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Health Professionals: More about the EGAPP™ UGT1A1 Genotyping Recommendation

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EGAPP™ Evidence Review at a Glance

Test Application Quality of Evidence
Adequacy of information to address:
Overall Recommendation*
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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EGAPP™ Recommendation Statement [PDF 200.16 KB]

"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 (CRC) who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia)."

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
Slow a
Risk of severe neutropenia
 
1.0
1.8-fold b
3.5-fold b
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-fold b

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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