Cost-Effectiveness of Microsatellite Instability Screening as a Method for Detecting Hereditary Nonpolyposis Colorectal Cancer

Genetic testing for predisposition to many hereditary cancer syndromes is now feasible. One important hereditary cancer syndrome is hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal dominant syndrome that is estimated to account for between 1% to 5% of all cases of colorectal cancer (1, 2). Persons with the syndrome have been found to carry germline mutations in one of six DNA nucleotide mismatch repair genes. Mutation carriers are at high risk for colorectal cancer at an early age (median age at diagnosis, 45 years) and have increased risk for several extracolonic neoplasms, such as endometrial, small-bowel, gastric, renal pelvis, ureter, and ovarian cancer (3, 4). A recent controlled study suggested that regular intensive screening with colonoscopy can significantly prolong the lives of HNPCC mutation carriers (5). Detection of the HNPCC mutation is problematic because there are no overt symptoms or signs before onset of the associated malignancies. Because of the complexity and expense of direct DNA analysis, population-wide genetic screening for HNPCC is not currently considered feasible (6). Several groups have proposed algorithms that focus testing efforts on persons who are at high risk for HNPCC. Most algorithms define high-risk persons as those with newly diagnosed colorectal cancer who meet certain clinical criteria and have one or more first-degree relatives with an HNPCC-associated malignancy (711). In patients who meet the criteria, tumors are tested for microsatellite instability. Microsatellite instability is a tumor phenotype that is characteristic of HNPCC but can also occur in up to 15% of cases of sporadic colon cancer (12, 13). Because this test is sensitive but less specific patients who have microsatellite instabilitypositive tumors are then tested for the most common mutations associated with HNPCC, MLH1 and MSH2. One of these algorithms, known as the Bethesda guidelines, is described in Table 1. Table 1. Algorithm for Identifying Potential Carriers of the Hereditary Nonpolyposis Colorectal Cancer Mutation among Those with New Colorectal Cancer Because colon cancer is highly prevalent, widespread application of the screening programs for HNPCC could have an important impact on the health care community and on society. During 1999, approximately 129 000 new cases of colorectal cancer were diagnosed in the United States (14). To carefully review the clinical and family histories of each patient with new colorectal cancer to determine whether they warrant microsatellite instability testing would require substantial time and resources. In addition, several thousand patients with new colorectal cancer would receive genetic counseling and genetic testing. For the estimated 1300 to 6500 persons with HNPCC who would be identified, clinical management would change. Finally, once a person is found to carry a mutation, it is likely (and perhaps desirable) that immediate family members will be notified. Given this potential cascade of effects, it is important to understand the economic and policy implications of implementing screen g programs for HNPCC. Using a decision model and available data, we estimated the cost-effectiveness of identifying HNPCC carriers among patients with newly diagnosed colorectal cancer. We compared this approach with the current practice of not screening for genetic susceptibility. Since patients with colorectal cancer and their close relatives may be affected by the guidelines, we present our results two ways: considering costs and benefits only for probands (patients with colorectal cancer) and for probands and their siblings and children. Methods Overview Our hypothetical cohort included all 129 400 patients with newly diagnosed colorectal cancer in the United States in 1999. Two separate cost-effectiveness evaluations were performed: one that considered costs and outcomes for probands only, and a second that included costs and outcomes for probands and their siblings and children. The first cost-effectiveness analysis considered probands at the time of diagnosis, when the initial decision between current management (standard treatment and post-treatment surveillance) and a management strategy that included microsatellite instability screening was made. For the latter strategy, we followed the recommendations of the National Cancer Institute, which are known as the Bethesda guidelines (8). The primary measure of effectiveness was life-years gained. The second cost-effectiveness analysis extended the decision algorithm beyond the Bethesda guidelines to include contacting the siblings and children of patients found to carry the HNPCC mutation. These relatives were offered genetic testing, and those that had HNPCC mutations were offered intensive lifelong screening for colorectal cancer. Data used to inform both analyses were drawn from several sources. In cases where data elements needed to inform the decision pathways were not available, we made conservative assumptions (that is, assumptions less favorable to the screening program) about their values. We created the decision model for the analysis using Microsoft Excel (Microsoft Corp., Redmond, Washington); subsequent sensitivity analyses were performed by use of @Risk, version 3.5. 