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. 2017 Feb 25;8(4):691–703. doi: 10.7150/jca.17210

Predictive Value of UGT1A1*28 Polymorphism In Irinotecan-based Chemotherapy

Xing-Han Liu 1,*, Jun Lu 2,*, Wei Duan 3, Zhi-Ming Dai 4, Meng Wang 1, Shuai Lin 1, Peng-Tao Yang 1, Tian Tian 1, Kang Liu 1, Yu-Yao Zhu 1, Yi Zheng 1, Qian-Wen Sheng 1, Zhi-Jun Dai 1,✉
PMCID: PMC5370513  PMID: 28367249

Abstract

The UGT1A1*28 polymorphism was suggested to be significantly connected with irinotecan-induced toxicity and response to chemotherapy. However, the results of previous studies are controversial. Hence we carried out a meta-analysis to investigate the effect of UGT1A1*28 polymorphism on severe diarrhea, neutropenia, and response of patients who had undergone irinotecan-based chemotherapy. The PubMed, Web of Science, Wanfang, and CNKI databases were searched for clinical trials assessing the association of UGT1A1*28 polymorphism with severe diarrhea, neutropenia, and response to irinotecan-based chemotherapy. The combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the relationship under a fixed- or random-effects model. Fifty-eight studies including 6087 patients with cancer were included. Our results showed that patients carrying the TA6/7 and TA7/7 genotypes had a greater prevalence of diarrhea and neutropenia than those with the TA6/6 genotype (TA6/7+TA7/7 vs. TA6/6: diarrhea, OR = 2.18, 95%CI = 1.68-2.83; neutropenia, OR = 2.15, 95%CI = 1.71-2.70), particularly patients with metastatic colorectal cancer. Stratified analysis showed that Asians with the TA6/7 and TA7/7 genotypes were more likely to have diarrhea and neutropenia, and Caucasians with the TA6/7 and TA7/7 genotypes were more likely to have neutropenia than other groups. However, patients with the TA6/7+TA7/7 genotypes showed a higher response than patients with TA6/6 genotype (OR = 1.20, 95%CI = 1.07-1.34), particularly Caucasians (OR = 1.23, 95%CI = 1.06-1.42) and patients with metastatic colorectal cancer (OR = 1.24, 95%CI = 1.05-1.48). Our data showed that the UGT1A1*28 polymorphism had a significant relationship with toxicity and response to irinotecan-based chemotherapy. This polymorphism may be useful as a monitoring index for cancer patients receiving irinotecan-based chemotherapy.

Keywords: UGT1A1*28, diarrhea, neutropenia, response.

Introduction

According to the estimation, there are probably 1,658,370 people suffer from cancer and 589,430 people die of cancer in the United States in 20151. In China, the corresponding data were 4,292,000 and 2,814,000 in 2015, respectively, which means cancer is an urgent problem to be solved 2. Several methods such as surgery, radiotherapy, and chemotherapy are widely applied for the clinical treatment of cancer. Irinotecan-based chemotherapy is one of the most used chemotherapies for patients with advanced gastric cancer, ovarian cancer, metastatic colorectal cancer, and other cancers 3-5. Irinotecan, a camptothecin derivative, is mainly transported into liver by solute carriers and metabolized into ametabolite, SN-38, by a carboxylesterase 6. In turn, SN-38 is glucuronidated by uridinediphosphate (UDP)-glucuronosyltransferases (UGTs) to an inactive form, SN-38G. Lower glucuronidation rates lead to higher SN-38 concentrations, resulting in irinotecan-induced severe toxicity 7. Diarrhea and neutropenia are the most common side effects of irinotecan-based chemotherapy, limiting its application 8. Recent studies have confirmed thatUDP UGT 1A1 play a vital role in the process of glucuronidation 9, 10.

The UGT1A1*28 polymorphism contains an extra TA repeat in the 5′-promoter region, whose mutant genotype is A(TA)7TAA (TA7/7) and has a wide genotype of A(TA)6TAA (TA6/6). Toffoli et al.11 found that UGT1A1*28 TA7/TA7 genotype is related to a lower glucuronidation ratio. Previous studies investigated the relationship of UGT1A1*28 with neutropenia and diarrhea and have shown conflicting results. TA6/6 was reported to be a main predictive factor for diarrhea in a study of 56 advanced colorectal carcinoma (CRC) 12. In contrast, some studies found that patients with the TA6/7 or TA7/7 genotypes are more inclined to suffer severe neutropenia and diarrhea 13-16. However, no correlation was defined between the UGT1A1*28 polymorphism and neutropenia according to data from Hirata et al.17 and Ferraldeschi et al.18.

To clarify the predictive value of the UGT1A1*28 polymorphism in patients receiving irinotecan-based chemotherapy, we conducted this study to investigate the impact of the UGT1A1*28 polymorphism on tumor response and the common toxicities, diarrhea and neutropenia.

