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 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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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

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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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