|Year : 2014 | Volume
| Issue : 7 | Page : 195-200
Uridine diphosphate glucuronide transferase 1A1*28 gene polymorphism and the toxicity of irinotecan in recurrent and refractory small cell lung cancer
Fan Yun1, Miao Lulu2, Huang Zhiyu2, Gong Lei2, Yu Haifeng2, Lei Tao2, Yang Haiyan2, Xie Conghua3
1 Department of Radiotherapy and Chemotherapy, Zhongnan Hospital of Wuhan University, Wuhan; Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
2 Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
3 Department of Radiotherapy and Chemotherapy, Zhongnan Hospital of Wuhan University, Wuhan, China
|Date of Web Publication||29-Nov-2014|
Department of Radiotherapy and Chemotherapy, Zhongnan Hospital of Wuhan University, Wuhan
Source of Support: None, Conflict of Interest: None
Objective: The aim was to investigate the association between uridine diphosphate glucuronide transferase 1A1 (UGT1A1) gene promoter region polymorphism and irinotecan-related adverse effects and efficacy on recurrent and refractory small cell lung cancer (SCLC).
Materials and Methods: A total of 31 patients with recurrent and refractory SCLC were enrolled in this study from June 2012 to August 2013 and received at least two cycles of single-agent irinotecan chemotherapy. The efficacy and adverse effects of irinotecan were evaluated. DNA was extracted from peripheral blood and direct sequencing method was employed to test UGT1A1*28 polymorphism, thus analyzing the correlation between UGT1A1*28 polymorphism and irinotecan-related side-effects and efficacy.
Results: A total of 25 cases (80.6%) were UGT1A1*28 wild-type (TA) 6 /(TA) 6 ; 6 cases (19.4%) were heterozygous mutant (TA) 6 /(TA) 7 , no homozygous mutant genotype (TA) 7 /(TA) 7 was found. The incidences of grade 3/4 neutropenia, diarrhea and thrombocytopenia were 35.5%, 25.8% and 22.6% in all the patients, respectively. The incidence of 3/4 adverse effects in patients with genotype (TA) 6 /(TA) 6 and heterozygous (TA) 6 /(TA) 7 had no statistical difference (P > 0.05 for all). The overall response rate (ORR) was 32.3%. Median progression free survival (PFS) and overall survival (OS) were 4 months and 7.5 months in all patients, respectively. There was no statistical difference in ORR, PFS and OS between genotype (TA) 6 /(TA) 6 patients and heterozygous (TA) 6 /(TA) 7 patients.
Conclusion: Irinotecan showed efficacy in patients with recurrent and refractory SCLC; UGT1A1 * 28 polymorphism failed to predict the incidence of serious adverse effects and efficacy of irinotecan.
Keywords: Uridine diphosphate glucuronide transferase 1A1, gene polymorphism, irinotecan, small cell lung cancer, recurrent, refractory
|How to cite this article:|
Yun F, Lulu M, Zhiyu H, Lei G, Haifeng Y, Tao L, Haiyan Y, Conghua X. Uridine diphosphate glucuronide transferase 1A1*28 gene polymorphism and the toxicity of irinotecan in recurrent and refractory small cell lung cancer. J Can Res Ther 2014;10, Suppl S3:195-200
|How to cite this URL:|
Yun F, Lulu M, Zhiyu H, Lei G, Haifeng Y, Tao L, Haiyan Y, Conghua X. Uridine diphosphate glucuronide transferase 1A1*28 gene polymorphism and the toxicity of irinotecan in recurrent and refractory small cell lung cancer. J Can Res Ther [serial online] 2014 [cited 2019 Dec 10];10:195-200. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/195/145871
| > Introduction|| |
Small cell lung cancer (SCLC) representing approximately 15-20% of all lung cancer cases. More than half of these patients are diagnosed with extensive-stage disease (ED). SCLC is a very aggressive tumor characterized by rapid growth, early dissemination and development of drug resistance during the course of disease. Although SCLC is highly sensitive to first-line chemotherapy with a platinum agent and etoposide, and has response rates of 60-80%, the majority of patients will relapse shortly after first-line treatment.  