Materials and methods

Publication Search

Studies were selected by retrieving the Web of Science, PubMed, CNKI, and WanFang databases, up to June 2016. Similar keywords were used in different databases: “UGT1A1*28” and “diarrhea,” “UGT1A1*28” and “neutropenia,” “UGT1A1*28” and “response,” “UGT1A1*28” and “irinotecan,” “UGT1A1*28” and “CPT-11,” and related terms. No language restrictions were applied. All qualified studies were searched and a cross search was also used to identify the remaining relevant studies. When overlapping data exist in different reports, the most complete article was included. Disagreements between two authors will be settled by discussion and consensus.

Selection Criteria

Studies were included if they fulfilled the following criteria: (a) clinical trials; (b) evaluated the association of the UGT1A1*28 polymorphism with irinotecan-induced toxicities and chemotherapeutic effect; and (c) contained key information about the number of patients who have severe diarrhea, neutropenia and response to chemotherapy or not. Duplicate studies, review articles, letters, non-original studies, or case reports were excluded.

Data Extraction

Detailed information of included studies had been extracted and recorded in a standardized table by two reviewers. The following information was recorded: first author's surname, year of publication, ethnicity, cancer subtype, methods of mutation detection, number of patients with and without response, severe diarrhea and neutropenia, genotypes were extracted. If these data were not reported, items were marked “NR” (not reported).

Data Synthesis

This meta-analysis was conducted according to the PRISMA guidelines 19. We used the Newcastle-Ottawa-Scale (NOS) to assess the qualities of including studies and calculated the combined odd ratios (ORs) and 95% confidence intervals (CIs) to evaluate the strength of relationship between the UGT1A1*28 polymorphism and irinotecan-induced diarrhea or neutropenia under the four models (TA6/7 vs. TA6/6, TA7/7 vs. TA6/6, TA6/7+TA7/7 vs. TA6/6, and TA7/7 vs. TA6/6+TA6/7) 20. The association between tumor response and the UGT1A1*28 polymorphism was calculated only in the dominant model (TA6/7+TA7/7 vs. TA6/6). Pooled ORs were tested by the Z test, and a P value <0.05 was considered significant. Chi-square test and Q test were used to examine the heterogeneity among the studies. We also performed stratified analysis depending on tumor types (advanced gastric cancer, metastatic non-small cell lung cancer, metastatic colorectal cancer, or others), ethnicity (Asian, Caucasian or mixed people) and study design (retrospective or prospective study). Publication bias were determined by Egger's and Begg's tests 21, 22. Specific methods are described in our pervious study 23. A trim and fill method of adjusting for publication bias was carried out when the P value of Egger's test was less than 0.05 24. Trial sequential analysis (TSA) was conducted to calculate the required sample size to get a robust conclusion 20. When P values of two-sided comparisons were less than 0.05, we considered the difference was significant. We performed all the statistical calculations by STATA 12.0 (StataCorp LP, College Station, TX, USA).

Results

Characteristics of the Studies Included

As shown in Figure 1, we performed the primary literature retrieval using the PubMed, Web of Science, Wanfang, and CNKI databases by the end of June 2016. First, 307 articles were included and 119 articles were excluded after searching for duplicates. Second, we read the titles and abstracts and excluded 78 articles because they were letters, case reports, reviews or reporting about other polymorphisms. Finally, after reading the full-text of all articles, 53 articles were excluded due to lacking of useful data or evaluation about other toxicities and 58 studies from 57 articles including 6087 patients with cancer were found to meet the inclusion criteria.

Figure 1.

Figure 1

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Flow diagram of included studies for the meta-analysis. CNKI = China National Knowledge Infrastructure

Among these studies, 16 studies investigated the associations in Caucasians 11-15, 18, 25-35, 40 in Asians 3, 9, 16, 17, 36-62, and two in mixed population or not reported 63, 64. All studies were retrospective or prospective studies, including 29 metastatic colorectal cancer (mCRC) studies, five metastatic non-small cell lung cancer (mNSCLC), three advanced gastric cancer (GC) studies, two SCLC studies, and two advanced esophageal cancer studies and others. Table 1 summarized the basic information of the included studies.

Table 1.

