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. 2011 May 2;29(16):2247–2252. doi: 10.1200/JCO.2010.32.9979

Testing Women With Endometrial Cancer to Detect Lynch Syndrome

Janice S Kwon 1,✉, Jenna L Scott 1, C Blake Gilks 1, Molly S Daniels 1, Charlotte C Sun 1, Karen H Lu 1
PMCID: PMC4874206  PMID: 21537049

Abstract

Purpose

Women with endometrial cancer as a result of Lynch syndrome may not be identified as such by Amsterdam II criteria. We estimated the costs and benefits of different testing criteria to identify Lynch syndrome in women with endometrial cancer.

Methods

We developed a Markov Monte Carlo simulation model to compare six criteria for Lynch syndrome testing for women with endometrial cancer: Amsterdam II criteria; age younger than 50 years with at least one first-degree relative having a Lynch-associated cancer at any age (FDR); immunohistochemistry (IHC) triage if age younger than 50 years; IHC triage if age younger than 60 years; IHC triage at any age if 1 FDR; and IHC triage of all endometrial cancers. Net health benefit was life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new colorectal cancers associated with each strategy.

Results

IHC triage of women with endometrial cancer having at least 1 FDR yielded a favorable ICER of $9,126 per year of life gained. This strategy would subject fewer cases to IHC but identify more mutation carriers than age thresholds of 50 or 60 years. IHC triage of all endometrial cancers could identify the most mutation carriers and prevent the most colorectal cancers but at considerable cost ($648,494 per year of life gained).

Conclusion

IHC triage of women with endometrial cancer at any age having at least 1 FDR with a Lynch-associated cancer is a cost-effective strategy for detecting Lynch syndrome.

INTRODUCTION

The lifetime risk of endometrial cancer among women with Lynch syndrome may be as high as 60%, and this risk may be greater than their lifetime risk of colorectal cancer.1 Endometrial cancer may be the sentinel cancer among women with Lynch syndrome, being diagnosed at an earlier age than colorectal cancer.2 Therefore, women with endometrial cancer represent an important subgroup for Lynch syndrome testing, because if a mutation is identified, they can undergo risk-reducing interventions for colorectal cancer, which may prolong their overall life expectancy.3,4 Furthermore, their family members can be tested for known mutations and have the opportunity to undergo risk-reducing interventions for both gynecologic and colorectal cancers.

Testing all women with endometrial cancer for Lynch syndrome has the potential to identify a significant number of mutation carriers, but this would incur substantial cost to the health care system, as endometrial cancer is the most common gynecologic cancer in North America and the fourth most common cancer among all women.5,6 In general, genetic testing for Lynch syndrome is encouraged in women with endometrial cancer if their family history fulfills Amsterdam II criteria.7–9 This guideline implies that they must have at least two other relatives with a Lynch syndrome-associated cancer (for a total of three affected individuals), within two successive generations, and one of them must have been diagnosed younger than the age of 50 years.10 However, not all women with Lynch syndrome will fulfill these criteria.11–16 Recognizing that a significant proportion of women with Lynch syndrome are diagnosed with endometrial cancer under the age of 50 and many of them will have at least one first-degree relative with a Lynch-associated cancer, it may be reasonable to include this specific subgroup of women when offering genetic services for Lynch syndrome.17–20 A more inclusive option is to test all women with endometrial cancer younger than the age of 50 or 60 years, regardless of family history, beginning with immunohistochemistry (IHC) triage, then referring those with abnormal results for genetic testing. In the absence of a direct comparison of these different testing criteria, we developed a cost-effectiveness analysis to compare the benefits and costs of each testing strategy.

