Med Oncol (2013) 30:630 DOI 10.1007/s12032-013-0630-8
ORIGINAL PAPER
Associations between UGT1A1*6/*28 polymorphisms and irinotecan-induced severe toxicity in Chinese gastric or esophageal cancer patients Jing Gao • Jun Zhou • Yanyan Li • Zhi Peng • Yilin Li Xicheng Wang • Lin Shen
•
Received: 23 May 2013 / Accepted: 10 June 2013 Ó Springer Science+Business Media New York 2013
Abstract The aim of this study was to investigate the associations between UDP-glucuronosyltransferase (UGT) 1A1 polymorphisms and irinotecan-induced toxicities in Chinese advanced gastric or esophageal cancer patients. The genotypes of UGT1A1*6 and UGT1A1*28 were analyzed by PCR amplification and Sanger sequencing in 42 gastric and 91 esophageal cancer patients receiving irinotecan-containing chemotherapy. The influences of UGT1A1*6/*28 polymorphisms on severe diarrhea and neutropenia were analyzed. The overall incidence of UGT1A1*6/*28 variants in gastric cancer and esophageal cancer was 38.1 % (GA: 31.0 %; AA: 6.9 %), 28.6 % (TA6/TA7: 26.2 %; TA7/TA7: 2.4 %) and 33.0 % (GA: 28.6 %; AA: 4.4 %), 25.3 % (TA6/TA7: 23.1 %; TA7/ TA7: 2.2 %) in our cohort, respectively. A total of 10 patients (gastric cancer: 9.5 %, 4/42; esophageal cancer: 6.6 %, 6/91) had severe diarrhea and 35 patients (gastric cancer: 35.7 %, 15/42; esophageal cancer: 22.0 %, 20/91) had severe neutropenia. Statistic analysis between UGT1A1 genotyping and severe diarrhea was not conducted due to the limited number of patients. For gastric cancer, it seemed that only UGT1A1*6 variant was associated with severe neutropenia (P = 0.042), while among esophageal cancer patients, UGT1A1*6 (P = 0.011) or UGT1A1*28 (P = 0.026) variants were significantly associated with severe neutropenia. UGT1A1*6 variant Jing Gao and Jun Zhou contributed equally to this work. J. Gao J. Zhou Y. Li Z. Peng Y. Li X. Wang L. Shen (&) Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China e-mail:
[email protected]
was closely associated with severe neutropenia both in gastric cancer and in esophageal cancer, but the association between UGT1A1*28 variant and severe neutropenia in gastric and esophageal cancer was not consistent in this study, which would be validated in the future large samples. Keywords UGT1A1 Irinotecan Toxicity Gastric cancer Esophageal cancer
Introduction It was well known that irinotecan was widely used in many kinds of malignancies including gastrointestinal cancers [1–4]. Among all gastrointestinal cancers, irinotecan was mainly used in colorectal cancer, and it was also frequently used in gastric cancer, esophageal cancer, and other cancers [5, 6]. However, the serious issue of irinotecan in clinical practice was its dose-limiting toxicity, including severe delayed-onset diarrhea and neutropenia, regardless of any cancers [7]. Many studies reported that UGT1A1 polymorphisms, especially UGT1A1*28 and UGT1A1*6, could predict irinotecan-induced toxicities, but controversial conclusions still remained due to the distinct frequency of UGT1A1 genotypes between western and eastern countries [8, 9]. Up to now, studies about UGT1A1 polymorphisms and irinotecan toxicity were mainly focused on colorectal cancer, lung cancer, and gynecological cancers [10, 11]. However, very few studies paid attention to other cancers with a high incidence in Asia, such as gastric cancer and esophageal cancer. Only one study from Korea indicated that patients with UGT1A1*6 variants showed a higher incidence of severe neutropenia not diarrhea, and
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UGT1A1*28 polymorphism was not associated with irinotecan toxicities in gastric cancer [12]. We have previously reported the associations between UGT1A1*6/*28 polymorphisms and irinotecan-induced toxicities in Chinese colorectal cancer patients on a large scale [13]. This study was conducted to investigate the associations between UGT1A1*6/*28 polymorphisms and irinotecan-induced toxicities in Chinese advanced gastric and esophageal cancer patients for the first time.
