In today’s cost-conscious environment, it is important to consider both clinical and economic consequences of new screening programs. Because of their expense and social implications, this may be particularly true for screening programs that involve genetic testing. Screening for mutations linked to cancer susceptibility is not yet part of routine clinical practice. Because population-wide genetics-based screening is not yet feasible and may not be desirable due to privacy concerns,41–43
experts in screening policy have focused on those with colorectal cancer as the initial point for considering genetic testing. Previous analyses suggest that this strategy is preferable when the population prevalence of the mutation is likely to be low.10,44
The economic efficiency of the Bethesda strategy will still be within what many consider reasonable at lower prevalence rates of HNPCC. This is not true for the other strategies, particularly those that bypass MSI analysis. Thus, from an economic standpoint, this article supports the role of MSI testing in identifying persons with HNPCC.45
The sensitivity and specificity of MSI testing is variable, because the test exhibits a Receiver Operating Curve-type relationship, where sensitivity may be exchanged for specificity depending on the combination of microsatellite markers that are used to identify replication errors in the tumor DNA. Although the Bethesda criteria allow up to 10 markers if needed, we chose a 4-marker MSI test based on a balance of sensitivity and cost.5
Recent studies suggest that immunohistochemical assay may be superior to MSI testing for identifying hMLH1 and hMSH2 protein products in colorectal tumors.46
Our sensitivity analysis suggests that increasing the specificity of phenotype testing at a stable cost could substantially improve the cost-effectiveness of the Bethesda guidelines. Some laboratories now test for the MSH6 mutation in addition to MLH1 and MSH2, although we do not include the added costs and potential change in specificity in this analysis.
Other clinical risk-assessment algorithms for identifying persons with HNPCC have been proposed, including the Amsterdam criteria, which uses more restrictive family history criteria than does the Bethesda guidelines.8,9,47,48
Comparing other strategies, including the Amsterdam criteria, Reyes and colleagues found that a mixed strategy including MMR mutation evaluation of those who meet the Amsterdam criteria and those who meet less stringent modified criteria and show high MSI was the most cost effective option.49
From an economic perspective, the specificity of the initial clinical screening algorithm is critical, as it will reduce the number of false positive screenings, and thus the number of downstream follow-up tests for those who are HNPCC negative. To incorporate new knowledge about HNPCC, testing strategies, and technological advances, an update of the Bethesda criteria is underway.50
Efforts to promote genetics education for primary care providers emphasize the use of family history as a triage tool in routine practice, to identify patients who might be candidates for early screening and/or genetic testing.51
Our analysis does not address this approach to HNPCC detection. Some may question the choice to offer genetic counseling before mutation testing but not before MSI testing. We believe this approach accurately reflects current practice; however, we recognize a potential argument for some form of genetic counseling before MSI testing to alert the patient that the testing pathway leads to the potential outcome of a genetic diagnosis.
The cost-effectiveness of each strategy is highly dependent on our health system’s ability to identify and test unaffected relatives of those found to be mutation carriers. There is less to gain from an HNPCC diagnosis for the colorectal cancer patient than for a relative who is not yet affected with cancer. The level of physicians’ responsibility for ensuring that relatives of their patients know about their risk is not yet resolved. A New Jersey court case suggested that physicians might have an obligation to contact relatives directly to inform them of genetic risk; by contrast, a Florida ruling stated that a physician’s duty was discharged by informing the patient of a genetic risk to family members.52,53
This issue is notably absent from the American Gastroenterological Association’s recent position statement on hereditary colorectal cancer and genetic testing.54
More research is needed to determine the most effective and efficient method for disseminating risk information to family members after a diagnosis of HNPCC is made, and the feasibility of using family history as a screening tool in primary care practice.
Clinicians may be troubled by the fact that of the four approaches we consider in this study, the Bethesda strategy “misses” the greatest number of mutation carriers. This issue is at the crux of the controversy between the economic and clinical perspective when evaluating diagnostic tests. highlights the implications of choosing a strategy with higher sensitivity, in terms of the cost of adding an additional year of life for those being screened. This issue is worthy of debate. Our purpose has been to make explicit the clinical and economic consequences of alternative strategies.
We note several important limitations of the analysis. Some of the input variables are based on expert opinion. Our uncertainty analysis suggests that changing the values of these variables will not influence the rank of cost-effectivenessness outcomes of each strategy, although the magnitude of difference may change. For the multivariate analysis, the large ranges and, more importantly, assumed independence of the individual parameters lead to rather large predictive regions in the cost/effectiveness space. If it were possible to specify the correlation between parameters, these regions (and thus the overall uncertainty) could be reduced. This analysis does not consider indirect costs associated with screening, such as the cost of job discrimination as a result of screening. Although important, including these costs are not likely to influence the ranking of the strategies.
Strategies that start with MSI testing of all persons regardless of history and those that bypass MSI testing altogether are also reasonably cost-effectiveness and not beyond a range of uncertainty at which options would be clearly inferior to the Bethesda guidelines strategy. The benefit of intensive surveillance and the population prevalence of HNPCC are important issues influencing the cost-effectiveness of all strategies. If the true prevalence of HNPCC mutations and the benefits of surveillance are lower than current estimates, then this will further favor the Bethesda guidelines from an economic perspective, as the cost-effectiveness of this strategy is less influenced by changes in the estimates than are the other approaches.