Characteristics of the Studies Included in the Meta-Analysis

Study Year Study design Race Cancer Mutation detection methods Regimen IRI dose (mg/m2)/schedule Population source No. of patients Age ECOG NOS
Yan8 2016 R Asian mixed tumors PCR-Sanger sequence FOLFIRI, IRI + CDDP, IRI + BEV 125, 150 or 180 mg/m2 S 157 53 NR 8
Xu64 2016 R Asian mCRC Direct Sequencing FOLFIRI, IRI+CAP 150mg/m2, every 2 or 3 weeks S 183 NR 0-1 9
Gui65 2016 R Asian mCRC SPR FOLFIRI, IFL 180mg/m2, every 2 or 3 weeks S 384 NR 0-2 8
Wang5 2016 P Asian Advanced GC SPR IRI+CDDP 80 or 125mg/m2 S 40 54 0-2 8
Li4 2016 P Asian mCRC SPR FOLFIRI, mCapeIRI, IRI NR M 160 50 0-2 9
Yang63 2015 R Asian pancreatic or biliary tract cancer Direct Sequencing FOLFIRI, IRI alone 180mg/m2, biweekly S 48 56.2 0-1 7
Peng60 2015 P Asian mCRC Sequencing FOLFIRI; mFOLFIRI 180mg/m2, biweekly S 208 59.8 0-3 7
Wu59 2015 P Asian Advanced esophageal cancer NR IRI+PLA 180mg/m2, every 3weeks S 42 55 0-2 7
Xu3 2015 NR Asian advanced OC PYRS IRI+CDDP 60mg/m2 IRI (d1, 8) every 3 weeks S 89 48 NR 7
Xiao9 2015 R Asian SCLC PYRS IRI+CDDP/CBP/LOB 60 mg/m2 (d1,8,15), every 4 weeks; 85mg/m2 (d1,8), every 3 weeks S 67 NR 0-2 8
Shi61 2015 P Asian SCLC Direct Sequencing IRI+CDDP 65mg/m2 (d1, 8) M 30 59 0-2 8
Atasilp10 2015 R Asian mCRC PYRS FOLFIRI, FOLFIRI+CET, FOLFIRI+BEV, mFOLFIRI, IRI alone, IRI+CET/CAP 180mg/m2, biweekly; 100mg/m2 S 44 6 0-2 7
Chen62 2015 P Asian mNSCLC Sequencing IRI+DDP 100mg/m2, every 3 weeks S 86 63 0-2 8
Wang35 2015 P Asian mCRC Sequencing NR NR S 111 NR 0-1 7
Li54 2014 R Asian mCRC PYRS FOLFIRI, IRI + CET/BEV, IRI + RAL, IRI+ CAP 180 mg/m2, every 2 or 3 weeks S 167 50 0-2 8
Hirata17 2014 P Asian mCRC SPR FOLFIRI 150mg/m2, biweekly M 34 62 0-2 7
Zhao55 2014 P Asian SCLC Direct sequencing IRI+CDDP 60mg/m2 (d1,8,15), every 3 weeks S 34 49 0-2 8
Song56 2014 P Asian Advanced OC NR IRI+PLA 60mg/m2 (d1,8), every 3 weeks S 89 48 NR 8
Zhang57 2014 P Asian mCRC Sequencing FOLFIRI, XELIRI, IRIR 180mg/m2, biweekly; 200mg/m2, every 3weeks S 102 55 NR 8
Xu53 2014 P Asian GC Sequencing NR NR S 67 62.7 0-2 8
Zhou58 2014 P Asian mCRC SPR IRI+5-FU/TMZ/CAP 180mg/m2 S 82 59 NR 8
Zhou52 2013 P Asian gastrointestinal cancer Direct Sequencing FOLFIRI 180mg/m2, biweekly S 94 58.5 0-1 8
Hirasawa50 2013 R Asian cervical or ovarian cancer Invader assay IRI+CDDP, IRI alone 60 or 100mg/m2 (d1, 8, 15), every 4 weeks S 53 48 NR 7
Gao48 2013 R Asian mCRC Sanger Sequencing FOLFIRI, IRI alone or IRI+CET/CAP 180mg/m2 S 276 55 NR 7
Gao49 2013 R Asian advanced GC Sanger Sequencing IRI+CDDP, FOLFIRI, IRI alone, IRI+CET 180mg/m2 S 42 53 NR 7
Gao49 2013 R Asian advanced esophageal cancer Sanger Sequencing IRI+CDDP, FOLFIRI, IRI alone, IRI+CET 130mg/m2; 180mg/m2 S 91 54 NR 7
Qin51 2013 R Asian advanced gastrointestinal carcinoma Sequencing IRI, IRI+CDDP, IRI+5-FU NR S 183 NR NR 7
Wang45 2012 NR Asian mCRC Direct Sequencing FOLFIRI, IRI+LEU 180mg/m2, biweekly; 125mg/m2 (d1, 8, 15, 22), every 6 weeks S 130 52 0-2 7
Zhang46 2012 P Asian mCRC Direct Sequencing FOLFIRI, IRI+LEU 180mg/m2, biweekly; 125mg/m2 (d1, 8, 15, 22), every 6 weeks S 56 55.5 NR 8
Lamas34 2012 R Caucasian mCRC Fluorescent DNA length fragment analysis FOLFIRI, FOLFIRI-CET, FOLFIRI-BEV, IRI+CET 180mg/m2, biweekly S 101 67 0-2 7
Wang47 2012 P Asian mCRC Sequencing IFL, FOLFIRI 125mg/m2, weekly;180mg/m2,biweekly S 180 54 0-2 7
Shulman33 2011 R Caucasian mCRC SPR FOLFIRI, IFL, TEGAFIRI, XELIRI U M 214 63.1 NR 8
Okuyama43 2011 P Asian mCRC SPR FOLFIRI 150mg/m2 S 39 64 0-2 7