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Clinical response was evaluated every two cycles by computed tomography (CT) according to the response evaluation criteria in solid tumors (RECIST). Patients were categorized by complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Toxicity was evaluated according to NCI-CTC 3.0 criteria (National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 3.0). Grade III or IV diarrhea and neutropenia were defined as severe toxicity. DNA preparation and genotyping of UGT1A1
Materials and methods Patients A total of 42 gastric and 91 esophageal cancer patients with advanced disease treated in Gastrointestinal Department of Peking University Cancer Hospital from October 2005 to October 2012 were retrospectively included in this study. All patients gave their written informed consents for their peripheral blood to be used for research. The peripheral blood was drawn prior to chemotherapy and stored at -80 °C until analysis. All patients received irinotecancontaining chemotherapy, with irinotecan-induced toxicities of delayed-onset diarrhea and neutropenia being recorded in detail. This study was approved by the Medical Ethics Committee of Peking University Cancer Hospital and was performed according to the Declaration of Helsinki Principles. Treatment, response evaluation, and toxicity assessments Before irinotecan-containing chemotherapy, an adequate bone marrow function, hepatic and renal function, and performance status of each patient were ensured. For gastric cancer patients, irinotecan-containing chemotherapy was given as first-line treatment in 11 patients, second-line treatment in 16 patients, and third-line or more treatment in 15 patients. For esophageal cancer patients, irinotecancontaining chemotherapy was given as first-line treatment in 44 patients, second-line treatment in 41 patients, and third-line or more treatment in 6 patients. The chemotherapy regimens and dose of irinotecan in this study contained irinotecan plus cisplatin (gastric cancer: n = 15, 180 mg/m2; esophageal cancer: n = 48, 130 mg/m2), FOLFIRI (gastric cancer: n = 19, 180 mg/m2; esophageal cancer: n = 37, 180 mg/m2), and irinotecan alone or plus cetuximab (gastric cancer: n = 8, 180 mg/m2; esophageal cancer: n = 6, 180 mg/m2). Each patient received irinotecan-containing chemotherapy at least once, and complete blood counts were performed after each administration of irinotecan or before the initiation of next use.
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Genomic DNAs were extracted from peripheral blood using QIAamp Blood Kit (Qiagen, Hilden, Germany). DNA fragments aligned, respectively, with TATA box of UGT1A1 promoter and exon 1 of UGT1A1 were amplified by PCR using primers (UGT1A1*28-F: 50 -AGCCAGTTC AACTGTTGTTGC-30 , UGT1A1*28-R: 50 -TTTGCTCCT GCCAGAGGTTC-30 ; UGT1A1*6-F: 50 -ACGCCTCGTTG TACATCAGAG-30 , UGT1A1*6-R: 50 -TCCTTGTTGTGC AGTAAGTGG-30 ). Each PCR consisted of 2 lL of 109 LA PCR buffer II, 2 lL of 10 mmol/L dNTPs, 0.2 lL of LA Taq (DRR200A, TAKARA), 2 lL of genomic DNA, and 0.5 lL of each primers (10 lmol/L) in a final volume of 20 lL. The cycling conditions were 94 °C for 5 min, 40 cycles of 94 °C for 30 s, 56 °C for 30 s, 72 °C for 20 s, and final extension at 72 °C for 10 min and ended at 4 °C. The PCR products were determined by 3 % agarose gel electrophoresis and sequenced by Invitrogen 3730XL genetic analyzer. The sequencing results were analyzed with Chromas software under the condition of signal/noise [98 %. Each sample was sequenced at least twice. Genotypes were described as TA6/TA6, TA6/TA7, TA7/ TA7 for UGT1A1*28 and GG, GA, AA for UGT1A1*6. Statistical analysis Statistical software SPSS 18.0 (SPSS Inc, Chicago, Illinois, USA) with Fisher’s exact test and Student’s t-test was used to analyze the relationship between genotyping and irinotecan-induced toxicity. All statistical analyses were twosided test, and P \ 0.05 was considered as significant difference.