METHODS

We developed a Markov Monte Carlo simulation model to estimate the costs and benefits of Lynch syndrome testing for a hypothetical cohort of women diagnosed with endometrial cancer in the general population. We compared six criteria for Lynch syndrome testing by determining the incremental cost-effectiveness ratio (ICER), defined as the additional cost of a specific strategy divided by its health benefit compared with an alternate strategy. The numerator of the ICER was the average lifetime cost in United States dollars (USD) in the year 2010, and the denominator was the average life expectancy gain in years. A strategy that was less effective (lower life expectancy gain) and more costly than an alternate strategy was considered strongly dominated. A strategy that was more costly but more effective than an alternate strategy was considered cost-effective if its ICER was below $50,000 per year of life gained, a commonly used willingness-to-pay threshold for cost-effectiveness analyses evaluating preventive health measures.21 In keeping with recommendations of the US Panel on Cost-Effectiveness in Health and Medicine, we adopted a societal perspective and discounted all costs and health benefits at a rate of 3% per year.22

In the model, we assumed that women with endometrial cancer were still at risk for colorectal cancer. They were comparable across testing strategies with respect to demographics, stage, and histologic type of endometrial cancer, and risk factors for colorectal cancer. For those who were directly referred for genetic counseling and testing, four mismatch repair genes would be sequenced (MLH1, MSH2, MSH6, PMS2). For those who underwent IHC triage, this would be performed on formalin-fixed, paraffin-embedded sections from hysterectomy specimens, and abnormal IHC results would prompt referral for genetic counseling and relevant DNA sequencing. For those who were confirmed mutation carriers, we assumed that they would undergo annual colonoscopy, as recommended by several consensus guidelines.8,9,23–25 For those who were confirmed noncarriers, approximately 50% would have at least one colonoscopy over the next 10 years, as expected in the US population.26,27 Risks of colorectal cancer and associated mortality rates were governed by mutation status and the presence or absence of screening, which were estimated from published literature. The proportion of all endometrial cancer cases diagnosed at younger than age 50 and 60 years were estimated from the Surveillance, Epidemiology, and End Results database of 12 geographic regions in the United States from 1988 to 2001.28 Health care costs were also estimated from a number of sources, including published literature on genetic counseling, IHC for mismatch repair proteins, gene sequencing, colonoscopy, and colorectal cancer treatment costs.29–36 Selected data are presented in Tables 1, 2 through 3.37–48

Table 1.

Lynch Syndrome Prevalence by Testing Strategy

Testing Strategy Proportion of All Endometrial Cancer Patients
 Prevalence of Lynch Syndrome
% Range % Range
Amsterdam II criteria 118,37 0-2.3 3018,37 21-39
Endometrial cancer younger than 50 years with at least 1 FDR 4*17,19,20 2.2-5.3 3517,19,20 23-43
Endometrial cancer younger than 50 years 1428 12-20 917–20 4.9-18
Endometrial cancer younger than 60 years 36.528 30-45 418,37 0.2-8
Endometrial cancer at any age with at least 1 FDR 1238 10-15 1738 15-20
All endometrial cancers, any age 100 217,18,38,39 1-3
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Abbreviation: FDR, first-degree relative with a Lynch-associated cancer at any age.

*

Approximately 16% to 38% of all women with endometrial cancer younger than 50 years have at least one FDR, and 14% of all endometrial cancers are diagnosed at younger than 50 years.

Table 2.

Probability Estimates

Subgroup Lifetime Risk of CRC
 5-Year Mortality From CRC
% Range % Range
Lynch syndrome, screened3,4,40,41,42 15 10-20 6 3-10
Lynch syndrome, unscreened41,43 40 30-50 47 35-60
Sporadic, screened44–46 3 2-4 15 10-20
Sporadic, unscreened47 5 4-6 37 20-50
Test Characteristic Sensitivity
 Specificity
% Range % Range
Amsterdam II criteria11–16,48 62 41-78 62 45-78
Immunohistochemistry17–19 92 80-100 70 60-83
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Abbreviations: CRC, colorectal cancer; Lynch syndrome, screened, women with endometrial cancer and Lynch syndrome who undergo annual colonoscopy; Sporadic, screened, women with sporadic endometrial cancer who have at least one colonoscopy over the next 10 years.

Table 3.

Cost Estimates

Item CPT Code Estimated Cost in US$ Range
Immunohistochemistry triage for four mismatch repair genes30,34 88342 540 400-700
Genetic counseling, initial consult30 96040 83 41-164
Genetic counseling, follow-up30 96040 41 20-83
Physician counseling for genetic testing and screening30 99203 100 40-200
DNA sequencing of each gene31,35 83890 1,200 600-1,800
Colonoscopy29 45378, HCPSC level II code G0105 950 382-979
Average total lifetime cost of colorectal cancer treatment29,33,36 35,000 30,000-40,000
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Abbreviations: CPT, Common Procedural Terminology (American Medical Association); HCPCS, Healthcare Common Procedure Coding System (Medicare).

