Top

Cancer Chemotherapy and Pharmacology

Published in:

01-07-2016 | Original Article

UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer

Authors: Chunlei Xu, Xushan Tang, Yanli Qu, Saifuding Keyoumu, Ning Zhou, Yong Tang

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2016

Abstract

Objectives

To investigate the relationship between uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1)*28/*6 and toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer (CRC) in Xinjiang Uygur and Han population.

Methods

A total of 183 patients (Uygur, 114; Han, 69) with advanced CRC who received the irinotecan-based chemotherapy were enrolled in this retrospective analysis. Polymerase chain reaction amplification and direct sequencing method were used for UGT1A1*28 and UGT1A1*6 polymorphism detection. The patients were followed up to analyze the relationship between different genotypes with adverse reactions and the clinical outcome of irinotecan-based chemotherapy.

Results

Significant differences were found in genotype frequencies of UGT1A1*28 and UGT1A1*28/*6 between Uygur and Han (P = 0.02 and P = 0.002). Uygur and Han patients carrying wild UGT1A1*28 and *6 genotypes appeared to have significantly lower diarrhea incidence (I/II and III/IV) than those carrying mutant genotypes (all P < 0.05). In Uygur patients, UGT1A1*28 genotypes were related with objective response rate and disease control rate (P < 0.05). Compared with *1 allele *1/*1, *1 allele *1/*28*1/*28 mutant of UGT1A1*28 was associated with shorter OS in both Uygur and Han ethnicities (all P < 0.05). Compared with double allele variants (DW), single allele variants (SV), and double allele variants (DV) of UGT1A1*28/*6 were associated with shorter overall survival (OS) in Uygur and Han (all P < 0.05). Cox regression analysis revealed factors significantly influencing OS, including UGT1A1*28, UGT1A1*6, combined genotypes and chemotherapy line in Ugyur, and only combined genotypes in Han (all P < 0.05).

Conclusion

UGT1A1 gene polymorphism predicts irinotecan-related adverse reactions in advanced CRC patients of Xinjiang Uygur and Han nationality; UGT1A1 gene polymorphism is correlated with efficacy and prognosis in Uygur nationality, but only related to prognosis in Han nationality in irinotecan-based chemotherapy.

Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMed

Liu S, Zheng R, Zhang M et al (2015) Incidence and mortality of colorectal cancer in China, 2011. Chin J Cancer Res 27:22–28CrossRefPubMedPubMedCentral

Morand Bounaix, du Puch C, Nouaille M, Giraud S et al (2016) Chemotherapy outcome predictive effectiveness by the Oncogramme: pilot trial on stage-IV colorectal cancer. J Transl Med 14:10CrossRef

Gustavsson B, Carlsson G, Machover D et al (2015) A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer 14:1–10CrossRefPubMed

Hammond WA, Swaika A, Mody K (2016) Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol 8:57–84PubMedPubMedCentral

(2010) Chemotherapy of metastatic colorectal cancer. Prescrire Int 19(109):219–224

Kim MJ, Han SW, Lee DW et al (2016) Splenomegaly and its associations with genetic polymorphisms and treatment outcome in colorectal cancer patients treated with adjuvant FOLFOX. Cancer Res Treat. doi:10.4143/crt.2015.296

Yu M, Tong X, Qi B et al (2014) Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NFkappaB. Mol Med Rep 9:249–254PubMed

Fujita K, Sparreboom A (2010) Pharmacogenetics of irinotecan disposition and toxicity: a review. Curr Clin Pharmacol 5:209–217CrossRefPubMed

10.

O’Dwyer PJ, Catalano RB (2006) Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol 24:4534–4538CrossRefPubMed

11.

Cecchin E, Innocenti F, D’Andrea M et al (2009) Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol 27:2457–2465CrossRefPubMed

12.

Fujita K, Kubota Y, Ishida H, Sasaki Y (2015) Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. World J Gastroenterol 21:12234–12248CrossRefPubMedPubMedCentral

13.