Results Genotyping of UGT1A1*6/*28 in gastric cancer patients A total of 42 gastric cancer patients were analyzed in this study with 29 males and 13 females, with the median age of 53 years (range 23–71 years). As shown in Table 1, the
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frequencies of GG, GA, AA genotypes for UGT1A1*6 and TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 61.9 % (n = 26), 31.0 % (n = 13), 7.1 % (n = 3) and 71.4 % (n = 30), 26.2 % (n = 11), 2.4 % (n = 1), respectively. Only one patient (2.4 %) carried double heterozygosity (GA concurrent with TA6/TA7), and the AA genotype and TA7/TA7 genotype were exclusive in this study. We further divided patients into three groups according to the numbers of mutational alleles: wild type (patients with genotype: GG and TA6/TA6, n = 15, 35.7 %), single allele variants (patients with genotypes: GA and TA6/TA6; or GG and TA6/TA7; n = 22, 52.4 %), and two alleles variants (patients with genotypes: AA and TA6/TA6; or GA and TA6/TA7; or GG and TA7/TA7; n = 5, 11.9 %). No significant differences were seen between UGT1A1*6/*28 variants and patients’ sex, age, primary tumor sites, and so on. Genotyping of UGT1A1*6/*28 in esophageal cancer patients A total of 91 esophageal cancer patients were analyzed in this study with 81 males and 10 females, with the median age of 54 years (range 37–77 years). As shown in Table 1, the frequencies of GG, GA, AA genotypes for UGT1A1*6 and TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 67.0 % (n = 61), 28.6 % (n = 26), 4.4 % (n = 4) and 74.7 % (n = 68), 23.1 % (n = 21), 2.2 % (n = 2), respectively. Five patients (5.5 %) carried double heterozygosity (GA concurrent with TA6/TA7), and the AA Table 1 Genotyping of UGT1A1 in gastric and esophageal cancer patients
Genotyping
genotype and TA7/TA7 genotype were also exclusive in this cohort. We further divided patients into three groups according to the numbers of mutational alleles: wild type (patients with genotype: GG and TA6/TA6, n = 43, 47.3 %), single allele variants (patients with genotypes: GA and TA6/TA6; or GG and TA6/TA7; n = 37, 40.7 %), and two alleles variants (patients with genotypes: AA and TA6/TA6; or GA and TA6/TA7; or GG and TA7/TA7; n = 11, 12.1 %). Also, no significant differences were seen between UGT1A1*6/*28 variants and patients’ age, primary tumor sites, and so on.
Analysis of irinotecan-induced toxicity In this study, severe delayed-onset diarrhea occurred in 10 patients (gastric cancer: 9.5 %, 4/42; esophageal cancer: 6.6 %, 6/91), and 35 patients (gastric cancer: 35.7 %, 15/42; esophageal cancer: 22.0 %, 20/91) developed severe neutropenia (Table 2). No associations were found between severe neutropenia and patients’ sex, age, chemotherapy regimens, and so on, both in gastric and in esophageal cancer patients (all P [ 0.1). However, the incidence of severe diarrhea in patients treated with irinotecan plus cisplatin was nonsignificantly higher than other chemotherapy regimens: A total of 4 gastric cancer patients developed severe diarrhea and 3 patients with severe diarrhea were treated with irinotecan plus cisplatin; however, 6 esophageal cancer patients with severe diarrhea were all treated with irinotecan plus cisplatin.
