Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Authors: Dan Liu, Jian Li, Jing Gao, Yanyan Li, Rui Yang, Lin Shen

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

To evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).

Methods

The genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.

Results

In the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395–3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138–30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946–11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136–4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression-free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001).

Conclusion

Results still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.
Appendix
Available only for authorised users
Literature
1.
Garcia-Alfonso P, Chaves M, Muñoz A, et al. Capecitabine and irinotecan with bevacizumab 2-weekly for metastatic colorectal cancer: the phase II AVAXIRI study. BMC Cancer. 2015;15(1):1–9.CrossRef
2.
Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan study group. N Engl J Med. 2000;343(13):905–14.CrossRefPubMed
3.
Lamas MJ, Duran G, Balboa E, et al. The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan⁃based regimens. Cancer Chemother Pharmacol. 2012;69(6):1591–9.CrossRefPubMed
4.
Miyata Y, Touyama T, Kusumi T, et al. UDP-glucuronosyltrans-ferase 1A1*6 and ∗28 polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer. Int J Clin Oncol. 2016;21(4):696–703.CrossRefPubMed
5.
Gao J, Zhou J, Li Y, et al. UGT1A1∗6/∗28 polymorphisms could predict irinotecan induced severe neutropenia not diarrhea in Chinese colorectal cancer patients. Med Oncol. 2013;30(3):1–6.
6.
Cheng L, Li M, Hu J, et al. UGT1A1*6 polymorphisms are correlated with irinotecan-induced toxicity: a system review and meta-analysis in Asians. Cancer Chemother Pharmacol. 2014;73(3):551–60.CrossRefPubMed
7.
Tsunedomi R, Hazama S, Fujita Y, et al. A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes. Int J Oncol. 2014;45(4):1381–90.PubMedPubMedCentral
8.
Mego M, Chovanec J, Vochyanova-Andrezalova I, et al. Prevention of irinotecan induced diarrhea by probiotics: a randomized double blind, placebo controlled pilot study. Complement Ther Med. 2015;23(3):356–62.CrossRefPubMed
9.
Yan L, Wang XF, Wei LM, et al. Effects of UGT1A1*6, UGT1A1*28, and ABCB1-3435C>T polymorphisms on irinotecan induced toxicity in Chinese cancer patients. Int J Clin Pharmacol Ther. 2016;54(3):193–9.CrossRefPubMed
10.
Sunakawa Y, Ichikawa W, Fujita K, et al. UGT1A1*1/*28 and *1/*6 genotypes have no effects on the efficacy and toxicity of FOLFIRI in Japanese patients with advanced colorectal cancer. Cancer Chemother Pharmacol. 2011;68(2):279–84.CrossRefPubMed
11.
Gentile G, Botticelli A, Lionetto L, et al. Genotype-phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction. Pharmacogenomics J. 2016;16(4):320–5.CrossRefPubMed
12.
Mazzuca F, Borro M, Botticelli A, et al. Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort. Oncotarget. 2016;7(15):20612–20.PubMedPubMedCentral
13.
Etienne-Grimaldi MC, Boyer JC, Thomas F, et al. UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice. Fundam Clin Pharmacol. 2015;29(3):219–37.CrossRefPubMed
14.
Leung HW, Chan AL. Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: a meta-analysis. Biomed Rep. 2015;3(6):879–83.PubMedPubMedCentral
15.
Teh LK, Hamzah S, Hashim H, et al. Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients. Ther Drug Monit. 2013;35(5):624–30.PubMed
16.
Falvella FS, Cheli S, Martinetti A, et al. DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan. Br J Clin Pharmacol. 2015;80(3):581–8.CrossRefPubMedPubMedCentral
17.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed
18.
Mik M, Berut M, Dziki L, et al. Right- and left-sided colon cancer – clinical and pathological differences of the disease entity in one organ. Arch Med Sci. 2017;13(1):157–62.CrossRefPubMed
19.