Inoue K, Sonobe M, Kawamura Y et al (2013) Polymorphisms of the UDP-glucuronosyl transferase 1A genes are associated with adverse events in cancer patients receiving irinotecan-based chemotherapy. Tohoku J Exp Med 229:107–114CrossRefPubMed

14.

Tsunedomi R, Hazama S, Fujita Y et al (2014) A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes. Int J Oncol 45:1381–1390PubMedPubMedCentral

15.

Fukui T, Mitsufuji H, Kubota M et al (2011) Prevalence of topoisomerase I genetic mutations and UGT1A1 polymorphisms associated with irinotecan in individuals of Asian descent. Oncol Lett 2:923–928PubMedPubMedCentral

16.

Innocenti F, Grimsley C, Das S et al (2002) Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 12:725–733CrossRefPubMed

17.

Kaniwa N, Kurose K, Jinno H et al (2005) Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C > T (P229L) found in an African-American. Drug Metab Dispos 33:458–465CrossRefPubMed

18.

Marques SC, Ikediobi ON (2010) The clinical application of UGT1A1 pharmacogenetic testing: gene-environment interactions. Hum Genomics 4:238–249PubMedPubMedCentral

19.

Liu X, Cheng D, Kuang Q, Liu G, Xu W (2014) Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians. Pharmacogenomics J 14:120–129CrossRefPubMed

20.

Chen YJ, Hu F, Li CY et al (2014) The association of UGT1A1*6 and UGT1A1*28 with irinotecan-induced neutropenia in Asians: a meta-analysis. Biomarkers 19:56–62CrossRefPubMed

21.

Premawardhena A, Fisher CA, Liu YT et al (2003) The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications. Blood Cells Mol Dis 31:98–101CrossRefPubMed

22.

Zhang A, Xing Q, Qin S et al (2007) Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations. Pharmacogenomics J 7:333–338CrossRefPubMed

23.

Fujita K, Ando Y, Nagashima F et al (2007) Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer. Cancer Chemother Pharmacol 60:515–522CrossRefPubMed

24.

Hazama S, Mishima H, Tsunedomi R et al (2013) UGT1A1*6, 1A7*3, and 1A9*22 genotypes predict severe neutropenia in FOLFIRI-treated metastatic colorectal cancer in two prospective studies in Japan. Cancer Sci 104:1662–1669CrossRefPubMed

25.

Matsuoka A, Ando Y (2015) UGT1A1 genotyping for proper use of irinotecan. Rinsho Byori 63:876–882PubMed

26.

Cleeland CS, Gonin R, Baez L, Loehrer P, Pandya KJ (1997) Pain and treatment of pain in minority patients with cancer. The Eastern Cooperative Oncology Group Minority Outpatient Pain Study. Ann Intern Med 127:813–816CrossRefPubMed

27.

Kaba H, Fukuda H, Yamamoto S, Ohashi Y (2004) Reliability at the National Cancer Institute-Common Toxicity Criteria version 2.0. Gan To Kagaku Ryoho 31:1187–1192PubMed

28.

Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD (2010) Revised RECIST guideline version 1.1: what oncologists want to know and what radiologists need to know. AJR Am J Roentgenol 195:281–289CrossRefPubMed

29.

Xiao XG, Xia S, Zou M et al (2015) The relationship between UGT1A1 gene polymorphism and irinotecan effect on extensive-stage small-cell lung cancer. Onco Targets Ther 8:3575–3583CrossRefPubMedPubMedCentral

30.

Zhou CF, Ma T, Su Y et al (2013) UGT1A1 gene polymorphisms and the toxicities of FOLFIRI in Chinese Han patients with gastrointestinal cancer. Anticancer Agents Med Chem 13:235–241CrossRefPubMed

31.

Chantry AS, Quaranta S, Ciccolini J, Lacarelle B (2014) Clinical application, limits and perspectives of pharmacogenetic and pharmacokinetic analysis of anticancer drugs. Ann Biol Clin (Paris) 72:527–542

32.

