = 6.28 ng/mg cr). Thus, a reduction of 33.5% based on these previously reported values may be consistent with reduced risk for advanced adenoma. The dashed line and shaded area represent the minimum threshold for change (−33.5%) at which individuals might expect a decrease in risk for recurrent neoplasia. Each green bar represents an individual’s percent change in PGE-M from baseline (left y-axis). Individual pre- and post-treatment PGE-M in ng/mg Cr appears as the red and blue trace lines, respectively (right y-axis). Aspirin intervention with 81 or 325 mg/day significantly reduced individual PGE-M levels below this threshold in a greater proportion of participants (green bars contained within gray box), 23 of 57 (40.4%) and 27 of 54 (50.0%), respectively (both p < 0.001; χ2), compared to 7 of 58 (12.0%) of those randomized to placebo.

Figure 3.

Absolute change in urinary PGE-M in individual ASPIRED participants according to treatment assignment in context of risk thresholds for recurrent advanced adenoma based on the Aspirin/Folate Polyp Prevention Study (AFPPS). The AFPPS clinical trial (Fedirko et al.; Reference 19) reported that individuals with urinary PGE-M levels below 5.34 ng/mg cr after 3 years of aspirin treatment were at significantly reduced risk of recurrent advanced adenoma compared to individuals above this threshold. Individuals are separated by treatment arm, ranked by post-treatment PGE-M level (red bar), and plotted with pre-treatment PGE-M levels (blue diamond). The dashed line and shaded area represent the minimum threshold for change (5.34 ng/mg cr) at which individuals might expect a decrease in risk for recurrent advanced neoplasia. Aspirin intervention with 81 or 325 mg/day significantly reduced PGE-M levels below this threshold in a greater proportion of individuals,14 of 57 (24.6%; p = 0.04, χ2) and 22 of 54 (40.7%; p = 0.0002, χ2), respectively, compared to 6 of 58 (10.3%) of those randomized to placebo. One individual in each of the aspirin treatment arms had abnormally high pre-treatment PGE-M levels (denoted by asterisk [*] in the figure). Pretreatment PGE-M values for these individuals equaled 113.7 and 98.5 ng/mg cr in the 81 mg/d and 325 mg/d arms, respectively.

Figure 4.

PGE₂ measurement in serum of ASPIRED participants. A) Spearman correlation of baseline urinary PGE-M (systemic) and serum PGE₂ (circulating) demonstrates measures are not well correlated. B) Aspirin intervention with 81 or 325 mg/day significantly reduces serum PGE₂ from baseline compared to placebo. Mann-Whitney test, **p<0.01; ***p <0.001; ns = not significant. C) The percent decrease in urinary PGE-M, is modestly correlated with the percent change in serum PGE₂ following aspirin intervention. Spearman r = 0.40; one-tailed p-value = 0.035.