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Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer?

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Certain changes in a gene known as UGT1A1 have been found to affect how quickly the body metabolizes the chemotherapy drug irinotecan from its active, to inactive form. This can affect drug activity, and the type and severity of side effects a person may experience. UGT1A1 genotyping has been proposed as a means of guiding use of irinotecan in the management of patients with metastatic colorectal cancer to improve effectiveness and reduce side effects.

EGAPP Recommendation Statement: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia).

EGAPP Recommendation (January 2009)

Evidence Report (January 2009)

Summary Manuscript (January 2009) 

CDC Summary of EGAPP Recommendation (July 2010)

Key Questions:

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

  • 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.