Prediction of Response to Irinotecan and Drug Toxicity Based on Pharmacogenomics Test: A Prospective Case Study in Advanced Colorectal Cancer

Background: FOLFIRI regimen, which is composed of 5-FU, Leucovorin, and Irinotecan, is used in the first-line chemotherapy of metastatic colorectal cancer. Irinotecan life threatening toxicity is partly related to cytotoxic drug metabolite which is primarily inactivated by the UGT1A1 enzyme. The primary aim of the present research was to find the correlation between UGT1A1-genotype and clinical toxicity of irinotecan. Methods: In a prospective study from March 2011 to December 2013, all patients with metastatic colorectal cancer who had been referred to Medical Oncology Department of Iran Cancer Institute were genotyped for UGT1A1*28 before the first cycle of chemotherapy. All of the patients signed informed consent and trial approved by Ethics Committee of the Tehran University of Medical Sciences. Reduction of the standard dose of Irinotecan (180 mg/m2 body surface area) was measured based on NCI toxicity criteria after the first cycle of chemotherapy. Patients with previous treatment with Oxaliplatin and fluorouracil (5-FU) in the adjuvant setting and adequate liver, kidney, and heart function were included in the trial. Both synchronous and metachronous metastatic disease were noticeable. Results: A total of 50 patients with median age of 52 years were included. Most (70%) of the patients had more than one site of metastases in peritoneum, liver, and/or lung. Thirty-one patients had UGT1A1*1 normal genotype, 13 were in heterozygote and 6 were in homozygote state ofUGT1A1*28/*28. A clinically relevant increase in early toxicity was found in patients carrying the UGT1A1*28/*28 genotype with odds Ratio (OR) of 2.6 (95%CI 2.5-27.28). Similarly, there was a trend of lower overall survival in homozygote group with an HR (Hazardous Ratio) of 2.76 (95%CI .88-.61). No statistically significant relationship was found between UGT1A1genotypes and response to therapy. Conclusions: UGT1A1 28*/28* is strongly associated with drug’s life-threatening toxicity even in a moderate dose of Irinotecan. On the other hand, UGT1A1 genotype data was not helpful to differentiate response to treatment.

[1]  M. Takano,et al.  UGT1A1 polymorphisms in cancer: impact on irinotecan treatment , 2017, Pharmacogenomics and personalized medicine.

[2]  E. Schuetz,et al.  Interindividual Variability in Cytochrome P450–Mediated Drug Metabolism , 2016, Drug Metabolism and Disposition.

[3]  Y. Hamamoto,et al.  A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes , 2014, International journal of oncology.

[4]  Shun'ichi Suzuki,et al.  Development of a Novel, Fully-Automated Genotyping System: Principle and Applications , 2012, Sensors.

[5]  M. Ingelman-Sundberg,et al.  Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects , 2012, The Pharmacogenomics Journal.

[6]  H. Guchelaar,et al.  Pharmacogenetics: From Bench to Byte— An Update of Guidelines , 2011, Clinical pharmacology and therapeutics.

[7]  H. Sorbye,et al.  Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer , 2010, The Pharmacogenomics Journal.

[8]  U. Amstutz,et al.  Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment. , 2009, Pharmacogenomics.

[9]  E. Bandrés,et al.  Pharmacogenomics in colorectal cancer: the first step for individualized-therapy. , 2007, World journal of gastroenterology.

[10]  Joseph G Ibrahim,et al.  UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. , 2007, Journal of the National Cancer Institute.

[11]  D. Tregouet,et al.  Thymidylate Synthase Gene Polymorphism Predicts Toxicity in Colorectal Cancer Patients Receiving 5-Fluorouracil-based Chemotherapy , 2004, Clinical Cancer Research.

[12]  Soma Das,et al.  Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Howard L McLeod,et al.  Pharmacogenomics--drug disposition, drug targets, and side effects. , 2003, The New England journal of medicine.

[14]  S. Groshen,et al.  Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  Ali Montazeri,et al.  The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): translation and validation study of the Iranian version , 1999, Supportive Care in Cancer.

[16]  S. Marsh,et al.  Irinotecan pharmacogenomics. , 2010, Pharmacogenomics.

[17]  J. Sanderson,et al.  The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients , 2009, Cancer Chemotherapy and Pharmacology.

[18]  R. Schilsky,et al.  UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity , 2002, The Pharmacogenomics Journal.