Aspirin for Cancer Prevention: One Step Closer

In this issue of JAMAOncology, Cao et al1 present an analysis ofaspirinuse for cancerprevention in lightof the recentUSPreventive Services Task Force (USPSTF) draft recommendation2 regarding the use of aspirin for prevention of colorectal cancer (CRC) in individuals at risk for cardiovascular disease. The USPSTF does not recommend aspirin use for the sole purpose of CRC prevention, but rather acknowledges an additional benefit of aspirin use among a group of individuals who are already likely to benefit from aspirin for the preventionof cardiovascular events.Advancing theuseof aspirin as a truecancer chemopreventiveagentwould typically requireadditional data fromdedicated randomized clinical trials regarding theabilityofaspirin toprotectagainst cancerswith thedefinition of an effective dose, the frequency and duration of treatment, and theclinicalpopulationat risk. Inaddition, aswe haveseenwiththeUSFoodandDrugAdministration’spriorconsideration of other agents for possible CRC and polyp prevention effects, the impact of such agents in the context of establishedandeffective screeningmodalities, suchas colonoscopy with polypectomy, is also important. Cao and colleagues1 attempt to address several important issuesusing2of the largest andbest-characterizedcohorts, the Nurses’ Health Study and theHealth Professionals Follow-up Study. The strengths of these cohorts include their size; the length and completeness of follow-up; the availability of reasonable, albeit self-reported,dataonaspirinuse,dose, andduration; and their thorough ascertainment of cancer incidence. In addition, the cohorts are broadly representative of the US general population in terms of prevalence of risk factors and screening rates. The investigative team iswell versed in the issues surrounding the use of aspirin as a potential preventive agent in the general population andhas experience in performing careful observational evaluations of aspirin’s effects on cancer risk.3 Their findings are generally consistent with earlier reported preventive effects of aspirin on gastrointestinal (GI) tract cancers.4 In the combined cohort analysis, regular aspirin users experienced a statistically significant 15% reduction in the risk for all GI tract cancers, with a significant 19% reduction in the risk for CRC and a nonsignificant 15% reduction in the risk for gastroesophageal cancer. They also demonstrate that protection against GI tract cancers occurs at relatively low doses (0.5-1.5 standard tablets per week) that were used for various other reasons (eg, cardioprotection, headache, arthritis, musculoskeletal pain), with greater risk reduction seen at increasing doses and with longer duration of use and 6 years suggested as the minimum duration of use needed to realize cancerprotective benefits. The associations seen with GI tract cancers and CRC were not modified by any of the numerous lifestyle and clinical variables examined. A small but statistically significant 3% reduction in overall cancer incidence (relative risk, 0.97; 95% CI, 0.94-0.99) was also seen among regular aspirin users, although this reduction is largely driven by the lower incidence of GI tract cancers within this group. Regular aspirin use was not associated with a reduced risk for breast, advanced prostate, or lung cancers in these analyses. Despite these careful analyses, perhaps the most important andunique contributions of this study1 are the team’s assessmentof aspirin’s potential population-wide impact and its absolute benefits in the context of screening. They calculated the proportion of incident cancers that could have been prevented with regular aspirin use, or the partial populationattributable risk, and found that 8.0% of all GI tract cancers and 10.8%ofCRCs couldhavebeenpreventedwith regular aspirin use. In addition, their findings suggest that regular aspirin use could have prevented 33 CRCs per 100000 personyears (17.0% of CRCs) among those who did not have lower endoscopy, and another 18 CRCs per 100000 person-years (8.5%) could have beenprevented among thosewhodid have lower endoscopy. This finding is important because it suggests that aspirinusemaycomplementCRCscreeningandmay haveanabsolutebenefit regardlessofendoscopystatus, a critical insight that few other studies have provided thus far. As the authors note, CRC screening rates remain suboptimal in theUnited States and, according to their calculations, regular aspirin use could prevent 9800 CRCs among the nearly 30 million age-eligible individuals who remain unscreened.1 Given the rising rates of CRC in low-resource settings where screening with endoscopy is often not feasible, the findings suggest that aspirin may serve as a relatively low-cost primary prevention modality to complement the wellestablished but underused preventive benefits of CRC screening with polypectomy. Although the analysis by Cao and colleagues1 provides more context to the use of aspirin as a CRC-preventive agent, the studyprovidesnoassessmentof thepotential harmsof aspirin in these cohorts and does not assess the full range of aspirin’s benefits beyond its cancer-preventive effects. Moreover, aspirin’s long-term effects, if any, on cancer and overall mortality are not addressed, although earlier observational studies suggest inverse associationswith cancer-specific and all-cause mortality.3,5,6 To reflect accurately the often complex, real-world clinical scenarios inwhichphysicians andpatients contemplate the use of aspirin, any truly informative analysis of its usemust weigh its cumulative benefits against its cumulative risks. Few studies are capable of such an assessment, but 2 ongoing randomized clinical trials of aspirin Related article page 762 Research Original Investigation Effect of Long-term Use of Aspirin on the Risk for Cancer