Once recurrence occurs, most patients will be resistant to chemotherapy and eventually die of their disease. Currently, the standard second-line therapy drug is topotecan,  but it has shortcomings of low efficacy and significant toxicity in clinical use. Irinotecan is a topoisomerase I inhibitor and plays an important role in the treatment of various solid tumors. Irinotecan combined with cisplatin is the standard first-line therapy for ED-SCLC,  but it has significant neutropenia and delayed diarrhea, thus its application is limited.  According to the literature, there is a correlation between gene polymorphism caused by changes in uridine diphosphate glucuronide transferase 1A1 (UGT1Al) gene promoter region TA basic group repetitive sequence and irinotecan-related adverse effects and efficacy in western populations. However, incidences of UGT1A1 mutations are significantly lower in Asians than in Western. ,,, The results of studies on the correlation between UGT1A1 gene polymorphism and irinotecan-related toxicity conducted by Chinese scholars are not totally in line with those by foreign scholars. ,, Therefore the valve of prediction of UGT1A1 gene polymorphism in irinotecan toxicity remains controversial in Chinese patients. At present, the studies on association UGT1A1 gene polymorphism and irinotecan-related toxicity are mainly based on advanced colorectal cancer rather than SCLC. Hence, we designed a phase II study in which irinotecan monotherapy was used to treat patients with recurrent and refractory SCLC; before treatment, UGT1A1*28 gene polymorphism was tested in all patients. After treatment, adverse effects and efficacy were observed and its correlation with UGT1A1 gene polymorphism was evaluated.
| > Materials and methods|| |
0 Patient eligibility
Small cell lung cancer patients, pathologically or cytologically confirmed, also with first-line chemotherapy failure, were enrolled in the study. First-line chemotherapy regimens were etoposide combined with platinum. All of them met the following inclusion criteria: (1) At least one measurable lesion; (2) Eastern Cooperative Oncology Group (ECOG) score: 0-2; (3) age >18 years, ≤75 years; (4) expected survival times ≥3 months; (5) interval between recurrence and end of first-line chemotherapy ≤3 months; (6) basically normal bone marrow hematopoietic function: Peripheral white blood cell count ≥3.5 × 10 9 /L, absolute neutrophil count ≥1.5 × 10 9 /L, hemoglobin ≥9.0 g/l, platelet count ≥100 × 10 9 /L; (7) liver and kidney function: Serum transaminases ≤upper limit of normal × 2, total bilirubin ≤ upper limit of normal × 1.5, serum inosine ≤upper limit of normal × 1.5, or serum creatinine clearance ≥50 ml/min. Exclusion criteria: (1) Pregnant and lactating women; (2) symptomatic brain metastases; (3) with a history of other malignancies, except for skin basal cell cancer and cervical carcinoma in situ; (4) with severe infections or organic disease; (5) first-line chemotherapy contained irinotecan. The study protocol and informed consent were reviewed and approved by Zhejiang Cancer Hospital Ethics Committee. All patients signed the informed consent before participating in the clinical trial (ClinicalTrials.govidentifier: NCT01635400).
85 mg/m 2 of single-agent irinotecan was intravenously injected for 90 min on the 1 st day and 8 th day, which was repeated every 3 weeks; the efficacy was evaluated every two cycles; each patient received at least 2 cycles of chemotherapy and at most 6 cycles of chemotherapy. Dose adjustment plan: Before start of a chemotherapy circle, absolute neutrophil count should be ≥1.5 × 10 9 /L and platelet count should be ≥80 × 10 9 /L, if the patient fails to meet the above criteria, the next cycle of chemotherapy will be delayed; if the patient still fails to meet the criteria above 14 days later, the patient will be withdrawn from the study. Chemotherapy dose adjustment: If febrile neutropenia, grade 4 thrombocytopenia, grade 2/3 hemorrhagic thrombocytopenia or delayed diarrhea higher than grade 3 occur in the therapeutic process, the irinotecan dose shall be adjusted to 75% of the original dose; if a patient still needs a third dose adjustment, the patient will be withdrawn from the study.