Women with endometrial cancer comprise a hypothetical cohort residing in one of five Markov health states: well; at risk for colorectal cancer, colorectal cancer, unscreened; colorectal cancer, screened; dead. All of them begin in the at-risk for colorectal cancer health state. If they are diagnosed with colorectal cancer, they transition to the colorectal cancer state, depending on whether or not they underwent screening. In this health state, they may die of colorectal cancer or age-dependent mortalities according to United States life tables.49 If they are alive at the end of a 1-year cycle, they remain in that health state and are subject to cancer-related and competing mortalities. If they are alive 10 years after their colorectal cancer diagnosis, they transition to the well state where they are still subject to age-dependent mortality risks. The process continues in yearly cycles until all women in the cohort reach the dead state, because of cancer or other causes.

The model was programmed using TreeAge Pro 2009 (TreeAge Software, Williamstown, MA). Six criteria (ie, strategies) for Lynch syndrome testing were defined for women with endometrial cancer in the general population, including two criteria for direct referral for genetic counseling and testing, and four criteria for IHC triage of endometrial cancers, followed by referral for genetic counseling and testing if the IHC results were abnormal. Direct referral for genetic counseling and testing would be offered to women with endometrial cancer who fulfilled: Amsterdam II criteria; or diagnosis younger than age 50 with at least one first-degree relative having a Lynch syndrome-associated cancer at any age (1 FDR). IHC triage would be offered to women diagnosed with endometrial cancer who fulfilled one of the following: age younger than 50 years; age younger than 60 years; any age if 1 FDR; or any age, regardless of family history.

We performed one-way and two-way sensitivity analyses to account for uncertainty around various parameters, including the probability of identifying Lynch syndrome according to specific testing criteria, risks of colorectal cancer, mortality rates, compliance with colorectal cancer screening, and costs. We conducted a Monte Carlo simulation using tracker variables within a Markov model to estimate the number of women who would be identified as having Lynch syndrome, and the subsequent number of colorectal cancer cases expected with each testing strategy.

RESULTS

The average discounted costs, life expectancy, and incremental cost-effectiveness ratios (ICERs) are provided in Table 4. Life expectancy was highest with the most inclusive testing strategy (IHC triage of all women with endometrial cancer). However, the ICER associated with this strategy was unfavorable ($648,494 per year of life gained). Testing by Amsterdam II criteria, IHC triage younger than age 50, and IHC triage younger than age 60 were all strongly dominated by IHC triage at any age if there was at least 1 FDR. The latter strategy had an ICER of $9,126 per year of life gained relative to the least costly testing strategy (genetic testing for all women younger than age 50 with at least 1 FDR). Therefore, we would consider IHC triage of all women with endometrial cancer having at least 1 FDR with a Lynch-associated cancer at any age to be a cost-effective testing strategy for detecting Lynch syndrome.

Table 4.

Average Discounted Lifetime Costs, Life Expectancy, and ICERs

Testing Strategy Average Lifetime Cost (US$) Average Discounted Life Expectancy (years) ICER
Age < 50, at least 1 FDR 2,254 14.52708 —
IHC triage < age 50 2,255 14.52686 Dominated
IHC triage any age, at least 1 FDR 2,277 14.52971 $9,126
IHC triage < age 60 2,484 14.52792 Dominated
IHC triage all endometrial cancers 3,131 14.53077 $648,494
Amsterdam II criteria 4,045 14.52733 Dominated
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NOTE. Dominated strategies are more costly and less effective than an alternate (preceding) strategy.

Abbreviations: ICER, incremental cost-effectiveness ratios; FDR, first-degree relative with a Lynch-associated cancer at any age; IHC triage, immunohistochemistry triage, then referral for genetic testing if abnormal IHC results.