Chibaudel B, Maindrault-Goebel F, Bachet JB et al (2016) PEPCOL: a GERCOR randomized phase II study of nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with leucovorin/5-fluorouracil as second-line therapy in metastatic colorectal cancer. Cancer Med 5:676–683CrossRefPubMedPubMedCentral

33.

Ando Y, Hasegawa Y (2005) Clinical pharmacogenetics of irinotecan (CPT-11). Drug Metab Rev 37:565–574CrossRefPubMed

34.

Soeda H, Shimodaira H, Gamoh M et al (2014) Phase II trial of cetuximab plus irinotecan for oxaliplatin- and irinotecan-based chemotherapy-refractory patients with advanced and/or metastatic colorectal cancer: evaluation of efficacy and safety based on KRAS mutation status (T-CORE0801). Oncology 87:7–20CrossRefPubMed

35.

Cheng L, Li M, Hu J et al (2014) UGT1A1*6 polymorphisms are correlated with irinotecan-induced toxicity: a system review and meta-analysis in Asians. Cancer Chemother Pharmacol 73:551–560CrossRefPubMed

36.

Wang Y, Shen L, Xu N et al (2012) UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil. World J Gastroenterol 18:6635–6644CrossRefPubMedPubMedCentral

37.

Atasilp C, Chansriwong P, Sirachainan E et al (2016) Correlation of UGT1A1(*)28 and (*)6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients. Drug Metab Pharmacokinet 31:90–94CrossRefPubMed

38.

Sukasem C, Atasilp C, Chansriwong P et al (2016) Development of pyrosequencing method for detection of UGT1A1 polymorphisms in thai colorectal cancers. J Clin Lab Anal 30:84–89CrossRefPubMed

39.

Green PM, Giannelli F (1994) Direct sequencing of PCR-amplified DNA. Mol Biotechnol 1:117–124CrossRefPubMed

40.

Biason P, Masier S, Toffoli G (2008) UGT1A1*28 and other UGT1A polymorphisms as determinants of irinotecan toxicity. J Chemother 20:158–165CrossRefPubMed

41.

Cortejoso L, Garcia MI, Garcia-Alfonso P et al (2013) Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer. Cancer Chemother Pharmacol 71:1463–1472CrossRefPubMed

42.

Li M, Wang Z, Guo J et al (2014) Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther 7:1653–1661PubMedPubMedCentral

43.

Boyer JC, Etienne-Grimaldi MC, Thomas F et al (2014) Interest of UGT1A1 genotyping within digestive cancers treatment by irinotecan. Bull Cancer 101:533–553PubMed

44.

Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD (2009) Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med 11:21–34CrossRefPubMedPubMedCentral

45.

Toffoli G, Cecchin E, Corona G et al (2006) The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 24:3061–3068CrossRefPubMed

46.

Schulz C, Heinemann V, Schalhorn A et al (2009) UGT1A1 gene polymorphism: impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World J Gastroenterol 15:5058–5066CrossRefPubMedPubMedCentral

47.

Liu X, Cheng D, Kuang Q, Liu G, Xu W (2013) Association between UGT1A1*28 polymorphisms and clinical outcomes of irinotecan-based chemotherapies in colorectal cancer: a meta-analysis in Caucasians. PLoS ONE 8:e58489CrossRefPubMedPubMedCentral

Title: UGT1A1 gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer
Authors: Chunlei Xu
Xushan Tang
Yanli Qu
Saifuding Keyoumu
Ning Zhou
Yong Tang
Publication date: 01-07-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3057-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2016

Effect of renal function on pemetrexed-induced haematotoxicity

Developing more effective, non-neurotoxic, methotrexate-based therapy in infants with brain tumors

Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours

Combinational strategies of metformin and chemotherapy in cancers

Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors

Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective

Keynote webinar | Spotlight on antibody–drug conjugates in cancer