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Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer Therapy

Abramson Cancer Center, University of Pennsylvania, Philadelphia PA

Robert B. Catalano

Drexel University School of Medicine, Philadelphia PA

For 50 years the dosing of anticancer drugs has been empirical—small phase I trials predict a tolerable dose, and subsequent studies refine the accuracy of that prediction. Because of population variability, however, a proportion of patients will inevitably experience more severe toxicity at doses selected for general use. Phase III trials routinely report grade 4 myelosuppression rates of up to 80% in certain solid tumors, without a recommendation for a dose adjustment.^1,2 Historically, this risk has been regarded as acceptable, compared with the greater risk of treating the greater part of the population with ineffective doses. Approaches to individualizing therapy have been sought through pharmacokinetic analyses, but recommendations to the community have never been practical.

In recent years, the potential of pharmacogenetic analyses to improve the therapeutic index of cancer therapy in pediatric malignancies has been described.^3,4 For example, thiopurines are subject to variable metabolic disposition through single nucleotide polymorphisms (mutations in a gene sequence that have a prevalence of at least 1%). Clinical studies have shown that identification of the variant population has the potential to ameliorate toxicity while enhancing therapeutic outcome.^5,6 Similar genetic signatures have long been sought in adult solid tumors. In colorectal cancer, several candidate genes have been identified that have the potential to determine risk of toxicity and possibly efficacy of fluoropyrimidines and oxaliplatin.^7-11

Such approaches have two distinct goals: to minimize toxicity and to maximize the effectiveness of therapy. In 2005, the US Food and Drug Administration (FDA) took two actions that may be perceived as an advance regarding how pharmacogenetic approaches might permit us to reduce the risk of chemotherapy. First, it was determined that a fraction of the population at higher risk for adverse effects associated with the use of standard doses of irinotecan can be identified prospectively. These are patients who, by virtue of a genetic polymorphism, have a lower than normal capacity to metabolize SN-38, the active metabolite of irinotecan. The polymorphism is found in the gene encoding uridine diphosphate glucuronosyltransferase (UGT) 1A1, which facilitates the excretion of SN-38. This risk was emphasized by a warning added to the package insert of irinotecan. The text added to the label states that "individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele."¹²

Second, the FDA approved a test to identify these individuals. The genetic test (Invader UGT1A1 Molecular Assay; Third Wave Technologies Inc, Madison, WI), conducted on genomic DNA isolated from peripheral blood, identifies patients homozygous for the UGT1A1*28 allele. Such patients clear irinotecan and its metabolites more slowly than the rest of the population, and so have greater exposure to active drug after a standard dose. The FDA-approved label for the test states that "a reduced initial dose [of irinotecan] should be considered for patients known to be homozygous for the UGT1A1*28 allele."¹³ What are practicing oncologists to do with this information?

IRINOTECAN: A KEY DRUG IN COLORECTAL CANCER TREATMENT

The topoisomerase I interactive drug irinotecan was introduced into clinical studies in the early 1990s, and was found to have activity in several malignancies for which limited treatment options existed, most prominently colorectal cancer.¹⁴ Added to fluorouracil (FU), irinotecan resulted in the first major advance in many years in the treatment of colorectal cancer, and the combined administration of these drugs became the standard of care.^15,16 Although studies in the adjuvant treatment of colon cancer have been disappointing,¹⁷ irinotecan remains a valuable agent in managing patients with advanced disease.

The toxicity of irinotecan in combination has been a concern: early studies identified dose-limiting diarrhea and neutropenia as the major adverse effects, and an aggressive preventive regimen of antidiarrheal and infection evolved. Both of these toxicities are of concern, given that severe neutropenia occurs most often in the context of accompanying diarrhea.¹⁸ An analysis of two studies of irinotecan with bolus administration of FU revealed an unacceptable early death rate, attributed largely to the combined occurrence of these two adverse effects.¹⁹ Therefore, it has been recommended that infusional FU be used in the FU/irinotecan regimen, or that doses be reduced, although the impact of the dose reduction on treatment efficacy in colorectal cancer has not been assessed.¹⁶ With either approach, the variability in toxicity has remained a concern.

