Cost-effectiveness of Lynch Syndrome Screening in Colorectal Cancer

The study you are referring to evaluates the cost-effectiveness of different Lynch syndrome (LS) screening strategies in patients newly diagnosed with colorectal cancer (CRC). Lynch syndrome is a hereditary cancer syndrome that significantly increases the risk of colorectal and other cancers. Timely and accurate identification of LS is critical for both the patient and their at-risk family members, as it enables targeted screening, prevention, and treatment strategies. Below is a detailed breakdown of the study's findings regarding the cost-effectiveness of LS screening approaches:

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### **1. Study Objective:**

The study aimed to assess the cost-effectiveness of three strategies for identifying LS in CRC patients while addressing the issue of diagnostic attrition in real-world multistep testing pathways. Diagnostic attrition refers to the loss of patients at various stages of the testing process, which reduces the effectiveness of LS identification.

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### **2. Screening Strategies Evaluated:**

The study compared three different approaches:

• **Current Standard-of-Care Sequential Tumor-Based Screening:**

This involves a multistep process starting with tumor-based tests (e.g., microsatellite instability [MSI] testing or immunohistochemistry [IHC]) followed by confirmatory germline testing if the tumor-based results indicate a high likelihood of LS.

• **Optimized Sequential Screening (CLEAR-LS Intervention):**

This strategy incorporates a systems-based intervention to improve compliance and reduce diagnostic attrition in the sequential testing process. The intervention ensures more patients complete the necessary steps in the testing pathway.

• **Upfront Universal Germline Testing:**

This approach involves offering germline genetic testing to all newly diagnosed CRC patients, bypassing tumor-based screening entirely.

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### **3. Methodology:**

The study used a **lifetime decision-analytic model** with nested Markov cohorts to simulate the long-term costs and health outcomes of these strategies. It integrated data from multiple sources, including:

• The **Prospective Lynch Syndrome Database** for clinical outcomes.
• The **SEER (Surveillance, Epidemiology, and End Results) program** for population-level cancer statistics.
• Data from pre- and post-intervention cohorts to evaluate the impact of the CLEAR-LS intervention.

The analysis was conducted from the perspective of the U.S. healthcare system, considering lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).

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### **4. Key Findings:**

#### **a) Health Outcomes (QALYs):**

• The **current standard-of-care** accrued the fewest QALYs due to high rates of diagnostic attrition and incomplete testing.
• The **CLEAR-LS intervention** modestly increased QALYs by improving compliance with sequential testing.
• **Upfront universal germline testing** yielded the highest QALYs, as it eliminates diagnostic attrition and ensures all patients are tested for LS.

#### **b) Cost-Effectiveness (ICERs):**

• The CLEAR-LS intervention was cost-effective, with a **favorable ICER** well within commonly accepted willingness-to-pay (WTP) thresholds (e.g., $50,000–$100,000 per QALY in the U.S.).
• Upfront universal germline testing was also cost-effective, particularly when **cascade testing** of family members was included. Cascade testing refers to offering genetic testing to family members of individuals diagnosed with LS, which can prevent cancers in at-risk relatives.

#### **c) Compliance and Attrition:**

• Sequential testing was only cost-effective if compliance with genetic testing exceeded approximately **75%**, a level rarely achieved in real-world settings without structured system-level interventions like CLEAR-LS.
• Universal germline testing was preferred when diagnostic attrition was high or when cascade testing was feasible.

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### **5. Implications for Practice:**

The study highlights that the current standard-of-care for LS screening is economically inefficient and leads to suboptimal health outcomes. To improve LS detection and population health outcomes, the following strategies should be considered:

• **Systematic Interventions (e.g., CLEAR-LS):**

Structured, system-level interventions can significantly improve compliance with sequential testing pathways, reducing diagnostic attrition and increasing cost-effectiveness.

• **Universal Germline Testing:**

Offering upfront germline testing to all CRC patients is an effective and cost-efficient strategy, particularly when combined with cascade testing of family members.

• **Screening Beyond Age 50:**

The findings suggest that LS screening should be considered even for CRC patients diagnosed after age 50, as this can still yield significant health benefits.

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### **6. Sensitivity and Threshold Analyses:**

The study conducted sensitivity analyses to test the robustness of its findings. Key results include:

• Sequential testing becomes cost-effective only if compliance exceeds 75%.
• Universal germline testing remains cost-effective in scenarios with high diagnostic attrition or when cascade testing is performed.

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### **7. Conclusion:**

The study concludes that the current standard-of-care for LS screening in CRC patients is suboptimal. To improve health outcomes and cost-effectiveness, healthcare systems should adopt either:

• Systematic interventions like CLEAR-LS to enhance compliance with sequential testing, or
• Universal germline testing for all CRC patients, especially when diagnostic attrition is high or cascade testing can be implemented.

These strategies not only improve the detection of LS but also have the potential to prevent cancers in at-risk family members, enhancing population health outcomes.