Genetics, Inheritance and Strategies for Prevention in Populations at High Risk of Colorectal Cancer (CRC)

Abstract

Hereditary forms of colorectal cancer account for less than 5 % of colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of carcinogenesis. Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of chemoprevention trials. There has been a longstanding interest in non-steroidal anti inflammatories in FAP where trials have shown regression of polyps with the “pro drug”sulindac and the selective COX2 inhibitors though impact on long-term cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design, aspirin and resistant starch or fermentable fibre. Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to short-chain fatty acids including butyrate which have anti-cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive aspirin (600 mg as 2 tablets/d) and/or 30 g as 2 sachets/d in a 1:1 blend of potato starch and high amylose maize starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months , the primary endpoint of a risk of an increased polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (aspirin; 95 % CI, 0.54–1.10;) and 1.05 (RS; 95 % CI, 0.73–1.49. The diameter of the largest polyp detected tended to be smaller in the aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest polyp in the aspirin versus non-aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009 Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600mg enteric coated aspirin and/or 30grams of the resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced development of colonic neoplasia. However, the design included double blind follow-up for at least 10 years. After a mean of 55.7 months, and despite regular colonoscopy and polyp removal, 48 recruits developed CRC. Of these, 18 received aspirin and 30 received AP; the HR for CRC for aspirin was 0.63 (CI 0.35–1.13, p = 0.12). Five of the 48 people who developed CRC each had two primary colon cancers. Poisson regression analysis to allow for multiple primary events indicated a protective effect: IRR 0.56 (CI 0.32–0.99, p = 0.05). For those who took aspirin (or AP) for a minimum of 2 years (per protocol) the HR was 0.41 (CI 0.19–0.86 p = 0.02) and the IRR, 0.37 (CI 0.18–0.78 p = 0.008). Combined analysis of all LS cancers including CRC revealed a similar effect. On intention to treat analysis, the HR was 0.65 (CI 0.42–1.00, p = 0.05 and IRR was 0.59 (CI 0.39–0.90 p = 0.01), while the Per Protocol analysis HR was 0.45 (CI 0.26–0.79 p = 0.005,) and IRR was 0.42 (CI 0.25–0.72, p = 0.001). Adverse events in the aspirin and placebo groups were similar with 11 significant gastrointestinal bleeds or ulcers in the aspirin group and 9 in the placebo group. The evidence is now sufficient to recommend aspirin to all Lynch syndrome gene carriers. CAPP3 will recruit 3000 gene carriers into a dose inferiority study to test the relative benefits of 100mg, 300 or 600mg daily doses.