Nakamura42 2011 P Asian mNSCLC Polyacrylamide gel electrophoresis IRI+PAC, IRI+GEM 50mg/m2 (d1, 8 and 15), every 4 weeks; 100mg/m2 (d1 and 8), every 3 weeks S 77 NR 0-1 8
Park44 2011 P Asian mGC Sequencing S-1+IRI+OXA 150mg/m2, every 3 weeks S 44 54 0-2 7
Mcleod32 2010 P Caucasian mCRC PYRS IRI+FU+LEU, IRI+OXA 100-125mg/m2 (d1, 8, 15 and 22), every 6 weeks; 200mg/m2, every 3 weeks M 212 61 0-2 8
Ji41 2010 R Asian mCRC Sequencing FOLFIRI 180mg/m2, biweekly S 64 NR 0-2 7
Balibrea31 2010 P Caucasian mCRC Sequencing IRI+ 5-FU, IRI+5FU/LV 80mg/m2, weekly; 180mg/m2, biweekly M 149 NR 0-2 8
Han39 2009 P Asian mNSCLC SBE IRI+CDDP 65 or 80mg/m2 (d1 and 8), every 3 weeks S 107 58 0-2 7
Onoue40 2009 P Asian Mixed tumors Direct Sequencing IRI alone; IRI+plat; IRI+ other anticancer agents, FOLFIRI 60-100mg/m2 S 133 NR 0-1 7
Ferraldeschi18 2009 P Mixed mCRC SPR IRI, FOLFIRI, IRI+VEGF inhibitor 350mg/m2, every 3 weeks; 180mg/m2, biweekly S 92 62.9 NR 8
Rouits29 2008 R Caucasian mCRC PYRS FOLFIRI 180mg/m2, biweekly S 44 60 0-2 8
Parodi28 2008 P Caucasian mCRC SPR FOLFIRI, mIFL, CapeIRI 125 or 180mg/m2, biweekly; 250mg/m2, every 3 weeks M 110 NR 0-2 8
Liu16 2008 R Asian mCRC SPR FOLFIRI 180mg/m2, biweekly S 128 NR 0-2 8
Kweekel15 2008 R Caucasian mCRC PYRS IRI+CAP+OAX 250 or 350mg/m2 (d1), every 3 weeks M 218 NR 0-2 8
Wang38 2007 P Asian mCRC SPR FOLFIRI 180mg/m2, biweekly M 70 NR 0-3 8
Ruzzo30 2007 P Caucasian mCRC SPR FOLFIRI 180mg/m2, biweekly M 146 61 NR 7
Jada37 2007 NR Asian Mixed tumors SPR IRI 375 mg/m2, every 3 weeks S 45 55 0-2 7
Cote14 2007 P Caucasian stage III colon cancer SPR LV5FU2+IRI 180 mg/m2 (d1), every 2 weeks M 89 NR NR 8
Toffoli11 2006 P Caucasian mCRC PYRS mFOLFIRI or FOLFIRI 180mg/m2 (d1), every 2 weeks M 250 60.6 0-2 8
Massacesi12 2005 P Caucasian mCRC Sequencing IRI+RAL 80 weekly (d1, 8, 15 and 22), every 5 weeks M 56 64 0-2 7
Jong13 2006 P Caucasian Mixed tumors SPR IR+NEO 350mg/m2, every 3 weeks M 52 58 0-2 8
Han36 2006 P Asian mNSCLC Direct Sequencing IRI+CDDP 80mg/m2 (d1 and 8), every 3 weeks S 81 NR 0-2 8
Rouits27 2004 R Caucasian mCRC PYRS IRIFUFOL, FOLFIRI 85mg/m2, weekly; 180mg/m2, biweekly S 73 62 0-2 8
Marcuello26 2004 P Caucasian mCRC SPR IRI alone, IRI+TOM, IRI+5-FU, IRI+5-FU+leuc 80mg/m2, weekly; 180mg/m2, biweekly;3 50mg/m2, every 3 weeks S 95 68 0-2 8
Innocenti67 2004 P Mixed Mixed tumors SBE IRI 350mg/m2, every 3 weeks S 59 60 NR 7
Font66 2003 NR NR mNSCLC Sequencing IRI+DOC 70mg/m2 (d1, 8 and 15), every 4 weeks S 47 55 0-2 7
Iyer25 2002 P Caucasian Mixed tumors SPR IRI 300mg/m2, every 3 weeks S 20 NR NR 8
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R, analysis was planned retrospectively; P, analysis was planned prospectively; NR, Not reported; mCRC, metastatic colorectal cancer; GC, gastric cancer; SCLC, small-cell lung cancer; NSCLC, non-small-cell lung cancer; SPR, Sizing of PCR products (analysis of fragment size); PYRS, Pyrosequencing; SBE, Single base prime extension assay; IRI, irinotecan; CDDP, cisplatin; BEV, bevacizumab; OXA, oxaliplatin; CET, cetuximab; PLA, platinum; IFL, FU+IRI; CAP, capecitabine; CBP, carboplatin; LOB, lobaplatin; RAL, raltitrexed; 5-FU, 5-fluorouracil; LV, leucovorin; GCB, gemicitabine; TOM, toumdex; DOC, docetaxel; PAC, paclitaxel; IFL, IRI+5-FU/LV; FOLFIRI, FOL stands for folinic acid, F for fluorouracil, IRIR for irinotecan+5-FU; S, single center; M, multicenter; ECOG, Estern Cooperative Oncology Group; NOS: Newcastle-Ottawa Scale.

