Japanese Journal of Clinical Oncology Advance Access originally published online on February 14, 2006
Japanese Journal of Clinical Oncology 2006 36(3):137-141; doi:10.1093/jjco/hyi231
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© 2006 Foundation for Promotion of Cancer Research
MDR1 Polymorphisms Predict the Response to Etoposide–Cisplatin Combination Chemotherapy in Small Cell Lung Cancer
1 Department of Internal Medicine, 2 Cancer Research Center and 3 Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
For reprints and all correspondence: Jae Yong Park, Department of Internal Medicine, School of Medicine, Kyungpook National University, Samduk 2Ga 50, Daegu, 700-412, Korea. E-mail: jaeyong{at}kyungpook.ac.kr
Received October 10, 2005; accepted December 13, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: The MDR1 gene encodes P-glycoprotein (PGP), which plays an important role in mediating multidrug resistance to chemotherapeutic agents. Polymorphisms in the MDR1 gene may have an impact on the expression and function of PGP, thereby influencing the response to chemotherapy.
Methods: We investigated the potential association of MDR1 polymorphisms (2677G>T at exon 21 and 3435C>T at exon 26) and their haplotypes with chemotherapy response in 54 small cell lung cancer (SCLC) patients who received a combination chemotherapy of etoposide–cisplatin.
Results: The 3435 CC genotype was associated with a significantly better chemotherapy response compared with the combined 3435 CT and TT genotype (P = 0.025). The 2677 GG genotype was also associated with a better chemotherapy response compared with the combined 2677 GT and TT genotype, although it was not statistically significant. Consistent with the results of genotyping analyses, patients harboring the 2677G–3435C haplotype had a statistically significant better response to chemotherapy compared with those with the other haplotypes combined (P = 0.015).
Conclusions: Our findings suggest that the MDR1 2677G>T and 3435C>T polymorphisms can be used for predicting treatment response to etoposide–cisplatin chemotherapy in SCLC patients.
Key Words: MDR1 • polymorphisms • chemotherapy response • small cell lung cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Lung cancer is one of the major causes of cancer-related death worldwide. Small cell lung cancer (SCLC) represents
20% of primary lung cancers and is characterized by rapid doubling time, high growth fraction and the early development of widespread metastases (1,2). Although chemotherapy is the primary treatment for SCLC, intrinsic or acquired drug resistance is a major limiting factor for the effectiveness of chemotherapy. Resistance to anticancer drugs happens through several mechanisms: decreased drug accumulation, drug inactivation and enhanced DNA repair (3). The human multidrug-resistance (MDR)-1 gene encodes P-glycoprotein (PGP), which functions as an energy-dependent membrane efflux pump for a wide variety of lipophilic compounds. The PGP protein plays an important role in multidrug resistance by impairing the intracellular retention of anticancer drugs such as Vinca alkaloids, taxanes, anthracyclines and topoisomerase inhibitors (4–6). There have been several studies showing that chemotherapy response is inversely related to the level of PGP expression in various human cancers including SCLC (7–11), suggesting that variations in the PGP expression level or activity contribute to the therapeutic efficacy of chemotherapy.
Although the mechanism for altered MDR1 expression has not been clearly elucidated, hypomethylation of the MDR1 promoter, altered activity of transcription factors and gene rearrangements have been implicated in MDR1 regulation (12–14). Several polymorphisms have been recently reported in the MDR1 gene (15) and some of these variants [2677G>T (Ala893Ser) at exon 21 and 3435C>T at exon 26] have been shown to affect the expression and function of PGP (16–18). Therefore, we have hypothesized that these two variants of the MDR1 gene, and particularly their haplotypes, could influence the response to chemotherapy. To test this hypothesis, we evaluated the association of 2677G>T and 3435C>T polymorphisms and their haplotypes with the response to chemotherapy for SCLC patients treated with a combination chemotherapy of etoposide and cisplatin (EP).