PHARMACOLOGY OF IRINOTECAN ACCOUNTS FOR VARIABILITY

The basis of variable toxicity was evident from the initial trials of irinotecan. As with most drugs, those patients with the greatest exposure to the drug were at the highest risk of toxicity.¹⁹ The pharmacology of this class of drugs, however, is complicated. Irinotecan is a prodrug, converted to its active metabolite SN-38 by carboxylesterases, which are distributed ubiquitously in the tissues.^20,21 Furthermore, both irinotecan and SN-38 are lactones that exist in a pH-dependent equilibrium with their ring-opened carboxylate forms; only the lactone is active. Given that plasma pH varies in a narrow range, most inferences regarding exposure to irinotecan or SN-38 are based on total plasma drug measurements. Excretion of the drug and its metabolites primarily is hepatic, with renal excretion playing a minor role.²² As with many drugs that undergo hepatic disposition, the excretion of SN-38 is facilitated by glucuronidation, a process catalyzed by the UGT1A family of phase II enzymes. In addition, SN-38 is subject to oxidation by the cytochrome P450 family.²² Ratain described the pharmacodynamic importance of glucuronidation by relating glucuronide formation to risk of toxicity.^23,24 A relationship could be shown with both diarrhea and myelosuppression when irinotecan was administered as a single agent. Hence glucuronidation by UGT1A enzymes was investigated further as a marker of the variability in irinotecan toxicity.

DETERMINANT OF DISPOSITION: UGT1A1

Like the cytochromes P450 and other enzyme families, the purpose of which is the detoxication of xenobiotics, this family of enzymes achieves broad substrate specificity through variation in the substrate-binding domain. Thus the UGT1A family of enzymes is represented in the genome by a series of four invariant exons, the transcribed product of which may be spliced to any one of nine exons representing different substrate-binding domains. The family members are thus designated UGT1A1, 1A2, and so on, in an agreed-on terminology. By virtue of this structural variability, UGT1A1 is the isoform with the greatest affinity for SN-38, and so is the most important catalyst in its metabolism; recent work also implicates both UGT1A7 and UGT1A9 in the process.²⁵

UGT1A1 is the enzyme primarily responsible for bilirubin glucuronidation. Lower than normal activity is a feature of Gilbert's syndrome, the genetic basis of which has been elucidated. It has been determined that UGT enzyme levels are regulated primarily through transcriptional control, and that variation in promoter structure influences the rate of transcription. In particular, a series of TA repeats in the proximal promoter vary from five to eight in length: the lower the number of repeats, the more efficient the transcriptional activity of the gene. The commonest alleles are those with six and seven repeats. Gilbert's syndrome is most commonly associated with homozygous presence of the TA₇ allele (which is also classified as UGT1A1*28).^26,27 The frequency of alleles of these repeats varies by ethnic and racial origin: in a white population, approximately 50% are [TA₆/TA₆], 40% are [TA₆/TA₇], and 10% are [TA₇/TA₇] genotypes. The proportion of [TA₇/TA₇] genotypes is also approximately 10% in individuals of African origin, but less than half that in Asians.²⁸ Other polymorphisms in the UGT1A1 gene have been shown to influence functional activity and to associate with Gilbert's syndrome or drug toxicity. Missense polymorphisms in exon 1 and in the shared exons 2 to 5 have been described. Of particular importance to East Asian populations is a mutation in exon 1 (a G to A transition termed UGT1A1*6) with an allele frequency of approximately 12%, which reduces catalytic function by 60% in homozygotes.²⁹ The impact of this polymorphism on irinotecan toxicity did not emerge in one study,³⁰ but was strikingly associated with greater toxicity in a population of Korean patients treated with irinotecan and cisplatin for advanced non–small-cell lung cancer.³¹

UGT1A1 GENOTYPE AND IRINOTECAN TOXICITY

Iyer et al³² first demonstrated that irinotecan disposition might be genetically determined, as shown in liver microsomes, and that UGT1A1 was responsible for irinotecan glucuronidation. Case reports of toxicity in colorectal cancer patients with Gilbert's syndrome and with UGT1A1*28 homozygosity^33,34 prompted more extensive investigation. A series of publications then demonstrated evidence that this genotype may be an important influence on the toxicity of irinotecan (Table 1). The analyses in patients treated with single-agent irinotecan (on a schedule of administration once every 3 weeks) demonstrate a relationship of the UGT1A1*28 genotype to toxicity.^35,36 This relationship is more easily discerned with neutropenia than with diarrhea, which was not common with this regimen. Perhaps such a finding is not unexpected, given that grading of neutropenia through a documented blood count may be more objective than that of diarrhea, which is a retrospective recall of stool number. There are three published analyses of the relationship of genotype to toxicity with combinations involving irinotecan. The study by Ando et al³⁰ merges hematologic and GI toxicity, and showed that the incidence of either is increased in the patients homozygous or heterozygous for the *28 genotype. The presence of additional chemotherapy drugs was an additional significant risk factor, and this is suggested also in the studies of Rouits and Marcuello.^37,38 In sum, the combination studies replicate the findings of the single-agent analyses; there is a clear association of UGT1A1*28 homozygosity with neutropenia from irinotecan alone or in combination. For diarrhea, there is a trend reaching significance in only one of the studies. Case reports and the combined analysis of Ando et al³⁰ indicate that the occurrence of both toxicities, known to be a major risk factor for early death in studies of irinotecan plus FU, may be associated with the genotype, although additional characterization of this aspect is needed. Preliminary analyses from a large cooperative group trial (N9741) in which genotyping was performed in 520 patients confirm the association of *28 homozygosity with risk of grade 4 neutropenia for an arm incorporating irinotecan with oxaliplatin (P = .004), but not for weekly irinotecan plus FU (IFL; P = .46). A higher risk of febrile neutropenia was also associated with *28 homozygosity. No association was found for severity of diarrhea.³⁹