Meta-Analysis of UGT1A1*28 Polymorphism and Severe Diarrhea

There were 44 studies of 4868 patients to evaluate the relationships between the UGT1A1*28 polymorphism and irinotecan-induced severe diarrhea. As shown in Table 2 and Figure 2, we found the UGT1A1*28 polymorphism was significantly related to severe diarrhea risk under all comparisons (TA 6/7 vs. TA6/6: OR = 1.56, 95%CI = 1.25-1.96; TA7/7 vs. TA6/6: OR = 3.97, 95%CI = 1.88-8.38; TA 7/7 vs. TA6/7+TA6/6: OR = 3.64, 95%CI = 2.01-6.58), regardless of the study design. By performing the subgroup analysis, we confirmed the relationship in the Asian group (TA6/7 vs. TA6/6: OR = 1.85, 95%CI = 1.37-2.50, P<0.001; TA7/7 vs. TA6/6: OR = 8.98, 95% CI = 5.21-15.47, P<0.001; TA6/7+TA7/7 vs. TA6/6: OR = 2.74, 95%CI = 2.21-3.40, P<0.001; TA 7/7 vs. TA6/6+TA6/7: OR = 8.64, 95%CI = 4.14-18.04, P<0.001) and in Caucasians (TA7/7 vs. TA6/6+TA6/7: OR = 1.62, 95%CI = 1.03-2.53). Stratified analysis according to cancer type was also carried out in this study. Individuals with mCRC carrying the TA7/7 or TA6/7 genotypes had a higher risk of getting diarrhea after irinotecan-based chemotherapy compared with the TA6/6 genotype (TA6/7 vs. TA6/6: OR = 1.60, 95%CI = 1.11-2.31, P = 0.011; TA7/7 vs. TA6/6: OR = 3.53, 95%CI = 1.54-8.09, P = 0.003). The same risk was also seen in SCLC patients (TA6/7+TA7/7 vs. TA6/6: OR = 3.95, 95%CI = 1.42-11.01, P = 0.009; TA7/7 vs. TA6/6+TA6/7: OR = 19.90, 95%CI = 2.57-154.1, P = 0.004).

Table 2.

Meta-analysis Results for diarrhea.

Compared genotype Group No. of studies No. of participants OR
(95%CI)		 P Test for heterogeneity
P I2
TA6/7 vs. TA6/6 All 28 3435 1.56
(1.25-1.96)		 <0.001 0.175 19.9%
mCRC 16 2563 1.60
(1.11-2.31)		 0.011 0.034 43.3%
SCLC 3 131 2.40
(0.74-7.74)		 0.144 0.208 36.3%
mNSCLC 3 235 0.92
(0.34-2.54)		 0.879 0.883 0.0%
Asian 18 2270 1.85
(1.37-2.50)		 <0.001 0.334 10.1%
Caucasian 9 1118 1.28
(0.91-1.80)		 0.117 0.136 35.3%
Retrospective 13 2123 1.70
(1.09-2.66)		 0.020 0.032 46.8%
Prospective 12 1090 1.69
(1.13-2.52)		 0.010 0.495 0.0%
TA7/7 vs. TA6/6 All 17 2610 3.97
(1.88-8.38)		 <0.001 0.007 51.7%
mCRC 14 1172 3.53
(1.54-8.09)		 0.003 0.004 57.5%
Asian 10 1805 8.98
(5.21-15.47)		 <0.001 0.152 32.0%
Caucasian 7 805 1.09
(0.56-2.13)		 0.807 0.259 22.3%
Retrospective 9 1737 4.84
(1.32-17.69)		 0.017 <0.001 71.7%
Prospective 7 743 2.86
(1.30-6.30)		 0.009 0.555 0.0%
TA6/7+7/7 vs. TA6/6 All 44 4868 2.18
(1.68-2.83)		 <0.001 0.003 40.8%
SCLC 3 131 3.95
(1.42-11.01)		 0.009 0.115 53.8%
mNSCLC 4 321 1.24
(0.58-2.65)		 0.582 0.560 0.0%
Advanced OC 2 178 7.09
(2.91-17.26)		 <0.001 1.00 0.0%
mCRC 25 3477 1.96
(1.42-2.70)		 <0.001 0.005 47.3%
Asian 32 3607 2.74
(2.21-3.40)		 <0.001 0.132 22.2%
Caucasian 11 1214 1.39
(0.84-2.32)		 0.202 0.038 47.9%
Retrospective 16 2359 2.17
(1.36-3.49)		 0.001 0.001 62.0%
Prospective 24 2198 2.12
(1.62-2.79)		 <0.001 0.263 14.3%
TA7/7 vs. TA6/7+TA6/6 All 24 3175 3.64
(2.01-6.58)		 <0.001 <0.001 57.6%
SCLC 2 64 19.90
(2.57-154.1)		 0.004 0.832 0.0%
mCRC 17 2656 3.16
(1.61-6.19)		 0.001 <0.001 64.1%
Asian 13 1917 8.64
(4.14-18.04)		 <0.001 0.092 36.3%
Caucasian 10 1211 1.62
(1.03-2.53)		 0.035 0.188 27.8%
Retrospective 11 2003 2.06
(1.23-3.44)		 0.006 0.168 32.5%
Prospective 11 995 2.92
(1.64-5.21)		 <0.001 0.219 26.2%
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mCRC, metastatic colorectal cancer; mNSCLC, metastatic non-small-cell lung cancer.