Our results were stable within a wide range of plausible costs and probability estimates. Even when compliance with genetic testing and colorectal cancer surveillance was estimated to be as low as 50%, the ICERs remained fairly stable. The sensitivity and specificity of Amsterdam II criteria both had to exceed 95% before this became a cost-effective testing strategy. If the sensitivity of IHC was lower than 70%, then IHC triage would no longer be cost-effective, and genetic testing for all women younger than age 50 with 1 FDR (without IHC triage) would be the most favorable testing strategy.

In the United States there will be approximately 45,000 women diagnosed with endometrial cancer in the year 2010.50 Our model predicts that 827 women (1.84%) would be identified as having Lynch syndrome if we triaged all of these cases with IHC. By applying IHC triage to those with endometrial cancer and at least 1 FDR, 755 carriers (1.68%) would be identified. If we applied Amsterdam II criteria to this cohort, only 539 carriers (1.2%) would be identified. IHC triage based on the diagnosis of endometrial cancer and 1 FDR would subject fewer cases to IHC but identify more mutation carriers than using age thresholds of 50 or 60 years. In general, the more mutation carriers identified, the lower the potential number of subsequent colorectal cancers, as seen in Table 5.

Table 5.

Monte Carlo Simulation of Women With Endometrial Cancer in the United States

Testing Strategy No. Cases Subject to IHC Triage No. Identified With Lynch Syndrome No. of Subsequent CRC Cases
Amsterdam II criteria NA 539 2,582
Age < 50, at least 1 FDR NA 530 2,470
IHC triage < age 50 6,285 520 2,442
IHC triage < age 60 16,226 548 2,450
IHC triage any age, at least 1 FDR 5,786 755 2,442
IHC triage all endometrial cancers 45,000 827 2,413
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Abbreviations: IHC triage, immunohistochemistry triage, then referral for genetic testing if abnormal IHC results; CRC, colorectal cancer; NA, not applicable, as women who fulfill these criteria are directly referred for genetic testing; FDR, first-degree relative with a Lynch-associated cancer at any age.

DISCUSSION

IHC triage of all women with endometrial cancer who have at least 1 FDR with a Lynch-associated cancer at any age is a cost-effective strategy for identifying those who should be referred for genetic testing. Amsterdam II criteria are still provided as guidelines for selecting individuals for Lynch syndrome testing,8,9 although it is well recognized that the sensitivity and specificity of these criteria are not high.9,16,51 This may be partly attributed to the fact that cancers in family members tend to be under-reported, even by individuals with personal histories of cancer.52,53 It has been suggested that those with personal histories of synchronous or metachronous Lynch-associated cancers, with the first diagnosed before age 50, should be referred for testing.54 However, the ideal scenario is that Lynch syndrome testing takes place before an individual is diagnosed with two cancers. The revised Bethesda criteria have a higher sensitivity than Amsterdam II criteria for detecting Lynch syndrome, but these are applicable only to those with a diagnosis of colorectal cancer.55 Testing all women with endometrial cancer younger than the age of 50 has been suggested as a potential strategy for identifying Lynch syndrome, as the estimated mutation prevalence in these women is approximately 9%.17,19 However, if the average age at diagnosis of endometrial cancer is 48,1 then almost 50% of women with Lynch syndrome are diagnosed with endometrial cancer after the age of 50. Furthermore, fewer than 20% of all endometrial cancers in the population are diagnosed at younger than age 50, and therefore this age threshold may be too restrictive in identifying potential carriers. Similarly, while the prevalence of Lynch syndrome is high in those with lower uterine segment cancers56 and those younger than age 50 with a normal body mass index,19 these subgroups are too small to identify a significant number of carriers at a population level.