Gastric cancer (n = 42)
Esophageal cancer (n = 91)
Number
%
Number
%
GG GA
26 13
61.9 31.0
61 26
67.0 28.6
AA
3
7.1
4
4.4
TA6/TA6
30
71.4
68
74.7
TA6/TA7
11
26.2
21
23.1
TA7/TA7
1
2.4
2
2.2
GG & TA6/TA6
15
35.7
43
47.3
GG & TA6/TA7
10
23.8
16
17.6
GG & TA7/TA7
1
2.4
2
2.2
GA & TA6/TA6
12
28.6
21
23.1
GA & TA6/TA7
1
2.4
5
5.5
GA & TA7/TA7
0
0.0
0
0.0
AA & TA6/TA6
3
7.1
4
4.4
AA & TA6/TA7 AA & TA7/TA7
0 0
0.0 0.0
0 0
0.0 0.0
UGT1A1*6
UGT1A1*28
UGT1A1*6 & UGT1A1*28
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Correlation of UGT1A1*6/*28 polymorphisms to irinotecan toxicity
Discussion
In this study, because only 10 patients developed severe diarrhea, statistical analysis between UGT1A1*6/*28 polymorphism and severe diarrhea was not conducted. Among 4 gastric cancer patients with severe diarrhea, two patients carried TA6/TA6 & GG genotype and two patients carried TA6/TA6 & GA genotype. For 6 esophageal cancer patients with severe diarrhea, four patients carried TA6/ TA6 & GG genotype, one patient carried TA6/TA6 & AA genotype, and one patient carried TA6/TA7 & GA genotype. Among gastric cancer patients, no association was found between UGT1A1*28 polymorphism and severe neutropenia, but the incidence of severe neutropenia in patients with AA genotype (100 %, 3/3) was significantly higher than that in patients with GA (38.5 %, 5/13) or GG (26.9 %, 7/26) genotypes (P = 0.042), which would be validated in the continuing large samples. For esophageal cancer patients, significant differences were found between UGT1A1*6/*28 polymorphisms and severe neutropenia (Table 3). Moreover, patients with two alleles or single allele variants had more chances to develop severe neutropenia than patients with wild-type patients (gastric cancer: 60 vs. 40.9 vs. 20 %, P = 0.206; esophageal cancer: 54.5 vs. 24.3 vs. 11.6 %, P = 0.008). Correlation of UGT1A1*6/*28 polymorphisms and toxicities to clinical response Eighty-seven patients receiving irinotecan-containing chemotherapy (65.4 %, 87/133; gastric cancer: n = 31; esophageal cancer: n = 56) were evaluable for clinical response. Patients with PR, SD, and PD in gastric and esophageal cancer patients were 5, 14, and 12 and 18, 23, and 15, respectively. No significant differences were observed between UGT1A1*6/*28 polymorphisms and clinical response both in gastric and in esophageal cancer patients (all P [ 0.5). It seemed that the response rate of patients with severe neutropenia was nonsignificantly higher than patients without severe neutropenia (Table 4).
According to the results from western countries [10], the US Food and Drug Administration (FDA) claimed in 2005 that UGT1A1*28 testing should be included in the label of irinotecan as a risk factor for severe toxicity, especially severe diarrhea. But for Chinese colorectal cancer patients, the incidence of severe delayed-onset diarrhea (5.8 vs. 22.7 %) induced by irinotecan and the percentage of TA7/ TA7 genotype (1.1 vs. 10 %) were much lower than those in Whites [7, 14–17]. We have reported previously that Chinese colorectal cancer patients had a distinct frequency of UGT1A1*6/*28 genotypes compared to western countries and suggested that the low incidence of severe diarrhea was not completely due to the low frequency of TA7/ TA7 genotype in Chinese patients [13]. For gastric and esophageal cancer patients, we could not estimate the differences of UGT1A1*6/*28 genotypes between Chinese and western patients due to the absence of results from western countries. Up to now, we have detected 505 colorectal cancer, 302 gastric and 197 esophageal cancer patients, and no significant differences of UGT1A1*6/*28 polymorphisms were found between different cancers. In this study, a total of 10 patients developed severe diarrhea described in results section, and it