Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov;23(12):2328-2338.e9.
doi: 10.1016/j.cgh.2025.03.006. Epub 2025 Apr 30.

Cost-effectiveness of Lynch Syndrome Screening in Colorectal Cancer: Universal Germline vs Sequential Screening

Satoko Ito  1 , Rosa M Xicola  2 , Manraj Sra  3 , Kunal C Potnis  4 , Vinit Singh  5 , Peter Gershkovich  6 , Edward Stites  7 , Joanna Gibson  6 , Harlan M Krumholz  8 , Xavier Llor  4 , George Goshua  9
Affiliations

Cost-effectiveness of Lynch Syndrome Screening in Colorectal Cancer: Universal Germline vs Sequential Screening

Satoko Ito et al. Clin Gastroenterol Hepatol. 2025 Nov.

Abstract

Background & aims: Testing all colorectal cancers (CRCs) for mismatch repair status to evaluate for Lynch syndrome (LS) has been recommended for years. Owing to attrition in the multistep diagnostic testing pathway, most qualifying patients still do not receive genetic testing for LS. This leads to missed diagnoses and preventable cancer incidence. To tackle this, we previously reported a systems approach that resulted in a dramatic increase in the identification of patients with LS. We aim to evaluate the cost-effectiveness of this intervention compared with both real-world pre-intervention experience and with upfront germline testing of all CRC probands.

Methods: We employed data from the Prospective Lynch Syndrome Database, the National Cancer Institute Surveillance, Epidemiology, and End Results program, and pre-/post-intervention cohort studies to build lifetime Markov cohorts of CRC probands, testing 3 strategies: (1) current standard-of-care; (2) optimized standard-of-care; and (3) upfront germline testing. The primary outcome was the incremental cost-effectiveness ratio (ICER) in $ per quality-adjusted life-year (QALY) from the United States health system perspective.

Results: Strategies #1 to #3 accrued 11.97, 11.98, and 11.99 discounted QALYs at discounted costs of $100,610, $100,980, and $102,290, respectively. The pairwise ICERs on the frontier were $34,500/QALY (95% credible interval [CI], $28,400-$44,200) and $98,500/QALY (95% CI, $73,700-$216,000), respectively. The cost-effectiveness of #3 vs #1 was $70,300/QALY (95% CI, $54,600-$92,500). Current standard-of-care was favored in 0.0% of 10,000 Monte Carlo iterations.

Conclusions: Current clinical practice is cost-ineffective. Prospective intervention to dramatically increase LS testing (ie, to reach a threshold of >75%) or, if this level cannot be reached, upfront germline testing are cost-effective interventions that improve quality-adjusted life expectancy.

Keywords: Colorectal Cancer; Cost-effectiveness; Diagnosis; Lynch Syndrome.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement: In the past three years, HMK has received options for Element Science and Identifeye and payments from F-Prime for advisory roles. He is a co-founder of and holds equity in Hugo Health, Refactor Health, and ENSIGHT-AI. He is associated with research contracts through Yale University from Janssen, Kenvue, Novartis, and Pfizer.

Figures

Figure 1.
Figure 1.. Three-step lifetime cohort simulation model.
All patients with incident colorectal cancer progress through step 1 (decision tree model), according to known test characteristics, leading to one of three corresponding lifetime Markov cohort models present within each strategy. Each Markov cohort model in Step 2 consists of six health states: 1) initial colorectal cancer, 2) remission from cancer, 3) recurrent colorectal cancer, 4) endometrial cancer, 5) ovarian cancer, and 6) death. A yearly cycle length was chosen following the prior economic evaluations of diagnostic strategies for LS. All patients start from initial colorectal cancer state in their respective Markov models. Probands with colorectal cancer move into remission after surviving age-, sex-, and colorectal cancer-specific mortality (across time-variant 5-year survival as informed by NCI SEER). The step 3 cascade testing model consists of five health states: 1) healthy state, 2) colorectal cancer, 3) endometrial cancer, 4) ovarian cancer, and 5) death. First-degree relatives start from healthy state, transitioning through the model as probands do in in Step 2. Legend: CRC=colorectal; GT=germline testing; IHC=immunohistochemistry; LS=Lynch syndrome.
Figure 2.
Figure 2.. Threshold analysis for compliance rate to complete germline testing.
The ICER for upfront germline testing compared to IHC strategy exceeds a WTP threshold of $100,000/QALY when referral compliance through to germline testing reaches 75%. Legend: ICER=incremental cost-effectiveness ratio; IHC=immunohistochemistry; QALY=quality-adjusted life-year
Figure 3.
Figure 3.. Cost-effectiveness acceptability curve of probabilistic sensitivity analysis.
The distribution of each parameter utilized in analysis are detailed in Table 1. At a WTP of $100,000/QALY, CLEAR-LS intervention and upfront germline testing is favored in 74.3% and 25.7% of 10,000 Monte Carlo iterations. Legend: IHC=immunohistochemistry; QALY=quality-adjusted life-year
See this image and copyright information in PMC

References

    1. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2017;26(3):404–412. DOI: 10.1158/1055-9965.EPI-16-0693. - DOI - PMC - PubMed
    1. Network NCC. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric. Version 3. 2024. National Comprehensive Cancer Network, Inc. 10/31/2024. - PubMed
    1. Moller P, Seppala TT, Bernstein I, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 2018;67(7):1306–1316. DOI: 10.1136/gutjnl-2017-314057. - DOI - PMC - PubMed
    1. Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354(3):261–9. DOI: 10.1056/NEJMoa052627. - DOI - PubMed
    1. Burn J, Sheth H, Elliott F, et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet (London, England) 2020;395(10240):1855–1863. (In eng). DOI: 10.1016/s0140-6736(20)30366-4. - DOI - PMC - PubMed