Figure 2.

Figure 2

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Forest plot of diarrhea risk related to UGT1A1*28 polymorphism under the homozygous model.

Meta-Analysis of UGT1A1*28 Polymorphism and Severe Neutropenia

The relationships of the UGT1A1*28 polymorphism with irinotecan-induced severe neutropenia risk were investigated in 49 studies of 5232 patients. The UGT1A1*28 polymorphism was significantly related to an increased severe neutropenia incidence (Table 3 and Figure 3, TA 6/7 vs. TA6/6: OR = 1.71, 95%CI = 1.41-2.08; TA7/7 vs. TA6/6: OR = 5.34, 95%CI = 3.05-9.33; TA 7/7 vs. TA6/7+TA6/6: OR = 4.12, 95%CI = 2.36-7.20). Caucasians and Asians with at least one TA7 allele had a higher risk of neutropenia (Caucasians: TA6/7 or TA7/7 vs. TA6/6: OR = 1.84 and 5.67; Asians: TA6/7 or TA7/7 vs. TA6/6: OR = 1.56 and 4.77). In the analysis stratified by cancer type and study design, an association was also found in retrospective and prospective designs, with mCRC patients having the TA7/7 and TA6/7 genotypes (TA6/7 or TA7/7 vs. TA6/6: OR = 1.76 and 5.07) and solid tumor patients with the TA7/7 genotype (TA7/7 vs. TA6/6 or TA6/6+6/7: OR = 7.66 and 6.68).

Table 3.

Meta-analysis Results for neutropenia.

Compared genotype Group No. of studies No. of participants OR (95%CI) P Test for heterogeneity
P I2
TA6/7 vs. TA6/6 All 32 3948 1.71 (1.41-2.08) < 0.001 0.104 24.8%
mCRC 19 2801 1.76 (1.40-2.23) <0.001 0.434 1.8%
mNSCLC 2 188 1.35 (0.55-3.34) 0.518 0.920 0.0%
Asian 21 2547 1.56 (1.07-2.27) 0.020 0.011 46.0%
Caucasian 10 1342 1.86 (1.34-2.60) <0.001 0.991 0.0%
Retrospective 14 1468 1.90 (1.43-2.53) <0.001 0.201 23.3%
Prospective 15 1448 1.53 (1.15-2.05) 0.004 0.882 0.0%
TA7/7 vs. TA6/6 All 27 3575 5.34 (3.05-9.33) <0.001 0.003 48.7%
mCRC 19 2801 5.07 (2.56-10.02) <0.001 0.001 59.3%
Asian 15 2154 4.77 (1.71-13.22) 0.003 0.001 62.6%
Caucasian 11 1362 5.39 (3.43-8.47) <0.001 0.342 10.7%
Retrospective 12 1914 5.61 (3.58-8.82) <0.001 <0.001 69.3%
Prospective 14 1531 5.81 (3.57-9.47) <0.001 0.291 14.8%
TA6/7+7/7 vs. TA6/6 All 49 5232 2.15 (1.71-2.70) <0.001 0.003 39.5%
mCRC 26 3473 2.47 (1.86-3.27) <0.001 0.013 42.1%
Advanced esophageal cancer 2 133 1.20 (0.48-3.05) 0.697 0.691 0.0%
Advanced GC 4 193 1.40 (0.64-3.06) 0.402 0.759 0.0%
mNSCLC 4 351 1.79 (0.97-3.33) 0.064 0.432 0.0%
Asian 35 3715 2.11 (1.54-2.89) <0.001 <0.001 53.9%
Caucasian 13 1458 2.29 (1.69-3.08) <0.001 0.992 0.0%
Retrospective 18 2318 2.52 (1.64-3.88) <0.001 <0.001 59.3%
Prospective 29 2739 1.90 (1.53-2.35) <0.001 0.530 0.0%
TA7/7 vs. TA6/6+6/7 All 28 3668 4.12 (2.36-7.20) <0.001 <0.001 60.7%
mCRC 20 2894 3.70 (1.88-7.30) <0.001 <0.001 69.4%
Asian 15 2154 4.16 (1.44-11.99) 0.008 <0.001 68.9%
Caucasian 12 1455 3.39 (1.92-5.98) <0.001 0.057 42.7%
Retrospective 12 1914 3.59 (1.05-12.28) 0.042 <0.001 76.4%
Prospective 15 1624 4.10 (2.36-7.12) <0.001 0.088 35.1%
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mCRC, metastatic colorectal cancer; GC, gastric cancer; mNSCLC, metastatic non-small-cell lung cancer.

