S30 - Can irinotecan dose reduction according to ugt1a1 genotype avoid severe toxicities?

Abstract

Background: Uridine diphosphoglucuronosyl transferase 1A1 (UGT1A1) *28 polymorphism reduces UGT1A1 enzymatic activity and is possibly associated with irinotecan(IRI)-induced neutropenia and diarrhea. The aim of this single-centre analysis is to assess if IRI dose-reduction according to UGT1A1 status can avoid severe toxicities. Patients and methods: Patients (pts) with different solid tumours candidate to chemotherapy with IRI were consecutively genotyped for UGT1A1*28 polymorphism at our Institution. DNA was extracted from peripheral blood cells and UGT1A1 promoter region was amplified with PCR, using primers marked with a fluorochrome; a specific kit prepared in our laboratories was used. Data about clinico-pathological features, IRI dose reduction, toxicity, objective response rate and progression free survival were retrospectively collected. Results: From January 2015 to March 2016, 122 pts were genotyped for UGT1A1 (M/F 59/63, median age 67): 39% were omozygous wild-type, 48% were heterozygous, 13% were omozygous mutated. At the time of our analysis IRI was administered to 32 pts with the following characteristics: M/F 13/19; median age 62.5 (range 38-85); colorectal cancer/pancreatic cancer/gastroesophageal cancer 23/7/2; UGT1A1 wild-type/heterozygous/omozygous 10/16/6. The median IRI-starting dose was 180 mg/mq in wild-type group, 135 mg/mq in heterozygous group and 135 mg/mq in omozygous group. A correlation between UGT1A1 homozygosis and G3-4 toxicity was observed (chi2 = 0.042). After the first cycle, grade = 3 neutropenia occurred in 2 pts in the omozygous group, grade = 3 diarrhea occurred in 1 wild-type and in 1 omozygous patient. 2 of the omozygous pts who experienced high grade toxicities had received high-doses of IRI (180 mg/mq). Response to treatment was evaluated in 19 pts: 3 partial responses, 6 stable diseases and 10 progressive diseases were observed. At the time of analysis 16 pts had progressed with a median progression free survival of 4.2 months, but data are still immature for further survival analysis. Conclusions: UGT1A1 genotype can be used to individualize IRI-dosage in order to reduce treatment related high-grade neutropenia and diarrhea in mutated pts. Further studies and longer follow-up are needed to assess the safer IRI-dosage in both omozygous and heterozygous mutated pts and to evaluate the efficacy of dose-reduction in terms of response to treatment and survival.