PRACTICAL INTERPRETATION OF THE CURRENT DATA

Should Every Patient Receiving Irinotecan for the First Time Be Considered for Testing?
Yes. A number of limitations in the state of current knowledge must, however, be emphasized. First, as listed in Table 1, not all of the patients with the variant genotype experience life-threatening toxicity with standard-dose irinotecan. However, according to studies of small numbers of patients, some 50% do experience life-threatening toxicity, and more complete studies are needed to provide a more accurate assessment of risk. Second, a normal UGT1A1 genotype does not ensure lack of toxicity, although the risk clearly is less. Innocenti et al⁴⁰ have indeed suggested that we may be underdosing those with the normal genotype and that a reassessment of dosing should be conducted. These two concerns have perhaps been best countered by Wang and Wenshilboum,³ responding to a criticism that not all myelosuppression was explained by an identified source of thiopurine methyltransferase (TPMT) pharmacogenetic variation: "the fact that TPMT pharmacogenetic testing would allow us to understand, anticipate, and avoid this potentially fatal drug reaction in a subset of patients clearly represents a significant clinical advance." Although the level of understanding of irinotecan pharmacogenomics is substantially less mature than that of the thiopurines, a strong argument can be made that until additional studies provide refinement of the model, UGT1A1 testing should be considered before the first dose of irinotecan in all patients.

Does the Genotyping Predict for All Toxicities of Irinotecan?
No. It is often pointed out that the predominant toxicity with the schedule of irinotecan administered once every 3 weeks is myelosuppression, and that these results are therefore of questionable relevance for a schedule administered once every 2 weeks, in which diarrhea predominates. The largest study fails to show a significant association between the UGT1A1*28 homozygous genotype and diarrhea in patients who received what, is arguably the regimen associated with the highest incidence of diarrhea, IFL.³⁹ Conversely, the greatest risk from irinotecan toxicity is when diarrhea and neutropenia coexist, a scenario that resulted in an unacceptably high rate of early death with the IFL regimen.¹⁹ Thus, it may be asserted that knowing which patients are at risk for myelosuppression, in itself, is a valuable predictor.

What Dose Should Be Used in UGT1A1*28 Homozygotes?
This has not been established. It is acknowledged that no clear dosing strategy for the variant phenotype has been defined. Concerns regarding undertreatment are appropriate and must be addressed prospectively. With current knowledge, it is clear that patients with this phenotype should receive less drug, but how much less? On the basis of a consideration of SN-38 area under the concentration-time curve, Innocenti et al⁴⁰ have recommended a 20% dose reduction. Until more data are available, this seems a reasonable approach. The concern regarding underdosing may be further allayed by a dose escalation to full doses in the second course, in the event of little or no toxicity at the reduced level.

What Additional Studies Need to Be Accomplished?
The limitations described, all of which are valid, indicate the need to better characterize the genotype-phenotype relationships, and their implications for specific therapies. Nonetheless, for immediate practical purposes, those limitations seem to us outweighed by the recognition of a subset of patients at greater risk of toxicity from noncurative therapy, and the availability of a test that can identify them. The test is increasingly available in the pathology departments of major institutions, but our experience has been that not all insurance carriers will agree to support its cost. This coverage issue needs to be resolved.

Although safety is a paramount priority in the management of incurable disease, it is not the only priority. Patients and oncologists have legitimate concerns that dose modifications might be required only in a subset of patients with UGT1A1*28 genotype. The oncology community as a whole should commit the necessary resources to conduct a hypothesis-driven study of patients who are representative of all three genotypes. This trial would extend the investigation of genotype to UGT1A1 haplotypes, and to genotypes involving other key determinants of toxicity and/or efficacy. It should establish appropriate dose modification strategies for irinotecan-containing regimens in patients of various genotypes. It should also incorporate molecular correlative studies to analyze simultaneously the pharmacogenomics of response in both tumor and normal tissue—a necessary step to advance the realization of individualized therapy.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Peter J. O'Dwyer Pfizer (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C) $100,000 (N/R) Not Required

Author Contributions

Conception and design: Peter J. O'Dwyer Data analysis and interpretation: Peter J. O'Dwyer, Robert B. Catalano Manuscript writing: Peter J. O'Dwyer, Robert B. Catalano Final approval of manuscript: Peter J. O'Dwyer

 

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