Uridine diphosphate glucuronide transferase 1A1*28 gene polymorphism was measured in all patients. Before the first cycle of chemotherapy, 5-10 ml peripheral blood was extracted from fasting patients in the morning and placed into an ethylenediaminetetraacetic acid anticoagulant tube and then placed into a refrigerator. QiaAmp kit (Qiagen, Valencia, CA, USA) was used to extract genomic DNA from peripheral blood. Operations were in strict accordance with the instructions. Primers were designed after DNA purity was determined to be qualified. The sequence was 5'-CCTGCTACCTTTGTGGACTGAC-3', polymerase chain reaction (PCR) amplification was conducted for extracted products. Amplification procedure: 95°C 5 min denaturation followed by 95°C 15 s, 60°C 25 s, 72°C 30 s; There were 40 cycling amplifications in total. Then 72°C 10 min extension was conducted. Electrophoretic observation was used to see whether the band of amplified product was clear and single. After it met the standard, the PCR amplification product UGTIA1 gene promoter region TATA nucleotide sequence was determined.
The primary objective was to evaluate the correlation between the adverse effects and UGT1A1 * 28 gene polymorphism; the secondary study objective included evaluating the efficacy of irinotecan and its correlation with UGT1A1*28 gene polymorphism.
Efficacy and toxicity assessment
Objective tumor response was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors The RECIST Working Group criteria. Efficacy was classified as complete remission (CR), partial remission (PR), stable disease and disease progression. Toxicity evaluation was based on American National Cancer Institute Common Toxicity Criteria (American National Cancer Institute, NCI) version 3.0.
Fisher's exact test and the Chi-square test were performed to compare the clinical and demographic characteristics of patients in UGT1A1 genotypes. PFS and OS curves were established using the Kaplan-Meier method. The log-rank test was applied to compare PFS and OS in patients with different UGT1A1 genotypes. Statistical tests were based on a two-sided significance level of 0.05. All statistical analyses were performed using SPSS 20.0.0 for Windows (IBM Corp, Armonk, NY, USA).
| > Results|| |
0 Patient population
Totally 31 patients were enrolled from January 2011 to August 2012. All 31 enrolled patients were included in the safety and efficacy analysis. Baseline characteristics for the overall population are summarized in [Table 1]. 27 males and 4 females; median age was 58 years (range, 18-75 years). ECOG PS score 0-1 were 23 patients; PS score 2 were 8 patients. 5 patients were with limited-stage (LD) disease; 26 patients were with ED. All LD SCLC patients received radiation in first-line treatment. 11 patients have ≥2 organs involved. 108 cycles of chemotherapy were completed for 31 patients. The median number of cycles of chemotherapy administered was four.
Uridine diphosphate glucuronide transferase 1A1*28 genotypes
The distribution of the UGT1A1 genotypes in 31 patients, 25 (80.6%) patients were wild genotype (TA) 6 /(TA) 6 , 6 (19.4%) patients were nonwild heterozygous mutant genotype (TA) 6 /(TA) 7 . No homozygous mutant genotype (TA) 7 /(TA) 7 were found. Baseline characteristics between the wild genotype (TA) 6 /(TA) 6 patients and heterozygous mutant genotype (TA) 6 /(TA) 7 are no differences [Table 2].
|Table 2: Summary of the most commonly reported AEs (incidence >5% of patients) during irinotecan therapy |
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[Table 3] lists the toxicity data. The incidences of grade 3/4 toxicities ≥5% experienced during the study were neutropenia, delayed diarrhea and thrombocytopenia. No grade 5 treatment-related toxicity was seen. Grade 3/4 toxicities in the entire group patient were observed as follows: 11 (35.5%) patients neutropenia, 8 (25.8%) patients delayed diarrhea, 7 (22.6%) patients thrombocytopenia. The incidences of other grade 3/4 toxicities (such as anemia, Alopecia) were <5%. Febrile neutropenia were observed in 5 patients (grade 1/2 for all). 7 patients required reduction of irinotecan dose because of adverse effects. Treatment administration is delayed for 5 patients due to toxicities. Red blood cell transfusion was needed for 1 patients with anemia during treatment and platelets were transfused for 3 patients.
