Key Questions:

• Question 1: Does testing for UGT1A1 mutations in patients with metastatic CRC treated with irinotecan lead to improvement in outcomes? (Overarching question)

• Question 2: What is the analytic validity of the test(s) that identify key UGT1A1 mutations?

• Question 3: What is the clinical validity of UGT1A1 testing?

• Question 3a: How well does UGT1A1 testing predict phenotypic markers (e.g., increased plasma SN-38 levels or decreased enzyme activity) and associated adverse drug reactions (e.g., diarrhea or neutropenia)?

• Question 3b: How well does UGT1A1 testing in patients with metastatic CRC predict morbidity (diarrhea, neutropenia) and mortality (survival)?

• Question 3c: Do other factors (e.g., race/ethnicity, other medications) affect clinical validity?

• Question 4: What are the benefits and harms related to UGT1A1 testing for patients with metastatic CRC treated with irinotecan?

• Question 4a: Based on UGT1A1 test results, what are the management options for patients?

• Question 4b: Do these options improve patient outcomes or management decisions by patients or providers?

Why EGAPP Selected this topic for Review:

Key criteria: Prevalence and severity of colorectal cancer; irinotecan therapy is an increasingly common intervention; relevance to healthcare providers and patients for decision-making; FDA-approved test with potential impact on clinical practice.

Other Considerations: Limited literature that allows application of EGAPP methodology for a targeted review.