Aspirin for Lynch syndrome: a legacy of prevention
Authors: Matthew B Yurgelun, Andrew T Chan
Journal: The Lancet (2020)

Lynch syndrome—caused by pathogenic germline MLH1, MSH2, MSH2, PMS2, or EPCAM variants—is among the most common forms of inherited cancer susceptibility and predisposes to high risks of colorectal cancer, endometrial cancer, and other malignancies. Frequent colonoscopies confer a substantial mortality benefit in Lynch syndrome carriers but have inherent limitations.1Engel C Vasen HF Seppala T et al.No difference in colorectal cancer incidence or stage at detection by colonoscopy among 3 countries with different Lynch syndrome surveillance policies.Gastroenterology. 2018; 155: 1400-1409Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar Some Lynch syndrome-associated colorectal cancers bypass a precursor adenoma phase, thereby making such tumours impossible to prevent via colonoscopic polypectomy.2Ahadova A Gallon R Gebert J et al.Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.Int J Cancer. 2018; 143: 139-150Crossref PubMed Scopus (63) Google Scholar Thus, systemic management approaches such as chemoprevention are particularly appealing in Lynch syndrome. The first large-scale, genetically targeted chemoprevention trial in Lynch syndrome was the CAPP2 study of 861 individuals randomly assigned to aspirin (600 mg/day) versus placebo.3Burn J Bishop DT Mecklin JP et al.Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.N Engl J Med. 2008; 359: 2567-2578Crossref PubMed Scopus (221) Google Scholar After a mean of 25 months of treatment, the CAPP2 investigators initially reported in 2008 no significant difference in incident colorectal neoplasia (adenomas and colorectal cancers analysed in aggregate).3Burn J Bishop DT Mecklin JP et al.Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.N Engl J Med. 2008; 359: 2567-2578Crossref PubMed Scopus (221) Google Scholar However, a subsequent 2011 analysis4Burn 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: 2081-2087Summary Full Text Full Text PDF PubMed Scopus (693) Google Scholar done when the first CAPP2 participants reached 10 years of follow-up (mean follow-up 55·7 months) found those randomly assigned to aspirin to have significantly fewer incident colorectal cancers (hazard ratio [HR] 0·41; 95% CI 0·19–0·86) on per-protocol analysis (≥2 years aspirin), but the result was not significant in the intention-to-treat analysis. In The Lancet, John Burn and colleagues5Burn J Sheth H Elliott F et al.Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.Lancet. 2020; 395: 1855-1863Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar now report preplanned, updated analyses of CAPP2 with all participants having surpassed 10 years of follow-up, offering several key insights. First, a robust reduction in incident colorectal cancer was evident in Lynch syndrome carriers taking aspirin 600 mg/day (per-protocol analysis; HR 0·56; 95% 0·34–0·91), which, unlike the 2011 analysis,4Burn 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: 2081-2087Summary Full Text Full Text PDF PubMed Scopus (693) Google Scholar was also significant by intention-to-treat analysis (HR 0·65; 95% CI 0·43–0·97).5Burn J Sheth H Elliott F et al.Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.Lancet. 2020; 395: 1855-1863Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar Second, the benefit emerged 5 years after randomisation, consistent with a delayed effect of aspirin, as has been suggested in non-Lynch syndrome populations.6Drew DA Cao Y Chan AT Aspirin and colorectal cancer: the promise of precision chemoprevention.Nat Rev Cancer. 2016; 16: 173-186Crossref PubMed Scopus (233) Google Scholar Third, a powerful so-called legacy effect was identified,5Burn J Sheth H Elliott F et al.Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.Lancet. 2020; 395: 1855-1863Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar in that Lynch syndrome carriers taking daily aspirin for a finite duration (mean 25 months) had sustained reduction in colorectal cancer incidence persisting for 20 years. Finally, fewer incident endometrial cancers were reported among female Lynch syndrome carriers in the aspirin group (seven vs 17 cases in the placebo group; HR 0·50; 95% CI 0·22–1·11), but this was not statistically significant and therefore inconclusive. On the basis of these long-term results, should we routinely recommend 600 mg/day of aspirin for all Lynch syndrome carriers? Most clinical guidelines7Stjepanovic N Moreira L Carneiro F et al.Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 1558-1571Summary Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 8NCCNClinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: colorectal. Version 3.http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdfDate: 2019Date accessed: February 20, 2020Google Scholar recommend that aspirin be considered for Lynch syndrome carriers. These updated data, showing that only 24 Lynch syndrome carriers need to be treated with 600 mg/day aspirin to prevent one colorectal cancer, should strengthen such recommendations. Nonetheless, lingering uncertainties remain about the optimal dose, duration, and patient selection for Lynch syndrome-associated aspirin chemoprevention. Although major bleeding and other substantial adverse events were uncommon and no more frequent in participants randomly assigned to 600 mg/day aspirin versus placebo, CAPP2 participants were relatively young (mean age 45 years at randomisation).3Burn J Bishop DT Mecklin JP et al.Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.N Engl J Med. 2008; 359: 2567-2578Crossref PubMed Scopus (221) Google Scholar, 4Burn 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: 2081-2087Summary Full Text Full Text PDF PubMed Scopus (693) Google Scholar By contrast, the Aspirin in Reducing Events in the Elderly (ASPREE) trial9McNeil JJ Wolfe R Woods RL et al.Effect of aspirin on cardiovascular events and bleeding in the healthy elderly.N Engl J Med. 2018; 379: 1509-1518Crossref PubMed Scopus (425) Google Scholar examining aspirin 100 mg/day versus placebo in 19 114 healthy older adults (median age 74 years) showed significantly more aspirin-associated major bleeding events (HR 1·38; 95% CI 1·18–1·62) over 4·7 years of treatment. Moreover, aspirin was associated with a surprising increase in cancer-related deaths in ASPREE despite no increase in cancer incidence.10McNeil JJ Nelson MR Woods RL et al.Effect of aspirin on all-cause mortality in the healthy elderly.N Engl J Med. 2018; 379: 1519-1528Crossref PubMed Scopus (335) Google Scholar Whether this reflects a true difference in the biological effects of aspirin in older adults, including Lynch syndrome carriers, remains a crucial question.11Chan AT McNeil J Aspirin and cancer prevention in the elderly: where do we go from here?.Gastroenterology. 2019; 156: 534-538Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar The legacy effect identified in CAPP2 raises the intriguing possibility that there might be an optimal window in early adulthood for short-term aspirin exposure which maximises the benefit–risk profile. A previous subgroup analysis of CAPP212Movahedi 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.J Clin Oncol. 2015; 33: 3591-3597Crossref PubMed Scopus (68) Google Scholar also suggested that aspirin's chemopreventive benefits might be most pronounced in obese Lynch syndrome carriers. Lynch syndrome carriers who might obtain little benefit from aspirin might include those with similar low risks of incident colorectal cancer (eg, those with previous colectomy or pathogenic germline PMS2 variants). Such data coupled with growing understanding6Drew DA Cao Y Chan AT Aspirin and colorectal cancer: the promise of precision chemoprevention.Nat Rev Cancer. 2016; 16: 173-186Crossref PubMed Scopus (233) Google Scholar of the pharmacogenetics and molecular basis of aspirin's anticancer effects support the promise of precision prevention approaches to guide aspirin use in ways that maximise benefit–risk ratios in Lynch syndrome. We also eagerly await data from the CaPP3 trial of 1882 Lynch syndrome carriers, which will address the primary question about whether lower aspirin doses (100 mg/day and 300 mg/day) are non-inferior to 600 mg/day in reducing Lynch syndrome-associated colorectal cancer incidence. Until then, CAPP2 provides a compelling rationale for broader aspirin use in most Lynch syndrome carriers with dosing and duration tailored according to individual risks and benefits. MBY reports consulting and scientific advisory board fees from Janssen Pharmaceuticals for work that is unrelated to the CAPP2 study or the material discussed in this Comment. ATC reports consulting and scientific advisory board fees from Bayer Pharma AG, Pfizer, and Boehringer Ingelheim for work that is unrelated to the CAPP2 study or the material discussed in this Comment. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trialThe case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. Full-Text PDF Open Access