Correlation between toxicities and uridine diphosphate glucuronide transferase 1A1*28 gene polymorphism
The most common 3/4 toxicities of the 25 cases with wild genotype reported were neutropenia (32.0%), delayed diarrhea (16.0%), and thrombocytopenia (20.0%). 3/4 toxicities in the heterozygous mutant (TA) 6 /(TA) 7 patients were as follows: Neutropenia (50.0%), delayed diarrhea (33.3%), and thrombocytopenia (33.3%). The incidences of grade 3/4 delayed diarrhea was higher in patients with UGTlAl heterozygous mutant (TA) 6 /(TA) 7 than those patients with wild genotype (33.3% vs. 16.0%), however P value indicated no statistically difference (P = 0.567). There was no statistically significant difference in grade 3/4 neutropenia and thrombocytopenia between two groups [Table 2].
Correlation between clinical factors and toxicities
Correlation between different clinical features (age, gender, PS score, number of involved organs and stage) and grade 3/4 toxicities (neutropenia, delayed diarrhea and thrombocytopenia) were analyzed. Results showed that there was no significant correlation between these clinical factors and grade 3/4 toxicities (P > 0.05).
Among the entire patient group, there was no case of CR and 10 cases of PR. The objective response rate (ORR) was 32.3%. The ORR of patients with wild genotype (TA) 6 /(TA) 6 and heterozygous mutant (TA) 6 /(TA) 7 were 32.0% (8/25) and 33.3% (2/6) (P = 0.67), respectively [Table 4].
At the time of data cut-off (10 February 2014), 2 patients were alive. The median progression-free survival (PFS) and median overall survival (OS) were 4.0 months (95% confidence interval, 3.05-4.95) and 6.6 months (95% confidence interval 4.96-8.24) in entire patient group, respectively. The median PFS and OS of patients with wild genotype (TA) 6 /(TA) 6 were 4 months and 7.5 months, respectively (95% confidence intervals were 2.82-5.18 and 4.26-10.74, respectively). The median PFS and OS of patients with heterozygous mutant (TA) 6 /(TA) 7 were 3 and 6.6 months, respectively (95% confidence intervals were 1.40-4.60 and 6.49-6.71, respectively). The difference in PFS and OS between the two genotype groups was not statistically significant [Table 5]. PFS curve and OS curve of the two groups were listed in [Figure 1] and [Figure 2].
|Figure 1: Progression-free survival for different genotypes (Kaplan- Meier curve)|
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| > Discussion|| |
Small cell lung cancer is a highly malignant tumor, its preferred first-line chemotherapy has been etoposide combined with platinum for many years. , Although patients are sensitive to chemotherapy in the initial treatment, the recurrence rate is high. The current standard second-line therapy drug is topotecan. Phase III randomized controlled clinical studies have shown that compared with best supportive therapies, topotecan can prolong OS and improve the quality of life.  However, studies have also suggested that the efficacy of topotecan is limited with ORR of 7% and OS time of 25.9 weeks; it has high adverse effects rate. Several randomized controlled studies have shown that irinotecan combined with platinum has similar efficacy to EP regimen in first-line treatment in ED-SCLC. In the second-line treatment, some small sample phase II clinical studies have shown that irinotecan has a certain efficacy on recurrent and refractory SCLC. Ando et al.  used irinotecan combined with cisplatin to treat 25 SCLC patients with EP regimen failure; the PR rate was as high as 80% and the median time to progression and median survival time was 3.6 months and 7.9 months, respectively. However, a number of studies have shown that irinotecan therapy had a higher incidence of severe diarrhea. ,, It is a research hotspot to use biomarker to predict adverse effects and efficacy of irinotecan in recent years.
