• Predict toxicity from irinotecan therapy

• Assist in selection of initial irinotecan dosage

• Support diagnosis of Gilbert’s syndrome

Irinotecan (Campostar^®′, Pfizer Inc, New York, NY) is a topoisomerase-I inhibitor widely used for treatment of metastatic and recurrent colorectal cancer. The most common dose-limiting adverse effects of irinotecan are neutropenia, diarrhea, and asthenia. Variations in the gene encoding uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) may help predict which patients are most likely to develop these adverse effects.

UGT1A1 is a hepatic enzyme primarily responsible for conjugation of bilirubin. UGT1A1 also catalyzes the glucuronidation of SN-38, the active metabolite of irinotecan and the main source of treatment-related toxicity. Glucuronidation is thought to protect against the toxicity of SN-38.¹ However, the presence of an additional TA repeat in the TATA region of the UGT1A1 promoter (ie, 7 TA repeats; UGT1A1*28) markedly decreases UGT1A1 production, leading to reduced glucuronidation.^2,3 Patients homozygous for the UGT1A1*28 allele therefore accumulate higher levels of SN-38 and are more likely to experience severe adverse effects during irinotecan chemotherapy.^4,5,6 Thus, knowledge of the UGT1A1 polymorphism status could help guide the selection of appropriate starting dosages, reducing the risk of severe toxicity and improving the chances that therapy could be maintained. Homozygosity for this allele is also associated with Gilbert’s syndrome, a mild form of unconjugated hyperbilirubinemia.

Roughly 10% of the US population is homozygous for UGT1A1*28. The frequency of the UGT1A1*28 allele varies among ethnicities,⁷ being highest in those of African (43%) or European (39%) descent and lowest in those of Asian (16%) descent.⁸ Variants with 5 or 8 repeats occur at much lower frequencies, primarily in individuals of African descent. The presence of 8 TA repeats has been associated with Gilbert’s syndrome and with decreased glucuronidation in vitro.⁸ Other variations in the genes encoding UGT1A1 and other uridine diphosphate glucuronosyltransferases may also influence glucuronidation and have been reported at varying frequencies across ethnicities.

• Patients being considered for treatment with irinotecan

• Individuals with suspected Gilbert’s syndrome

5 mL room-temperature whole blood (EDTA lavender-top tube); 3 mL minimum.

• Fluorescent polymerase chain reaction (PCR) with primers specific for the 5′ untranslated region of UGT1A1

• Automated detection of PCR products

• Results reported as negative, heterozygous, or homozygous for the UGT1A1*28 allele

• CPT codes*:  83891, 83900, 83909, 83912

Absence of the UGT1A1*28 allele usually indicates a wild-type genotype, although some individuals—especially those of African descent—may have 5 or 8 TA repeats. Patients with a wild-type UGT1A1 genotype have a low risk of severe toxicity from standard starting dosages of irinotecan. Similarly, in patients with 1 copy of the UGT1A1*28 allele (heterozygous), the other copy is most likely wild-type. These patients are at increased risk of irinotecan toxicity but may still tolerate normal initial dosages. Individuals with 2 copies of the UGT1A1*28 allele (homozygous) are at increased risk of severe toxicity from irinotecan. Irinotecan product information indicates that a reduced initial dosage should be considered for such patients.⁹ Other chemotherapeutic options may also be considered.

This assay does not detect other polymorphisms or mutations in the UGT1A1 gene that may impair irinotecan detoxification, nor does it examine other modifiers of irinotecan metabolism such as CYP3A4 activity. Since genetic variation can affect the accuracy of direct mutation testing, the results should be interpreted in light of other clinical and laboratory findings.

In symptomatic patients, homozygosity for UGT1A1*28 is consistent with a diagnosis of Gilbert’s syndrome. Because other UGT variants have been associated with Gilbert’s syndrome, absence of the UGT1A1*28 allele does not rule out this condition.