2 (Palisade Corp., Newfield, New York). Management Pathway Patients with Colorectal Cancer When a patient received a diagnosis of colorectal cancer (Figure 1), the clinician determined whether his or her personal and family cancer history indicated eligibility for further testing (Table 1). Tumors from patients who met screening criteria were tested for microsatellite instability. Microsatellite instabilitypositive patients were then offered germline mismatch repair testing, preceded by genetic counseling from certified genetics counselors. Figure 1. Decision tree for microsatellite instability test and hereditary nonpolyposis colorectal cancer (HNPCC) mutation testing of patients with newly diagnosed colon cancer and their siblings and children. If results of the mismatch repair test were definitively negative, the patient returned to standard care and surveillance. Carriers of the HNPCC mutation were offered subtotal colectomy (16). Mutation carriers who declined subtotal colectomy (25% in the base case) received lifelong surveillance with regular colonoscopy, as recommended by the Cancer Genetics Studies Consortium (triannual examination in the base case) (16). Those with indeterminate mismatch repair evaluations received lifelong surveillance with triannual colonoscopy. Although it is recommended that mutation carriers also undergo surveillance for extracolonic cancer (particularly cancer of the endometrium and ovary), data supporting these interventions are lacking; therefore, we did not consider the costs or benefits of these tests in this model. Siblings and Children of Mutation Carriers The second cost-effectiveness analysis expanded the scope of the decision model to include costs and outcomes for siblings and children of patients who are found to be mutation carriers (Figure 1). Standard procedures for contacting and counseling family members have not been established and may be affected by state and federal laws protecting the privacy of the physicianpatient relationship, as well as laws regarding the duty of physicians to inform those who may be at risk but are not under their direct care (1720). Although siblings and children may not always be contacted by genetic counselors, we assigned a time cost that was based on counselors' hourly wages. The probability of locating relatives was determined according to whether the relatives were siblings or children. Relatives were offered genetic counseling and mismatch repair gene testing. Siblings and children who agreed to testing and had positi or indeterminate results were placed in lifelong colonoscopic surveillance every 3 years beginning at 25 years of age or their current age, whichever was greater (16, 21). Colorectal Cancer Stage and Age Distribution at Diagnosis The distribution of ages and stages of patients with sporadic colorectal cancer at diagnosis was based on data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry (22). The age and stage distribution at diagnosis for HNPCC carriers was based on data provided by the Creighton International Hereditary Colorectal Cancer Registry (Watson P. Personal communication). Performance Characteristics of Screening Tests for Hereditary Nonpolyposis Colorectal Cancer It has been estimated that after initial office screening of patients with new colorectal cancer, approximately 15% to 20% would be eligible for further testing (7). Between 86% and 92% of benign and malignant tumors in patients with the HNPCC mutation exhibit the microsatellite instability phenotype (23). The sensitivity and specificity of microsatellite instability testing vary, however, because the test exhibits a relationship similar to that of a receiver-operating characteristic curve; sensitivity may be exchanged for specificity depending on the combination of microsatellite markers used to identify replication errors in the tumor DNA. It is currently recommended that a minimum of four markers be used and that instability be defined as alterations in at least two of the four. In our base case, characteristics of the microsatellite instability test set sensitivity at 91% and specificity at 93% (2426). Although individual mismatch repair mutations are highly specific for HNPCC, the sensitivity of all known mutations for HNPCC is less clear. Most reports suggest that the hMSH2 and hMLH1 mutations account for most cases of HNPCC. In our base case, we assigned a sensitivity and specificity of 87% and 99.5%, respectively, to hMSH2 and hMLH1 assays. The likelihood of inconclusive test results was included in these calculations (21). Survival under Standard Care, Increased Surveillance, and Colectomy Survival for patients with colorect