Genetic Testing Strategies in Newly Diagnosed Endometrial Cancer Patients Aimed at Reducing Morbidity or Mortality from Lynch Syndrome in the Index Case or Her Relatives

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Abstract

Endometrial cancer is the first malignancy in 50% of women with Lynch syndrome, an autosomal dominant cancer-prone syndrome caused by germline mutations in genes encoding components of the DNA mismatch repair (MMR) pathway. These women (2-4% of all those with endometrial cancer) are at risk of metachronous colorectal cancer and other Lynch syndrome-associated cancers, and their first-degree relatives are at 50% risk of Lynch syndrome. Testing all women newly diagnosed with endometrial cancer for Lynch syndrome may have clinical utility for the index case and her relatives by alerting them to the benefits of surveillance and preventive options, primarily for colorectal cancer. The strategy involves offering germline DNA mutation testing to those whose tumour shows loss-of-function of MMR protein(s) when analysed for microsatellite instability (MSI) and/or by immunohistochemisty (IHC). In endometrial tumours from unselected patients, MSI and IHC have a sensitivity of 80-100% and specificity of 60-80% for detecting a mutation in an MMR gene, though the number of suitable studies for determining clinical validity is small. The clinical validity of strategies to exclude those with false-positive tumour test results due to somatic hypermethylation of the MLH1 gene promoter has not been determined. Options include direct methylation testing, and excluding those over the age of 60 who have no concerning family history or clinical features. The clinical utility of Lynch syndrome testing for the index case depends on her age and the MMR gene mutated: the net benefit is lower for those diagnosed at older ages and with less-penetrant MSH6 mutations. To date, women with these features are the majority of those diagnosed through screening unselected endometrial cancer patients but the number of studies is small. Similarly, clinical utility to relatives of the index case is higher if the family’s mutation is in MLH1 or MSH2 than for MSH6 or PMS2. Gaps in current evidence include a need for large, prospective studies on unselected endometrial cancer patients, and for health-economic analysis based on appropriate assumptions.

Clinical scenario

Approximately 2-4% of endometrial cancer (10% in women diagnosed under the age of 50) is attributable to Lynch syndrome,^1,2,3,4 an autosomal dominant cancer-prone syndrome caused by germline mutations in the MLH1, MSH2, MSH6 or PMS2 genes, which encode components of the DNA mismatch repair (MMR) pathway, or, in a small proportion of cases, by deletions in the EPCAM gene that lead to epigenetic silencing of the adjacent MSH2 gene (reviewed in ⁵). Individuals with Lynch syndrome are at increased risk for cancers of the colon, rectum, endometrium, ovary, small bowel, urothelium, pancreas, biliary tract, stomach, brain, skin and possibly breast (reviewed in ⁶). In 50-60% of women with Lynch syndrome, endometrial cancer is the first malignancy.^7,8 Those who have already been diagnosed with cancer are also at risk of developing a Lynch-syndrome-associated cancer at another site, or a second primary cancer in the same organ.......

"..... The risks of non-colorectal cancers in women with Lynch syndrome who have had endometrial cancer are difficult to assess. Win et al. found increased 10- and 20-year cumulative risks for cancers of the urinary tract (kidney, renal pelvis or ureter) [2% (95% CI 0-5%) and 11% (95% CI 3-20%)], urinary bladder [1% (95% CI 0-4%) and 9% (95% CI 2-17%)] and breast [5% (95% CI 1-10%) and 11% (95% CI 4-19%)].⁹⁷ Increased risks were also observed for small intestine and pancreatic cancer, though numbers of cases were small and confidence intervals for SIRs very large. In studies on cumulative lifetime risks for Lynch syndrome-associated ovarian, stomach, small intestine and biliary tract cancers, estimates vary so widely that few conclusions can be drawn.^{44,46,48,49,50,51,52,53} For women, the most significant risks from these studies appear to be for ovarian cancer and, in some recent studies, breast cancer. (see Table 3 in the paper by Win et al. at http://jco.ascopubs.org/content/30/9/958/T3.expansion.html);¹⁰¹ however, a recent systematic review from the same research group found that current evidence at the population level for an increased risk of breast cancer in Lynch syndrome was inconclusive.....

"Although there are no surveillance interventions of proven benefit for non-colorectal Lynch syndrome cancers, urinalysis with cytology every 1-2 years beginning age 25-35 and upper gastrointestinal endoscopy every 1-2 years beginning age 30-35 are often recommended by physicians as surveillance regimes for upper urinary tract and stomach cancer respectively (reviewed in ⁶). In view of the recent evidence that breast cancer risk may be elevated in women with Lynch syndrome,^97,101 enhanced surveillance for breast cancer may also be warranted, though Win et al. comment that risk may not reach the threshold lifetime risk of 20% recommended by the American Cancer Society for breast screening by MRI.9 "