Universal Screening for Endometrial Cancer

A. Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66:7810-7817. [Abstract See letter Cancer Res 2007;67:9603. [Abstract]

This study included universal screening of 543 endometrial cancer patients for Lynch syndrome using MSI followed by genetic testing. Most of the patients also received IHC screening. Results were that 2.5% (1 out of every 40 cases) of all newly diagnosed endometrial cancer patients have Lynch syndrome. Confidence intervals overlapped with the 2.8% incidence of Lynch syndrome among all newly diagnosed colorectal cancer patients in the same Columbus, Ohio population. 69% of those diagnosed with Lynch syndrome would have been missed if an age cut-off of 50 was used and if only patients who met Amsterdam or Bethesda criteria had been tested. The majority of mutations found were in MSH6.

B. Resnick K, Straughn JM Jr, Backes F, et al. Lynch syndrome screening strategies among newly diagnosed endometrial patients. Obstet Gynecol. 2009;114:530-536. [Abstract]

This study used the data from the Columbus-area HNPCC study to advocate for screening all newly diagnosed endometrial cancer patients diagnosed under age 60. Using a hypothetical cohort of 40,000 patients with newly diagnosed endometrial cancer to serve as the basis for the decision analysis, authors compared four LS screening strategies for women diagnosed with endometrial cancer to determine the most cost effective method. The four screening strategies were evaluated as follows: 1) Amsterdam criteria strategy: full gene sequencing for women with endometrial cancer who meet revised Amsterdam criteria; 2) Sequence all strategy: full gene sequencing for all women with endometrial cancer; 3) Sequence aged younger than 60 years strategy: full gene sequencing for women aged less than 60 with endometrial cancer, and 4) IHC/single gene strategy: IHC for all women with endometrial cancer after single gene sequencing (based on the lack of protein expression at IHC). Cost-effectiveness ratios, defined as the cost to detect one case of LS, were calculated for each strategy. Incremental cost-effectiveness ratio, defined as the cost to detect one additional case of LS, was also estimated for each strategy.

The sequence-all strategy resulted in the highest (least favorable) cost-effectiveness ratio. The Amsterdam criteria strategy was the least expensive but detected the fewest patients with LS. The IHC/single gene strategy had the lowest cost-effectiveness ratio. The sequence aged younger than 60 years strategy was less effective and more costly than the others, and was not recommended as a screening strategy. This study determined that the combination of IHC followed by directed genetic testing was the most efficacious and cost-effective strategy on a societal level to identify patients with LS. Results from this decision analysis suggested that age alone was not an effective way to screen for LS.

C. Kwon JS, Scott JL, Gilks B, et al. Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol. 2011;29:2247-2252. [Abstract]

In this study, authors developed a Markov Monte Carlo simulation model to compare the costs and benefits of six different LS testing criteria for a hypothetical cohort of women diagnosed with endometrial cancer in the general population. The six testing strategies included two criteria for direct referral for genetic counseling and four criteria for IHC triage followed by referral for genetic counseling and testing if the IHC results were abnormal. Criteria for direct referral for genetic counseling included: 1) Amsterdam II criteria, and 2) Endometrial cancer <50 years with at least 1 FDR having a Lynch-associated cancer at any age. Criteria for IHC triage included: 1) Endometrial cancer <50 years; 2) Endometrial cancer <60 years; 3) Endometrial cancer at any age with at least 1 FDR having a Lynch-associated cancer at any age, and 4) All endometrial cancers, any age. To determine cost-effectiveness for each of the six strategies, the incremental cost-effectiveness ratio (ICER), defined as the additional cost of a specific strategy divided by its health benefit (life expectancy) compared with an alternate strategy, was calculated and compared.

Analysis indicated that the most cost-effective strategy for detecting LS was IHC triage of all women with endometrial cancer with at least 1 FDR having a Lynch-associated cancer at any age, as long as IHC sensitivity was at least 70%. That strategy had an ICER of $9,126 per year of life gained relative to the least costly testing strategy (genetic testing for all women <50 years with at least 1 FDR having a Lynch-associated cancer at any age). That strategy would subject fewer cases to IHC but identify more mutation carriers than age thresholds of 50 or 60 years. Authors noted that IHC testing of all endometrial cancers regardless of age would identify the highest number of mutation carriers but would not be cost effective.

D. Zighelboim I, Goodfellow P, Gao F, Gibb RK, et al. Microsatellite Instability and epigenetic inactivation of MLH1 and outcome in patients with endometrial carcinomas of the endometrioid type. J Clin Oncol. 2007;25:2042-2048. [Abstract]

In this study conducted out of the University of Washington between 1991 and 2005, 446 endometrioid endometrial carcinomas were studied to determine whether MSI and MLH1 methylation status were associated with clinicopathologic variables and survival outcomes. MSI was identified in 147/446 (33%) of cases and was strongly associated with higher FIGO grade. MLH1 methylation analysis was successful for 138/147 of the MSI cases. Among the 138 cases analyzed, 102 (74%) were methylated and 36 (26%) were unmethylated. Results concluded that MSI and MLH1 methylation status was not associated with overall survival or disease-free survival. The analysis found that women with MSI/unmethylated tumors were, on average, diagnosed 10 years younger than women with MSI/methylated tumors; however, authors admitted that the analysis was underpowered to demonstrate whether MLH1 methylation status was due to inherited factors (seen with younger age of diagnosis) rather than epigenetic silencing. The authors concluded that MSI status lacks prognostic value in women with endometrioid endometrial carcinomas.

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