Sakar B, Gumus M, Basaran M, et al. XELOX followed by XELIRI or the reverse sequence in advanced colorectal cancer. Oncology. 2007;73(5–6):298–304.CrossRefPubMed
20.
Wang Y, Shen L, Xu N, et al. UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil. World J Gastroenterol. 2012;18(45):6635–44.CrossRefPubMedPubMedCentral
21.
Li M, Wang Z, Guo J, et al. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther. 2014;7:1653–61.PubMedPubMedCentral
22.
Xu C, Tang X, Qu Y, et al. UGT1A1, gene polymorphism is associated with toxicity and clinical efficacy of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Cancer Chemother Pharmacol. 2016;78(1):1–12.CrossRef
23.
Atasilp C, Chansriwong P, Sirachainan E, et al. Correlation of UGT1A1*28 and *6 polymorphisms with irinotecan-induced neutropenia in Thai colorectal cancer patients. Drug Metab Pharmacokinet. 2016;31(1):90–4.CrossRefPubMed
24.
Shimoyama S. Pharmacogenetics of irinotecan: an ethnicity⁃based prediction of irinotecan adverse events. World J Gastrointest Surg. 2010;2(1):14–21.CrossRefPubMedPubMedCentral
25.
Fujita K, Ando Y, Nagashima F, et al. 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. 2007;60:515–22.CrossRefPubMed
26.
Hazama S, Mishima H, Tsunedomi R, et al. UGT1A1∗6, 1A7 ∗3, and 1A9∗22 genotypes predict severe neutropenia in FOL⁃/FIRI⁃treated metastatic colorectal cancer in two prospective studies in Japan. Cancer Sci. 2013;104(12):1662–9.CrossRefPubMed
27.
Tziotou M, Kalotychou V, Ntokou A, et al. Polymorphisms of uridine glucuronosyltransferase gene and irinotecan toxicity: low dose does not protect from toxicity. Ecancermedicalscience. 2014;8:428.PubMedPubMedCentral
28.
Carlini LE, Meropol NJ, Bever J, et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res. 2005;11(3):1226–36.PubMed
29.
Cecchin E, Innocenti F. D Andrea M, et al. 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. 2009;27(15):2457–65.CrossRefPubMed
30.
Deenen MJ, Meulendijks D, Cats A, et al. Upfront genotyping of DPYD*2A to individualize Fluoropyrimidine therapy: a safety and cost analysis. J Clin Oncol. 2016;34(3):227–34.CrossRefPubMed
31.
Sirachainan E, Reungwetwattana T, Wisetpanit Y, et al. Pharmacogenetic study of 5-FU-related severe toxicity in Thai cancer patients: a novel SNP detection. J Pharmacogenomics Pharmacoproteomics. 2012;3:1–4.CrossRef
32.
Zhang XP, Bai ZB, Chen BA, et al. Polymorphisms of dihydropyrimidine dehydrogenase gene and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population. Chin Med J. 2012;125:741–6.PubMed
33.
Toffoli G, Cecchin E, Corona G, et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol. 2006;24:3061–8.CrossRefPubMed
34.
Lu CY, Huang CW, Wu IC, et al. Clinical implication of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab combined with FOLFIRI in the first⁃line setting. Transl Oncol. 2015;8(6):474–9.CrossRefPubMedPubMedCentral
35.
36.
Braun MS, Richman SD, Thompson L, et al. Association of Molecular Markers with Toxicity Outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol. 2009;27(33):5519–28.CrossRefPubMed
Metadata
Title
Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis
Authors
Dan Liu
Jian Li
Jing Gao
Yanyan Li
Rui Yang
Lin Shen
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3406-2

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer

Research article

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Research article

Metastatic polyp of the gallbladder from renal cell carcinoma

Research article

MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

Erratum

Erratum to: Feasibility outcomes of a presurgical randomized controlled trial exploring the impact of caloric restriction and increased physical activity versus a wait-list control on tumor characteristics and circulating biomarkers in men electing prostatectomy for prostate cancer

Research article

Distinct immunophenotypes and prognostic factors in renal cell carcinoma with sarcomatoid differentiation: a systematic study of 19 immunohistochemical markers in 42 cases
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
Image Credits