Irinotecan's active metabolite in the body is 7-ethyl-10-hydroxy-camptothecin (SN-38), which inhibits repair of broken DNA single-strand to interfere with DNA replication and transcription. SN-38 is inactivated by UGT enzyme family to become glucuronic acid products (SN-38G). Therefore, UGTs enzyme expression and activity are closely related to irinotecan-related efficacy and adverse effects. UGT1A1*28 is a relatively common UGT1A1 gene variant; since the number of many TA basic group repetitive sequence in the gene promoter region is changed and variation occurs, the UGT1A1*1 (wild-type) has 6 TA repetitive sequences, that is, (TA) 6 /(TA) 6 ; UGT1A1*28 has 7 TA repetitive sequences, including homozygous mutant (TA) 7 /(TA) 7 and heterozygous mutant (TA) 6 /(TA) 7 .  A number of studies confirm that UGT1A1*28 gene variation, especially homozygous mutant (TA) 7 /(TA) 7 , can increase the risks of severe diarrhea and/or neutropenia. ,,, Recently, Innocenti et al.  reported that the dose of irinotecan can be individualized based on different expressions of UGT1A1*28 genotypes. However, some scholars held the opposite opinion. For example, Stewart et al.  suggested that UGT1A1*28 cannot well predict irinotecan-related severe toxicity in the treatment of patients with solid tumors. The inconsistent results from these studies may be related to different dose levels of irinotecan. Hoskins et al.  conducted a meta-analysis of several clinical studies involving 821 patients. They found that the patients with high doses of irinotecan regimen (>250 mg/m 2 ), UGTlAl*28 polymorphism significantly increased the risks of hematologic adverse effects (≥grade 3). However, patients with moderate doses of irinotecan regimen (150-250 mg/m 2 ) were not seriously affected. Patients with small doses of irinotecan regimen (<150 mg/m 2 ) were basically not affected. The N9741 study by McLeod  found that different dose levels of CPT-11 and different combination regimens were closely related to the pharmacogenomics predicting adverse effects.
This phase II study did not show a statistically significant difference in incidence rates of 3/4 adverse effects in patients with genotype (TA) 6 /(TA) 6 and heterozygous (TA) 6 /(TA) 7 . The potential reasons were analyzed as follows: Firstly, this study used a lower dose of irinotecan. Second, incidences of homozygous mutant (TA) 7 /(TA) 7 and heterozygous mutant (TA) 6 /(TA) 7 in Asians were significantly lower than those of Caucasian and African populations, ,, so the predicting effect decreased correspondingly. Third, the number of cases included in this study was relatively small.
The results of this study showed that there was no statistical difference in the PFS and OS between patients with UGT1A1*28 wild genotype and heterozygous mutant genotype; the correlation between UGT1A1*28 gene polymorphism and efficacy of irinotecan has not been validated in this study. Some studies have reported that the survival benefit of patients with wild genotype (TA) 6 /(TA) 6 was better than that of patients with homozygote (TA) 7 /(TA) 7 treated by irinotecan; homozygous patients' median survival time was relatively shorter. , However, other reports suggested that UGT1A1 gene polymorphism did not affect patient survival times. ,, The results of a recent meta-analysis of studies on the correlation between UGT1A1*28 genotype and prognosis of patients with colorectal cancer suggested that there were significant differences in PFS and OS between the gene subtypes. In low-dose irinotecan treatment subgroup, there was a difference in the OS of homozygous mutant patients. The cause may be related to the decreased dose or treatment interruption in mutant patients caused by serious adverse effects.  The correlation between UGT1A1*28 genotype and efficacy of patients treated with low-dose irinotecan in recurrent and refractory SCLC needs to be validated in large-sample clinical studies.
In summary, this study did not confirm correlation between UGT1A1*28 gene polymorphism and the grade 3/4 adverse effects and efficacy by irinotecan in recurrent and refractory SCLC. In order to give most appropriate treatment doses to patients with different genotypes to reduce toxic reactions and maximize the efficacy, prospective studies with larger patient samples are needed.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]