Prospective Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2016; 22(16): 4250-4258
Published online Apr 28, 2016. doi: 10.3748/wjg.v22.i16.4250
Predictive effects of bilirubin on response of colorectal cancer to irinotecan-based chemotherapy
Qian-Qian Yu, Hong Qiu, Ming-Sheng Zhang, Guang-Yuan Hu, Bo Liu, Liu Huang, Xin Liao, Qian-Xia Li, Zhi-Huan Li, Xiang-Lin Yuan
Qian-Qian Yu, Hong Qiu, Ming-Sheng Zhang, Guang-Yuan Hu, Bo Liu, Liu Huang, Qian-Xia Li, Xiang-Lin Yuan, Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Xin Liao, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Zhi-Huan Li, Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
Author contributions: Yuan XL designed the study; Yu QQ, Qiu H, Zhang MS and Hu GY performed the research; Yu QQ, Liu B, Huang L, Liao X and Li QX analyzed the data; Yu QQ and Li ZH wrote the paper; and Yuan XL revised the manuscript for final submission.
Supported by the National Natural Science Foundation of China, No. 81372664.
Institutional review board statement: The study was reviewed and approved by the Ethical Committee of Huazhong University of Science and Technology Institutional Review Board.
Clinical trial registration statement: This study is registered at http://www.clinicaltrials.gov. The registration identification number is NCT01282658.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors have no conflict of interest related to the manuscript.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at yxl@medmail.com.cn. Participants gave informed consent for data sharing. No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Xiang-Lin Yuan, PhD, MD, Professor of Medicine, Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, China. yxl@medmail.com.cn
Telephone: +86-27-83663342 Fax: +86-27-83663342
Received: January 20, 2016
Peer-review started: January 21, 2016
First decision: February 18, 2016
Revised: March 1, 2016
Accepted: March 14, 2016
Article in press: March 14, 2016
Published online: April 28, 2016
Processing time: 89 Days and 20.6 Hours
Abstract

AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy.

METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer (mCRC) patients treated with irinotecan-based chemotherapy (NCT01282658). Baseline serum bilirubin levels, including total bilirubin (TBil) and unconjugated bilirubin (UBil), were measured, and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve (ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or ≤ 13.0 groups; the UBil values were categorized into > 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as CoBil, patients were classified into three groups. The classifier’s performance of UGT1A1*28 and CoBil for predicting treatment response was evaluated by ROC analysis. Associations between response and CoBil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models.

RESULTS: Among the 120 mCRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil (P = 0.018) and a higher UBil (P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on CoBil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil > 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple (OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple (OR = 16.001; 95%CI: 2.802 -91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28 (TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous (TA)6 genotype in the simple (OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple (OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier’s performance of CoBil and UGT1A1*28 were comparable.

CONCLUSION: CoBil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of mCRC patients to irinotecan-based chemotherapy. After validation, CoBil, an easily determinable index in the clinic, might be helpful in facilitating stratification of mCRC patients for individualized treatment options.

Keywords: Bilirubin; Irinotecan; Metastatic colorectal cancer; Response; UGT1A1*28

Core tip: Serum bilirubin was reported to be associated with irinotecan-induced toxicity. The current study evaluated whether baseline bilirubin levels could predict treatment response of metastatic colorectal cancer patients given irinotecan-based chemotherapy in a Chinese population and found that a lower bilirubin level was an independent predictor of irinotecan treatment response.