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New guidelines stress identifying Lynch syndrome




Clinicians and researchers must get better at identifying Lynch syndrome because the diagnosis is so often missed, according to new AGA clinical guidelines for diagnosing and managing the disorder, published in the September issue of Gastroenterology.

Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC), is the most common heritable cause of colorectal cancer and also is associated with cancers of the endometrium, stomach, small intestine, pancreas, biliary tract, ovary, urinary tract, and brain. Lynch syndrome accounts for 2%-3% of all colorectal cancers in the United States, and the estimated prevalence is 1 in 440 in the general population. People with the syndrome are estimated to have a lifetime cumulative incidence of colorectal cancer approaching 80%, and affected women have an estimated 60% lifetime cumulative incidence of endometrial cancer.

The new AGA guidelines focus on identifying Lynch syndrome, both in patients without cancer who have a family history suggestive of the disorder and in all patients who develop colorectal cancer, said Dr. Joel H. Rubenstein and his associates on the clinical guidelines committee (Gastroenterology 2015 Jul. 28 [doi: 10.1053/j.gastro.2015.07.036]).

The guidelines strongly recommend that all colorectal cancers now be tested using immunohistochemistry or assessment of microsatellite instability to identify potential cases of Lynch syndrome. Given the high incidence of colorectal cancer in the United States, this recommendation in particular “may be ripe for consideration as a process measure of quality of care,” they noted.

Until now, older patients with colorectal cancer have not undergone such testing because the yield of positive results was lower than in younger patients, but now there is new appreciation that these results have a significant impact on younger family members, not just the patients themselves. From the perspective of preventing cancer in these relatives, such testing is actually cost effective, said Dr. Rubenstein of the Veterans Affairs Center for Clinical Management Research and the gastroenterology division at the University of Michigan, both in Ann Arbor, and his associates.

At present, the evidence is insufficient to recommend either of these tests above the other for identifying Lynch syndrome. The two have comparable sensitivities and specificities.

The guidelines also recommend that, in people who have no personal history of colorectal or other cancer but who have a family history that suggests Lynch syndrome, risk prediction should be performed, “rather than doing nothing.” If a first-degree relative is known to have a Lynch mutation, people should be offered germline genetic testing for that mutation. Alternatively, “if tumor tissue from an affected relative is available, the screening process should begin with testing on that tumor.”

If none of this information is available, online risk prediction models or free downloadable software incorporating such models can be used to quickly and easily estimate the probability of carrying a Lynch syndrome mutation. This approach is “imperative” to improve case finding, since it is likely that most Lynch syndrome kindreds are undiagnosed, Dr. Rubenstein and his associates said.

Such patients should be offered risk-prediction models rather than proceeding directly to germline genetic testing because of the currently high costs of genetic testing. People without cancer who have a family history suggestive of Lynch syndrome should proceed straight to germline testing if they are considered to be at high risk – for example, if they meet the highly specific Amsterdam criteria.

The AGA guidelines strongly recommend that patients identified as having Lynch syndrome undergo surveillance colonoscopy, as opposed to no surveillance. Good-quality evidence shows that this strategy decreases the overall burden of colorectal cancer and reduces disease-specific mortality. People who carry Lynch syndrome genetic mutations increase their life expectancy by 7 years if they undergo surveillance colonoscopy, and cost-effectiveness analyses indicate that the expense of such screening is lower than the expense of no screening.

The optimal screening interval for such patients has not been determined, but low-quality evidence suggests that undergoing colonoscopy every 1-2 years is the “most prudent” course and is better than doing so at longer intervals.

The guidelines also include a conditional recommendation that people found to have Lynch syndrome should be offered aspirin therapy as cancer prophylaxis. The optimal dose and frequency of aspirin use is not yet known, and there is no evidence that the treatment improves mortality, but some low-quality evidence suggests that aspirin therapy reduces the risk of colorectal and other cancers, and the risk of adverse events is quite low.

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