UGT1A1 Polymorphism Can Predict Hematologic Toxicity in Patients Treated with Irinotecan

^{1 1}Institut National de la Sante et de la Recherche Medicale UMR-S775, Bases moléculaires de la réponse aux xénobiotiques; Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou; Fédération Francophone de Cancérologie Digestive (FFCD), Paris, France; ²Unité de Biostatiques and ³Service d'Oncologie, Centre de Lutte contre le Cancer Val d'Aurelle; Groupe digestif de la Fédération Nationale des Centres de Lutte contre le Cancer (FNCLCC), Montpellier, France; ⁴Service d'Anatomie-Pathologique, Hôpital Laënnec (CHU de Nantes), St-Herblain, France; ⁵Service d'Anatomie-Pathologique, CHU de Reims, Hôpital Robert Debré, Reims, France; ⁶Service d'Anatomie-Pathologique, Institut Bergonié, Bordeaux, France; ⁷Service d'Anatomie-Pathologique, CHU de Rennes, Rennes, France; and ⁸Laboratoire d'Anatomie-Pathologiques, CHU Purpan, Toulouse, F-31300 France

^* To whom correspondence should be addressed. E-mail: pierre_laurent-puig{at}univ-paris5.fr.

	Abstract

Purpose: Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial.

Experimental Design: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and -3156G>A for UGT1A1.

Results: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005].

Conclusions: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)₆TAA>(TA)₇TAA polymorphism.

Key Words: UGT1A1, colorectal cancer, Irinotecan, hematologic toxicity