Utility of Pretreatment Bilirubin Level and UGT1A1 Polymorphisms in Multivariate Predictive Models of Neutropenia Associated with Irinotecan Treatment in Previously Untreated Patients with Colorectal Cancer

Abstract

PURPOSE: Statistical models for predicting hematologic toxicity were evaluated based on UGT1A1 polymorphisms and baseline serum bilirubin. METHODS: Blood DNA samples were collected from 113 patients with untreated metastatic colorectal cancer receiving irinotecan (FOLFIRI, n = 36; mIFL, n = 41; CapeIRI, n = 36). The primary endpoint was absolute neutrophil count nadir during first treatment cycle. Linear regression models, with increased R(2) implying important additional predictive power, sequentially added age, sex, baseline bilirubin level, and UGT1A1 genotype. RESULTS: All models demonstrated low R(2), suggesting unaccounted variables. UGT1A1 genotype added approximately 8-9% during cycle 1 and from approximately 7% [mIFL regimen] to 26% [CapeIRI regimen] after cycle 1. Correlation between genotype and overall ANC nadir without regard to treatment was low (R = -0.201, P = 0.035). Patients with genotype 7/7 may have increased risk for severe neutropenia, but data are insufficient to characterize this. Contribution of baseline bilirubin level was negligible. CONCLUSIONS: Ability of UGT1A1 or baseline bilirubin to predict neutropenia is low and depends on regimen.

Figure 1

Major pathways of irinotecan metabolism and disposition. A reaction catalyzed by carboxylesterase-2 yields SN-38, the active metabolite. Glucuronidation of SN-38 to SN-38G is catalyzed by the enzyme UGT1A1. Several UGT1A1 polymorphisms exist, coding for a spectrum of enzyme expression and varying ability to metabolize SN-38. This figure was published in Semin Oncol, 32, Tan BR, McLeod HL, Pharmacogenetic influences on treatment response and toxicity in colorectal cancer, 113–9, Copyright Elsevier (2005).

Figure 2

Baseline bilirubin levels and UGT1A1 indel genotype. A, baseline bilirubin and absolute neutrophil count (ANC) nadir. B, ANC nadir by UGT1A1 indel genotype. C, treatment group in patients receiving irinotecan.