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PATIENTS AND METHODS |
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STUDY POPULATION
In the present study, we included 54 SCLC patients who were histologically diagnosed at Kyungpook National University Hospital, Daegu, Korea, from January 2003 to June 2004. All these patients underwent complete staging procedures including chest radiograph, CT scan of the thorax and upper abdomen, brain MRI and bone scan. The clinical data for smoking habits, weight loss and Eastern Cooperative Oncology Group performance status (ECOG PS) were collected prospectively. The limited disease (LD) patients were randomized into two groups according to the timing of thoracic radiotherapy: early concurrent group (with the first cycle of chemotherapy) and late concurrent group (with the fourth cycle of chemotherapy). In this study, the LD patients in the late concurrent group were included in order to evaluate the response to chemotherapy alone. All the patients received EP combination chemotherapy for more than two cycles as a first therapy. The EP regimen consisted of etoposide 100 mg/m2 administered intravenously on days 1–3 and cisplatin 80 mg/m2 administered intravenously on day 1 and at 4 week intervals. If the leukocyte count decreased to <4000/mm3 or the platelet count decreased to <100 000/mm3 on the first day of the next cycle, chemotherapy was postponed until the counts had recovered. During cycle 3, the etoposide dose was reduced to 75% of the initial dose for patients with grade 4 hematologic toxicity in the previous cycle. The cisplatin dose was reduced by 50% if the serum creatinine level was 1.5–2.0 mg/dl. After two (in four cases) or three cycles of chemotherapy, the response to chemotherapy was assessed on day 1 of the next cycle of chemotherapy according the WHO criteria (19). Patients with a complete response or a partial response were defined as responders, and patients having stable disease or progressive disease were defined as non-responders. Toxicity resulting from treatment was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0. This study was approved by the institutional review board of the authors' institution, and written informed consent was obtained from all patients before enrollment.
MDR1 GENOTYPING
Genomic DNA was extracted from peripheral blood lymphocytes by proteinase K digestion and phenol/chloroform extraction. The MDR1 2677G>T (Ala893Ser) and 3435C>T (Ile1145Ile) genotypes were determined by the PCR–RFLP assay. PCR primers were designed based on the GenBank reference sequence (accession no. M29440
[GenBank]
). The PCR primers for 2677G>T and 3435C>T polymorphisms were 5'-GGTTCCAGGCTTGCTGTAAT-3' (forward) and 5'-TCACCTTCCCG (mutated A
G)G-3' (reverse) and 5'-GCTGCTTGATGGCAAAGAAA-3' (forward) and 5'-ATTAGGCAGTGACTCGATGATGA-3' (reverse), respectively. PCR was performed in a 20 µl reaction volume containing 100 ng of genomic DNA, each primer at 10 pM, 0.2 mM dNTPs, 10mM Tris–HCl (pH 8.3), 50 mM KCl, 1.5mM MgCl2 and 1 U of Taq polymerase (Takara Shuzo Co., Otsu, Shiga, Japan). The PCR cycle conditions consisted of an initial denaturation step at 94°C for 5 min followed by 35 cycles of 30 s at 94°C; 30 s at 58°C for 2677G>T and at 56°C for 3435C>T; 30 s at 72°C; and a final elongation step at 72°C for 10 min. The PCR products were digested overnight with the appropriate restriction enzymes (New England Biolabs, Beverly, MA, USA; BanI for 2677G>T and DpnII for 3435C>T) at 37°C. The digested PCR products were resolved on 6% acylamide gel. For quality control, the genotyping analysis was repeated twice for all the subjects. To confirm the genotyping results, selected PCR-amplified DNA samples (n = 2 for each genotype) were examined by DNA sequencing.
