David A. Drew, PhD
Director of Biobanking, Clinical & Translational Epidemiology Unit
Instructor of Medicine, Division of Gastroenterology
Massachusetts General Hospital and Harvard Medical School
Boston, MA, firstname.lastname@example.org
To date, cancer prevention has largely focused on early detection or chemoprevention to delay or intercept tumor development. Although we have enjoyed many notable successes with screening, there are barriers to implementation, associated harms, and inherent limitations to its efficacy. For chemoprevention, the field has largely rigorously tested putative agents through expensive randomized trials of generally unselected individuals. However, with the exception of aspirin, this “one-size-fits-all” approach has yielded few successes. These disappointing outcomes are likely due to incomplete information about how to appropriately tailor dose, duration, or timing of chemoprevention strategies to participants most likely to benefit. Somewhat surprisingly, “precision medicine” approaches, or the use of molecular biomarkers to optimize treatment regimens and predict therapeutic response, that have revolutionized the care of cancer patients has not yet been fully applied to cancer prevention. This largely owes to knowledge gaps regarding the biological mode of action of most preventive agents and as noted by Dr. Francis Collins, filling this gap is necessary to achieve the promise of “precision prevention.”
For aspirin, precision medicine approaches will be the key to advancing its use more broadly to prevent colorectal cancer. We have previously detailed the basis for a mechanistically-informed precision chemoprevention strategy (1) and potential biomarkers that are in need of further study to determine their suitability for tailoring personal recommendations. These biomarkers were primarily identified through molecular epidemiology methods, broadly including expression of circulating plasma inflammatory markers, transcriptional activity in colorectal mucosa, and levels of urinary metabolites that may stratify individuals according to risk for CRC, but also may predict chemopreventive benefit. Those biomarkers that are modifiable by aspirin use may act to inform precision prevention approaches by serving as surrogate measures of response or efficacy.
Perhaps the most promising biomarker identified so far is the major urinary metabolite of prostaglandin E2 known as PGE-M. Data has strongly supported the use of PGE-M as a marker for increased risk of numerous cancer types, including colorectal cancer, where elevated PGE-M is associated with increased risk. Moreover, prior studies have suggested that PGE-M may also be used to stratify individuals into those more likely to benefit from aspirin chemoprevention. The ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) double-blind, placebo-controlled trial (2) specifically aimed to test whether urinary PGE-M was modifiable by a short-term aspirin intervention (the trial is registered at https://clinicaltrials.gov/ct2/show/NCT02394769). The trial demonstrated that aspirin at 81 or 325 mg/day taken for 8 weeks significantly reduced elevated PGE-M levels in individuals with a recent history of colorectal adenoma, those at perceived higher risk for colorectal cancer, compared to those taking placebo (3). In secondary analyses, ASPIRED also demonstrated that aspirin was associated with a decrease in urinary PGE-M great enough to predict a reduction of 10% of future recurrent advanced adenomas in approximately half of the individuals randomized to aspirin based on previously reported risk thresholds. Similar results have recently been observed for a naproxen trial among Lynch patients that demonstrated significant decreases in PGE-M, mucosal levels of PGE2, and resultant activation of resident immune cell types and changed tissue expression patterns towards epithelial cell differentiation and stem cell regulation associated with naproxen intervention (4).
While these studies are an important step in supporting a central role for prostaglandin E2 inhibition in aspirin’s chemopreventive mechanism of action, the results also highlighted that while aspirin appears to benefit most individuals, for some individuals higher doses or longer durations of treatment may be required to meet risk reduction thresholds. Moreover, for a small fraction of individuals, the results also highlighted that aspirin may have very little effect on elevated urinary PGE-M and thereby may not benefit from an aspirin chemoprevention regimen. Nonetheless, this heterogeneous response across the population underscores the potential utility for PGE-M as a modifiable biomarker that could be used to guide personal recommendations and potentially inform clinical decision making. In light of the U.S. Preventive Services Task Force recommendation (5) that aspirin may be recommended to individuals aged 50-59 years old in context of cardiovascular disease risk (at least 10% increased risk) and life expectancy (at least 10 years), physicians may consider timing a discussion of use of aspirin for primary prevention to coincide with an individual’s first screening colonoscopy (currently recommended between age 45 and 50) which could be further informed by urinary PGE-M measures. In this model, assuming individuals are under the age of 60, after consideration of cardiovascular disease risk factors, life expectancy, and risk for bleeding events, providers may recommend aspirin directly. For other individuals, i.e. those over the age of 60 or without significant cardiovascular disease risk, providers may want to consider colorectal cancer risk factors including the presence of adenomas and baseline levels of biomarkers for colorectal cancer risk. Using PGE-M as an example marker given ASPIRED’s findings, physicians might assess baseline PGE-M, prescribe a short-term, low-dose aspirin intervention (2-3 months) and reassess urinary PGE-M levels while monitoring for potential harms to observe a response before continuing with an aspirin regimen. After assessing for toxicities and response, providers might adjust dose or duration of intervention in those that seem to tolerate aspirin well with periodic assessment of PGE-M to inform strategies that maximize individual preventive benefit without increasing harms. Future studies, including planned secondary endpoints of the ASPIRED trial may further identify modifiable biomarkers that may advance precision prevention. For example, aspirin appears to more potently inhibit colorectal cancers in individuals with higher levels of circulating inflammatory biomarkers, plasma macrophage inhibitory cytokine-1 (MIC-1; also known as growth differentiation factor-15 / GDF-15) and soluble tumor necrosis factor receptor 2 (sTNFR2) (1).
In summary, by building on the strong foundation of evidence and acceptance of aspirin as an effective chemopreventive agent, future research is poised to pivot from further establishing an overall preventative benefit towards the identification of personal characteristics, including biomarkers, to better tailor prevention strategies.
- Drew DA, Cao Y, Chan AT. Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer. 2016;16(3):173-86.
- Drew DA, Chin SM, Gilpin KK, Parziale M, Pond E, Schuck MM, et al. ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial. Trials. 2017;18(1):50.
- Drew DA, Schuck MM, Magicheva-Gupta MV, Stewart KO, Gilpin KK, Miller P, et al. Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial. Cancer Prev Res (Phila). 2020;13(10):877-88.
- Reyes-Uribe L, Wu W, Gelincik O, Bommi PV, Francisco-Cruz A, Solis LM, et al. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Gut. 2020.
- Bibbins-Domingo K, Force USPST. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164(12):836-45.
Dr. Drew is a translational researcher who focuses on the molecular mechanisms that are responsible for aspirin’s anti-cancer effects for colorectal cancer and their extension to precision chemoprevention. He received a Ph.D. in Biomedical Science from the University of Connecticut Health Center and a B.S. in Biochemistry/Biophysics.