Figure 3.

Figure 3

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Forest plot of neutropenia risk related to UGT1A1*28 polymorphism under the homozygous model.

Meta-Analysis of UGT1A1*28 Polymorphism and Response

Eighteen studies with 2024 patients were assessed to determine the association of the UGT1A1*28 polymorphism with tumor response to irinotecan-based chemotherapy (Table 4 and Figure 4). A partial or complete remission was grouped as a response, while stable tumor or progression was considered no response. A response occurred in patients with at least one mutation allele but not in patients with the wide genotype (TA6/7+TA7/7 vs. TA6/6: OR = 1.20, 95%CI = 1.07-1.34, P = 0.016). The association was significant in Caucasians (OR = 1.23, 95%CI = 1.06-1.42, P = 0.006), retrospective study designs (OR = 1.54, 95%CI = 1.06-2.23, P = 0.022), and mCRC patients (OR = 1.24, 95%CI = 1.05-1.48, P = 0.014).

Table 4.

Meta-analysis Results for response.

Group No. of studies No. of participants OR (95%CI) P Test for heterogeneity
P I2
All 18 2024 1.20 (1.07-1.34) 0.016 0.082 33.6%
mCRC 12 1691 1.24 (1.05-1.48) 0.014 0.060 42.2%
SCLC 2 64 0.87 (0.57-1.33) 0.514 0.458 0.0%
mNSCLC 3 202 1.08 (0.71-1.63) 0.726 0.127 51.5%
Asian 12 2270 1.08 (0.82-1.42) 0.168 0.019 51.7%
Caucasian 5 1118 1.23 (1.06-1.42) 0.006 0.669 0.0%
Retrospective 4 538 1.54 (1.06-2.23) 0.022 0.060 59.5%
Prospective 12 1292 1.07 (0.93-1.22) 0.343 0.511 0.0%
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mCRC, metastatic colorectal cancer; mNSCLC, metastatic non-small-cell lung cancer

Figure 4.

Figure 4

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Forest plot of response related to UGT1A1*28 polymorphism under the homozygous model.

Heterogeneity Analysis

There was high heterogeneity among studies evaluating severe diarrhea under the homozygous and recessive comparisons (TA7/7 vs. TA6/6: P = 0.007, I2= 51.7%; TA7/7 vs. TA6/6+TA6/7: P<0.001, I2= 57.6%). We performed meta-regression to explore the sources of heterogeneity. The data indicated that ethnicity and year of publication accounted for 76% and 26% of heterogeneity under the homozygous model and 54% and 41% under the recessive model, respectively (data not shown). There was high heterogeneity among studies of neutropenia under recessive comparison (P<0.001, I2= 60.7%). The meta-regression results only revealed that the number of patients represented 25% of the heterogeneity and no other factors were found (data not shown).

Publication Bias

To detect publication bias in studies that evaluated diarrhea and neutropenia, we performed the Begg and Egger tests (Table 5). As shown in Table 5, publication bias was found only among the studies of neutropenia under the dominant model (P = 0.027). Next, a trim and fill method was applied and the results (OR = 1.80, 95%CI = 1.37-2.36, P<0.001) showed no statistical difference compared from the results described above (OR = 2.15, 95%CI = 1.71-2.70, P<0.001). There was also no publication bias in studies evaluating response (P = 0.082). Thus, publication bias did not appear to affect our results.

Table 5.

P values for Begg's funnel plot and Egger's test for diarrhea and neutropenia.