seemed that no direct association was seen between UGT1A1 polymorphisms and severe diarrhea, which was consistent with our previous results in colorectal cancer [13] and would be validated in the future large samples. Our results demonstrated that the chemotherapy regimen of irinotecan plus cisplatin might be the major reason inducing severe diarrhea in gastric and esophageal cancer patients, which was confirmed in our clinical practice. As a result, this regimen was now rarely used in the treatment of gastric and esophageal cancer patients except for some clinical trials. We previously reported that UGT1A1*6/*28 polymorphisms could predict severe neutropenia not diarrhea in colorectal cancer [13]. From this study, UGT1A1*6 genotype could predict severe neutropenia both in gastric and esophageal cancer, but UGT1A1*28 genotype could predict severe neutropenia only in esophageal cancer not in gastric cancer, which also would be validated in future. The result of this study in gastric cancer was consistent with the
Table 2 Prevalence of diarrhea and neutropenia in gastric and esophageal cancer patients Grade of diarrhea 0 (%)
Grade of neutropenia I (%)
II (%)
III/IV (%)
0 (%)
I (%)
II (%)
III/IV (%)
3 (7.1 %)
4 (9.5 %)
11 (26.2 %)
4 (9.5 %)
12 (28.6 %)
15 (35.7 %)
11 (12.1 %)
6 (6.6 %)
34 (37.4 %)
14 (15.4 %)
23 (25.3 %)
20 (22.0 %)
Gastric cancer (n = 42) 32 (76.2 %)
3 (7.1 %)
Esophageal cancer (n = 91) 61 (67.0 %)
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13 (14.3 %)
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Table 3 Correlation of UGT1A1*6/*28 polymorphisms to severe neutropenia
Genotyping
Gastric cancer Neutropenia No. (%)
P
Esophageal cancer Neutropenia No. (%)
P
UGT1A1*28 TA6/TA6
11 (36.7 %)
TA6/TA7
4 (36.4 %)
TA7/TA7
0 (0.0 %)
14 (20.6 %) 0.752
4 (19.0 %)
0.026
2 (100 %)
UGT1A1*6 GG
7 (26.9 %)
GA
5 (38.5 %)
AA
3 (100 %)
8 (13.1 %) 0.042
11 (42.3 %)
0.011
1 (25 %)
Numbers of mutational alleles Wild type
3 (20 %)
Single allele variants Two alleles variants
9 (40.9 %) 3 (60 %)
Clinical response
5 (11.6 %)
0.008
9 (24.3 %) 6 (54.5 %)
International Agency for Research on Cancer, Lyon, France) for critical reading of this manuscript.
Table 4 Correlation of severe neutropenia to clinical response Patients
0.206
P
PR No. (%)
SD No. (%)
PD No. (%)
Yes (n = 11)
3 (27.3 %)
5 (45.4 %)
3 (27.3 %)
No (n = 20)
2 (10.0 %)
9 (45.0 %)
9 (45.0 %)
Yes (n = 15)
8 (53.3 %)
5 (33.3 %)
2 (13.3 %)
No (n = 41)
10 (24.4 %)
18 (43.9 %)
13 (31.7 %)
Conflict of interest
None.
Gastric cancer 0.385
References
Esophageal cancer 0.103
only report from Korea [12]. According to our and other results, UGT1A1*6 allele was closely related to severe neutropenia in Asian patients [18]. As discussed in our previous study, besides genotypes of UGT1A1*6 and UGT1A1*28, many other factors could influence the toxicity, such as the dose of irinotecan [19], the concentration of total bilirubin and SN-38/SN-38G ratio in plasma [20], and ABCB1 C3435T polymorphism [21], and so on. Further studies are needed to elucidate the unresolved questions. In summary, no significant differences of UGT1A1*6/ *28 genotypes were seen in colorectal cancer, gastric cancer, and esophageal cancer. UGT1A1*6 variant was closely associated with severe neutropenia both in gastric cancer and in esophageal cancer, but the association between UGT1A1*28 variant and severe neutropenia in gastric and esophageal cancer was not consistent in this study, which would be validated in the future large samples. Acknowledgments This work was supported by National Natural Science Foundation of China (No. 81172110), Beijing Municipal Science and Technology Commission Program (No. Z11110706730000). We thank Dr. Jiping Yue (Infections and Cancer Biology Group,
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