By examining primary genetic screening to detect mismatch repair mutation carriers prior to malignancy, and by capturing the important familial factors in risk assessment and in posttest screening of first-degree relatives of mutation-carrying probands, this study enabled the identification of strategies to cost-effectively reduce the burden of Lynch syndrome. This primary screening approach is distinct from current guidelines which recommend clinically informed genetic testing in individuals who have already developed malignancies.
From a clinical perspective, universal screening (0% risk threshold) starting at age 20 reduced the incidence of colorectal and endometrial cancer in mutation carriers compared with current practice (control) the greatest (43.9% and 39.6% respectively), and substantially increased the average life-years per mutation carrier (4.07 years gained), as shown in . As the risk threshold for genetic testing was increased, and fewer people qualified for testing (as in Strategy 20), the reductions in colorectal and endometrial cancer incidence were minimized (5.3% and 3.6%, respectively), as were life-years gained per mutation carrier (0.41 years).
From a cost-effectiveness perspective, although universal screening offered the greatest benefit in clinical outcomes, it did so at the least attractive cost-effectiveness ratios. Furthermore, universal screening required the largest number of tests—over 140—to identify one additional mutation carrier. However, as the risk threshold for genetic testing was set to 5.0% and 10%, the cost-effectiveness values fell below the benchmark of $50,000 per QALY, and the number of tests needed to identify one additional mutation carrier dropped to 7–8, and 2–3, respectively. Although the health outcomes in were sensitive to both screening age and risk of carrying a mutation, sensitivity of cost-effectiveness was dominated by the latter ( and ).
Between the extremes of universal testing and a strategy involving a high threshold for testing were strategies, such as 12, which achieved reductions in colorectal and endometrial cancer incidence of 13.5% and 9.0% respectively, at an average cost-effectiveness ratio of $27,571 per QALY and an incremental cost-effectiveness ratio of $44,537 per QALY. As the age at which to start screening increased from 25 to 35 (e.g., strategies 12, 14), screening had less of an effect on the reduction of colorectal cancer incidence (13.5% vs. 12.2%), and on the reduction of endometrial cancer incidence (9.0% vs. 8.1%), but improved cost-effectiveness ($44,537 per QALY vs. $40,645 per QALY). On the basis of the values in , several effective primary genetic screening strategies exist for start ages of 25 to 35, with a risk threshold of 5%. Cost per QALY of strategies 12 and 14, for example, are below the cost-effectiveness benchmark and are comparable to values of other accepted prevention activities described by Maciosek et al. (38
) including colorectal cancer screening (<$14,000 per QALY), cervical cancer screening ($14,000–$35,000 per QALY), and breast cancer screening ($35,000–$165,000 per QALY). Furthermore, relative to the other screening strategies studied, strategies 12 and 14 concomitantly achieved modest gains in absolute life-years and modest reductions in the incidence of colorectal and endometrial cancer.
As suggested in , the absolute benefits in health outcomes in strategies 12 to 14 depended on the projected adoption rates of the screening strategies. However, with the exception of slight variation due to random sampling, the cost-effectiveness ratio itself did not vary as a function of adoption rate, a finding which is consistent with similar observations described elsewhere (39
). Of note is that adoption of the proposed screening strategy is a dual function of individuals visiting with their physicians and physicians implementing the strategy. Although younger patients may be less likely to visit with their physicians, the modeled screening strategies indicate a start-age and not a single age for risk assessment. Because the simulated patients may return to their physicians for physical exams and for risk reassessments as their first- and second-degree relatives age and develop disease over time, a 25-year-old, for example, who does not comply with visiting his or her physician is not an opportunity lost, but merely an opportunity delayed. Ultimately, as adoption improves over time, exemplified by the successful and widespread adoption of history- and genetic-based screening strategies associated with BRCA1/2
, benefits in health outcomes will rise accordingly.
This analysis was based on a number of important but generally conservative assumptions. First, although we assumed that single-site testing was only offered to first-degree relatives of probands, in clinical practice efforts are commonly made to offer single-site tests to second-degree relatives as well. For example, in the study by Hampel, five to six relatives were tested per proband on the basis of cascade testing of family members beyond first-degree relation (40
). An estimate of the benefit of extending testing to second-degree relatives in whom mutation prevalence of 25% was assumed, resulted for strategy 13 in an average cost-effectiveness ratio of $16,564 per QALY if six second-degree relatives were tested. Second, the current study used an annual discount rate of 3% for both cost and QALYs in the base case calculation. It is possible that this approach is conservative over lifetime horizons in which testing costs are incurred upfront whereas treatment and QALY savings at substantial discounts are realized later. Third, we used conservative estimates related to diagnostic testing. We set the analytic sensitivity of genetic tests at 90% for MLH1
and 62% for PMS2
. These values are below subjective levels cited in the literature (e.g., 99.5%; 1), but allowed us to account for effects of such factors as genetic variants of uncertain significance known to occur in the genes modeled. Ongoing advances in testing techniques as well as emerging tests for BRAF and TAC/ STD1 will likely lead to higher sensitivities. We also estimated that in current practice, when taking the entire U.S. population into account, approximately 30% of individuals diagnosed with colorectal cancer have access to MSI and IHC testing. Although nearly all individuals diagnosed with and treated for colorectal cancer in academic and institutional clinical settings have access to these testing modalities, most individuals are diagnosed and treated at community hospitals where protocols for routine processing of tumors for MSI and IHC are not yet widely implemented. We acknowledge that this may change over time, with MSI increasingly recognized as a prognostic factor for survival and as a predictive factor for sensitivity to specific chemotherapies. Fourth, the costs of colorectal cancer treatment were based on SEER Medicare data from 1998 to 2003 (20
), rather than the much higher costs of recently available molecular-targeting agents. This approach was taken to minimize the favorable bias on outcomes that the uniform use of these high-cost agents in the control group would introduce. Had updated estimates of the costs of colorectal cancer treatment been implemented, the cost-effectiveness of primary genetic screening would have been further enhanced.
In summary, primary genetic screening for mutations in mismatch repair genes, with a screening start age between 25 and 35, and a risk threshold of 5%, leads to improvements in health outcomes among carriers and families with these mutations and is cost-effective relative to the common criterion of $50,000 per QALY. In the simulation, approximately 1% of the general population had risk in excess of the aforementioned 5% threshold, emphasizing the scope of the public health issue that could be addressed by such a screening strategy. This finding supports the concept that genetic screening of unaffected at-risk individuals, when conducted in association with appropriate risk assessment, and when followed by surveillance for colorectal and endometrial cancer would cost-effectively improve health outcomes. Furthermore, it offers an evidence-based justification for a shift in the clinical approach to Lynch syndrome from one that is reactive to one that is proactive. By providing clinicians with a simple and easily employed means of determining an individual’s future risk of developing Lynch syndrome, the primary care practitioner may now participate with the oncologic and surgical specialists in the fundamental roles of prevention, surveillance, and management of patients with Lynch syndrome mutations.