Begg Egger
Diarrhea
TA6/7 vs. TA6/6 0.635 0.244
TA7/7 vs. TA6/6 0.365 0.166
TA6/7+TA7/7 vs. TA6/6 0.927 0.282
TA7/7 vs. TA6/6+TA6/7 0.215 0.697
Neutropenia
TA6/7 vs. TA6/6 0.284 0.088
TA7/7 vs. TA6/6 0.755 0.999
TA6/7+TA7/7 vs. TA6/6 0.044 0.027
TA7/7 vs. TA6/6+TA6/7 0.782 0.617
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Sensitivity Analysis

Statistical analysis was conducted as described previously 23. As shown in Figure 5, 6, and 7, the results were not affected by omitting individual studies in this meta-analysis, indicating that our results are reliable.

Figure 5.

Figure 5

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Sensitivity analysis of the studies about diarrhea under the homozygous model.

Trial Sequential analysis

We used the dominant model as an example to perform the TSA, which included eighteen trials with 2024 patients. The results showed the required information size was 1078, which meant our sample size was enough to get a robust conclusion about the UGT1A1*28 polymorphism and chemotherapy response (Figure 8). The required sample sizes for determining the associations between UGT1A1 and diarrhea and neutropenia under the dominant model were 763 and 1162, respectively (data were not shown).

Figure 8.

Figure 8

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The required sample size to demonstrate the relationship between UGT11A1*28 polymorphism and chemotherapy response. The solid line represents the cumulative z-curve. The dashed curve represents the trial sequential monitoring boundary.

Discussion

A couple of meta-analyses have investigated the relationships between the UGT1A1*28 polymorphism and irinotecan-induced toxicity, severe diarrhea, and neutropenia. A study by Chen et al. in 2014 included six articles and found no statistically significant association between the UGT1A1*28 polymorphism and neutropenia in Asians (OR = 1.67, 95%CI = 0.94-2.97) 65. Liu et al.66 conducted a meta-analysis of 16 articles and found that mCRC patients carrying the TA7/7 genotype had a higher risk of neutropenia and diarrhea in Caucasians. In contrast to previous studies, we evaluated 58 articles including 6087 cancer patients and performed stratified analyses based on ethnicity, study design, and cancer type. Statistical difference between the UGT1A1*28 polymorphism and diarrhea was confirmed in Asian patients and mCRC patients under the five models. Individuals with at least mutation allele had a 1.71- and 5.34-fold greater risk of neutropenia than individuals carrying the wide genotype. Mutated genotypes of the UGT1A1*28 polymorphism may lower the glucuronidation rates of SN-38 and lead to greater susceptibility to severe toxicities 25, 36.

Patients evaluated in this study, particularly mCRC patients with the TA6/7 and TA7/7 genotypes, may have severe diarrhea and neutropenia after irinotecan-induced chemotherapy. However, the UGT1A1*28 TA6/6 and TA7/7 genotypes may show an increased treatment response according to our results. In contrast to our results, Xu et al.67 observed different clinical responses in Ugyur patients with different UGT1A1*28 polymorphism genotypes, but not in the Han population. Although the reduction of irinotecan was greater in patients with the TA7/7 or TA6/7 genotypes than the TA6/6 genotype, no difference in overall or progression-free survival between the two group patients were found by Dias et al.68. These results indicate that if the patients with mutant genotypes could tolerate the toxicities, irinotecan-based chemotherapy is a good choice for treatment. Additional studies of the treatment response should be carried out.

Previous meta-analyses included few than 20 studies and only focused on toxicities or chemotherapy response. In comparison with these studies, we included more research (58 studies) and investigated the associations of UGT1A1*28 polymorphism with toxicities and chemotherapy effect. We also got a novel conclusion that patients with a higher risk of chemotherapy toxicities have a tendency to better response to chemotherapy. However, there were some limitations to our study. First, the number of studies of SCLC, mNSCLC, advanced GC, solid tumors, and other cancers were limited, and thus, larger sample sizes for a single tumor are needed to validate our results. Second, high heterogeneity existed among studies related to severe neutropenia under the recessive comparison. Although the number of patients could explain 25% of the heterogeneity, other influencing factors were not identified. Third, the studies we including selected different irinotecan doses in the chemotherapies, which may lead to some bias.

Conclusions

In conclusion, we detected a significant relationship between the UGT1A1*28 polymorphism and irinotecan-induced toxicity and response to irinotecan-based chemotherapy. This polymorphism may be useful as a detective index for cancer patients receiving irinotecan-based chemotherapy.

Figure 6.

Figure 6

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Sensitivity analysis of the studies about neutropenia under the homozygous model.

Figure 7.

Figure 7

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Sensitivity analysis of the studies about response under the dominant model.

Acknowledgments

This study was supported by National Natural Science Foundation, China (No. 81471670; 81274136); China Postdoctoral Science Foundation (No. 2014M560791; 2015T81037); Science and Technology Plan of Innovation Project, Shaanxi Province, People's Republic of China (No 2015KTCL03-06) and the Fundamental Research Funds for the Central Universities, China (No. 2014qngz-04).

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