Evidence of microsatellite instability (MSI) or abnormal IHC in one of the mismatch repair genes has been recommended as an indication for genetic testing,54 as these tests have been proven to be highly sensitive and specific in detecting Lynch syndrome, both in colorectal and endometrial cancers.15,17–19,57–62 We did not include MSI testing in our model because MSI and IHC have comparable sensitivities for detecting Lynch syndrome in endometrial cancer,17–19 and IHC can be done in any pathology lab whereas MSI requires a more sophisticated analysis including polymerase chain reaction for DNA amplification and electrophoresis, which may not be readily available at all centers. Regardless of methodology for triage, using age thresholds of 50 or 60 years will miss a significant proportion diagnosed with endometrial cancer after age 60, especially those with MSH6 mutations.18 While IHC testing of all endometrial cancers regardless of age would identify the highest number of mutation carriers, we did not find this strategy to be cost effective. Furthermore, IHC triage is not necessarily practical because it would require discussion and informed consent from all of these women about the implications of an abnormal result, even if only a small subgroup has abnormal IHC and is selected for genetic testing. If IHC triage were limited to those diagnosed with endometrial cancer younger than age 60, this would still represent almost 40% of all endometrial cancers in our population. However, IHC triage for those with 1 FDR having a Lynch-associated cancer would apply to only 10% to 15% of all patients with endometrial cancer, and fewer than 20% of these women would be referred for genetic testing.

The incremental benefit of IHC triage of all women with endometrial cancer having at least 1 FDR with a Lynch-associated cancer at any age is an average life expectancy gain of 1 day compared to Amsterdam II criteria. This is comparable to the life expectancy gain from triennial cervical cancer screening (compared to less frequent screening),63 which is the current recommendation by the American College of Obstetricians and Gynecologists for women older than age 30 in the general population.64 Because the benefit of testing is averaged across the entire target population, the average life expectancy gain is dependent on the proportion of individuals having the condition within that population. The less prevalent the condition (ie, only 2% of all women with endometrial cancer having Lynch syndrome), the lower the average life expectancy gain from testing. The average life expectancy gain may appear to be very low, but it is very significant for those individuals identified as having Lynch syndrome who might have died prematurely without undergoing surveillance for colorectal cancer.

The advantage of this analysis is that we can estimate the costs and benefits of Lynch syndrome testing in a large cohort of women with endometrial cancer, which would be difficult to evaluate in the context of a clinical trial. The major disadvantage of this analysis is the uncertainty relating to various parameters, including the prevalence of Lynch syndrome within specific age subgroups, their colorectal cancer risks and mortality rates, and total lifetime costs for colorectal cancer treatment. We assumed that women allocated to each strategy were comparable with respect to other risk factors for colorectal cancer, including body mass index, smoking, diet, comorbidities such as diabetes, and alcohol consumption. We also assumed that they had comparable risks of other Lynch-associated cancers, such as gastric, small bowel, ureter and renal pelvis, although these were not modeled in this analysis. Our base case model results were based on 100% compliance with colonoscopic surveillance in confirmed mutation carriers,65 but much lower rates have also been observed, which underscores the need to improve screening rates across this population.66–68

If Amsterdam II criteria continue to be utilized to guide genetic testing for Lynch syndrome, a significant proportion of individuals with Lynch syndrome may be missed. The proportion of women with endometrial cancer and Lynch syndrome who fulfill Amsterdam II criteria may be as low as 30%.18 In contrast, the proportion of women with endometrial cancer and Lynch syndrome who have at least 1 FDR with a Lynch-associated cancer may be as high as 80% to 100%.17–19 These women should be triaged with IHC, then offered the opportunity to undergo genetic counseling and testing. If they are identified as carriers, they can undergo more frequent surveillance to prevent colorectal cancer. Furthermore, their unaffected FDRs have the opportunity to undergo genetic testing and risk-reducing interventions to prevent colorectal and gynecologic cancers, which will contribute to reducing the total cancer burden among families affected by Lynch syndrome.

Acknowledgment

Supported by a generous gift from an anonymous donor to the British Columbia Cancer Foundation.

Footnotes

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Janice S. Kwon, Karen H. Lu

Financial support: Janice S. Kwon

Administrative support: Janice S. Kwon

Provision of study materials or patients: Janice S. Kwon

Collection and assembly of data: Janice S. Kwon, Jenna L. Scott, C. Blake Gilks, Molly S. Daniels, Charlotte C. Sun

Data analysis and interpretation: Janice S. Kwon, C. Blake Gilks, Charlotte C. Sun, Karen H. Lu

Manuscript writing: All authors

Final approval of manuscript: All authors

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