Major Genetic Syndromes
The EGAPP analysis made several assumptions, including (1) IHC and MSI will not detect all LS patients and (2) not all patients with CRC will opt for testing.
Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify LS among persons with newly diagnosed CRC. The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline mutation testing followed by directed screening and risk-reducing surgery. Similar to the EGAPP working group, IHC followed by BRAF mutation testing was the preferred strategy in this study. An incremental cost-effectiveness ratio of $36,200 per life year gained resulted from this strategy. In this model, the number of relatives tested (3 to 4) per proband was a critical determinant of both effectiveness and cost-effectiveness.
A different approach based on risk assessments of 100,000 simulated individuals representative of the U.S. population who were tracked from age 20 and exposed to 20 different screening strategies has been reported. In this study, the strategies involved risk assessment at different ages utilizing the PREMM126 model followed by mutation analysis for MLH1, MSH2, MSH6, and PMS2 in individuals whose mutation risk threshold exceeded 0%, 2.5%, 5%, or 10%. In individuals whose risk assessment (starting at age 25, 30, or 35) for carrying a mutation exceeded 5%, colorectal and endometrial cancers in mutation carriers were reduced by 12.4% and 8.8%, respectively. In the whole population, this strategy increased the quality adjusted life-years by 135 years per 100,000 individuals with an average cost-effectiveness ratio of $26,000. The authors suggested that the outlined strategy was more cost effective than current practice and could improve health care outcomes.
Several aspects of the biologic behavior of LS suggest how the approach to surveillance should differ from that for average-risk people:
- CRCs in LS occur earlier in life than do sporadic cancers. For MLH1 and MSH2 mutation carriers, the estimated risks of CRC at age 40 years are 31% and 32% for females and males, respectively, and at age 50 years, the estimated risks are 52% and 57%, respectively. This suggests that screening should begin earlier in life.
- A larger proportion of LS CRCs (60%-70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon. Annual colonoscopic surveillance is recommended.
- The progression from normal mucosa to adenoma to cancer is accelerated,[287,288] suggesting that screening should be done at shorter intervals (every 1-2 years) and with colonoscopy.[288,289] Because patients with LS have an ordinary, or slightly increased, frequency of polyps but a substantially increased rate of cancer, it is clear that a larger proportion of polyps progress to cancer. It has been demonstrated that MMR gene mutation carriers develop adenomas at an earlier age than noncarriers. The mean age at diagnosis of adenoma in carriers was 43.3 years (range, 23-63.2 years), and the mean age at diagnosis of carcinoma was 45.8 years (range, 25.2-57.6 years).
- Incidence of CRC through life is substantially higher, suggesting that the most sensitive test available should be used.
- Patients with LS are at an increased risk of other cancers, especially those of the endometrium and ovary. The cumulative risk of extracolonic cancer has been estimated to be 20% by age 70 years in 1,018 women in 86 families, compared with 3% in the general population. There is some evidence that the rate of individual cancers varies from kindred to kindred.[215,290,291] Expert consensus suggests consideration of endometrial cancer screening by age 25 years.