Predictive effects of bilirubin on response of colorectal cancer to irinotecan-based chemotherapy.
OBJECTIVE
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.


CONCLUSIONS
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.
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.
Qian-Qian
QQ
Yu
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.
Hong
H
Qiu
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.
Ming-Sheng
MS
Zhang
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.
Guang-Yuan
GY
Hu
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.
Bo
B
Liu
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.
Liu
L
Huang
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
X
Liao
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.
Qian-Xia
QX
Li
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.
Zhi-Huan
ZH
Li
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.
Xiang-Lin
XL
Yuan
D000230:Adenocarcinoma / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016009:Chi-Square Distribution; D002681:China; D015179:Colorectal Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D016896:Treatment Outcome; D055815:Young Adult; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D001663:Bilirubin; D014408:Biomarkers, Tumor; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme
Bilirubin; Irinotecan; Metastatic colorectal cancer; Response; UGT1A1*28