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Health Professionals:
More about the EGAPP™ UGT1A1 Genotyping Recommendation

 

EGAPP™ Evidence Review at a Glance

Test Application Quality of Evidence
Adequacy of information to address:
Overall Recommen-dation*
Analytic Validity Clinical Validity Clinical Utility
UGT1A1 Genotyping Pharmacogenomic Adequate Adequate

to demonstrate a significant association between specific UGT1A1 genotypes and:

  • severe neutropenia
  • tumor response rate
No evidence identified Insufficient evidence to recommend for or against use

*Overall recommendation was decided on the basis of (a) evidence indicating a low level of certainty of net health benefits, and (b) contextual factors.

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Considerations for Practice

  • The two most common UGT1A1 alleles are *1 and *28, which comprise 98–99% of the genotypes found in the U.S. white population. The *1 allele is associated with a normal level of the UGT1A1 protein. The *28 allele is associated with a low level of the UGT1A1 protein and results in reduced metabolism of irinotecan from its active to inactive form.
  • Analytic validity was considered adequate for the common UGT1A1 variants (alleles) only (*1, *28)
  • Adequate evidence was found for a significant association between UGT1A1 *28 genotypes and
    • severe neutropenia (*1/*28 or *28/*28)
    • higher rate of tumor response with standard dosing (*28/*28 only)
  • Evidence for a possible association between UGT1A1 *28 genotypes and severe diarrhea was found, but the effect was small and not statistically significant
  • UGT1A1 genotyping may be of benefit in individual cases when used by practitioners knowledgeable about potential benefits and harms
  • Use of genotyping in selective cases based on patient preference is possible:
    • If patient prefers aggressive treatment: genotyping might allow higher dosing for *1/*1 and *1/*28 genotypes
    • If patient prefers maximizing quality of life: genotyping might allow lower dosing for *28/*28 genotype
  • Possible alternate drug use based on patient preference for those with the *28/*28 genotype can be considered
  • The rate of severe neutropenia is as high as 36% in patients with the *28/*28 genoytpe, but the proportion who experience associated fever is unknown

Note: See Contextual Factors for more information.

Note: See Public Health Implications for additional information that is not part of the EGAPP™ recommendation.

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Testing Information

The two most common UGT1A1 alleles are *1 and *28, which comprise 98—99% of the genotypes found in the U.S. white population. The *1 allele is associated with a normal level of the UGT1A1 protein. The *28 allele is associated with a low level of the UGT1A1 protein and results in reduced metabolism of irinotecan from its active to inactive form.

Feature Genotype
*1/*1 *1/*28 *28/*28
Rate of irinotecan metabolism (active to inactive form)
Rapid
Moderate
Slowa
Risk of severe neutropenia
1.0
1.8-foldb
3.5-foldb
Risk of severe (G III-IV) diarrhea
1.0
1.4-fold
1.6-fold
Tumor response rate
1.0
1.1-fold
1.7-foldb

a Results in longer exposure time to active form
b Statistically significant at p<0.05




Contextual Factors

Additional contextual factors were taken into account in the final recommendation statement because the EGAPP™ Working Group found insufficient evidence to support a recommendation for or against use of UGT1A1 genotyping to improve dosing guidance for irinotecan for patients with metastatic colorectal cancer. 

  • Potential benefits—
    • Colorectal cancer (CRC) is a major public health problem
    • Irinotecan is commonly used in treatment
    • Adverse reactions to irinotecan are relatively common
    • Alternative therapeutic regimens are available
    • Genetic testing may be of benefit in individual cases with careful weighting of benefits and harms
    • Considering patient preferences (quality of life vs. aggressive treatment) may be reasonable on a case by case basis
    • Limited evidence of improved survival among individuals with the *28/*28 genotype suggests the possibility that those with the common *1/*1 genotype are being under dosed.
  • Potential harms:
    • Using UGT1A1 testing and the impact on clinician decision making unknown.
    • Reduced tumor response rate and survival due to reductions in dosing based on genotype information
  • Other:
    • Potential for increased cost of widespread use may not be justified without evidence supporting clinical utility
    • Other options exist for slow metabolizers (*28/*28) – e.g. National Comprehensive Cancer Network recommends pretreatment with colony stimulating factor for individuals with a 20% or higher risk of febrile neutropenia

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Research Gaps

The EGAPP™ Working Group identified the need for research to address the following:

  • Prospective studies of UGT1A1 genotyping and impact on clinical decision making/outcomes
  • Data on UGT1A1 alleles other than *1, *28
  • Data to clarify finding of weak association between *28 allele and severe diarrhea
  • Research to determine if increasing irinotecan dose is safe and can improve tumor response rates for individuals with one or no *28 alleles
    • Several clinical trials are underway (see Resources for more information)
  • General studies to assess whether pharmacogenetic testing is acceptable to clinicians and to individuals with metastatic colorectal cancer

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Public Health Implications of UGT1A1 Genotyping and Use of Irinotecan Chemotherapy for Metastatic Colorectal Cancer that are not part of the EGAPP™ recommendation.


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