STATISTICAL ANALYSIS
A chi-square test was used to evaluate the association between clinical variables and chemotherapy response. The hardy–Weinberg equilibrium of alleles at individual loci was tested with a goodness-of-fit 
2 test with one degree of freedom to compare the observed genotype frequencies with the expected genotype frequencies among the subjects. Haplotypes and their frequencies were estimated based on the Bayesian algorithm using the Phase program (20), which is available at http://www.stat.washington.edu/stephens/phase.html. Logistic regression analysis was performed to examine the association between genotypes/haplotypes and chemotherapy response with adjustment for possible confounders [age as a continuous variable, and sex, staging (limited versus extensive stage) and PS (ECOG 0–1 versus ECOG 2) as nominal variables]. The referent and three alternative models (codominant, dominant and recessive for the minor allele) were applied in the analyses. When multiple comparisons were made, the corrected P values (Pc values) were also calculated for multiple testing using Bonferroni's inequality method. All analyses were performed using the Statistical Analysis Software for Windows, version 6.12 (SAS institute, Gary, NC, USA).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT CHARACTERISTICS
The patients consisted of 46 men and 8 women, and their average age was 61.6 ± 7.9 years. The clinical staging was limited disease (LD) in 28 patients and extensive disease (ED) in 26 patients. The ECOG PS was 0–1 in 35 patients and 2 in 19 patients. The overall response rate was 61% (complete response in 20% and partial response in 41%); 28% of patients had stable disease and 11% of patients had progressive disease. The overall response rate in the LD group tended to be higher than that in the ED group (75.0% versus 50.0%, P = 0.06), but age, sex and ECOG PS did not affect the response to chemotherapy.
ASSOCIATION BETWEEN MDR1 GENOTYPES/HAPLOTYPES AND CHEMOTHERAPY RESPONSE
The frequencies of the MDR1 2677 GG, GT and TT genotypes among the overall cases were 40.7, 44.4 and 14.8%, respectively. The frequencies of the MDR1 3435 CC, CT and TT genotypes among the overall cases were 38.9, 44.4 and 16.7%, respectively. The genotype distributions of both polymorphisms among the overall cases were in Hardy–Weinberg equilibrium. No significant difference was observed in the genotype distributions of both polymorphisms between the patients with LD and with ED (data not shown).
The distributions of the MDR1 2677G>T and 3435C>T genotypes among the responders and non-responders are shown in Table 1. The 2677 GG genotype was more frequent in the responders (47.1%) than in the non-responders (30.0%), and the 2677 GT and TT genotypes were less frequent in the responders (41.2 and 11.8%, respectively) than in the non-responders (50.0 and 20.0%, respectively), but these differences were not statistically significant. For the 3435C>T polymorphism, the 3435 CC genotype was associated with a significantly better chemotherapy response compared with the combined 3435 CT and TT genotype (P = 0.025).
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Table 2 shows the clinical characteristics of patients according to the MDR1 3435C>T genotypes. There were no significant differences in any of the baseline characteristics, including age, gender, performance status and clinical stage according to the MDR1 3435C>T genotypes. In addition, there was no significant difference in the occurrence of hematologic toxicities (grade III or IV) between the patients with the 3435 CC genotype and those with the 3435 CT or TT genotype. The MDR1 2677G>T genotypes were also not significantly associated with the clinical characteristics of patients (data not shown).
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The 2677G>T and 3435C>T polymorphisms were in linkage disequilibrium. The frequencies of the four haplotypes (G–C, G–T, T–C and T–T) among the overall cases were 55.6, 7.4, 5.6 and 31.5%, respectively. The haplotype distribution among the responders was significantly different from the haplotype distribution among the non-responders (Table 3; G–C, G–T, T–C and T–T haplotype; 64.7, 2.9, 4.4 and 27.9% versus 40.0, 15.0, 7.5 and 37.5%, respectively; P = 0.03). Patients harboring the 2677G–3435C haplotype had a significantly better response to chemotherapy compared with the chemotherapy response of the other haplotypes combined (P = 0.015).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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We investigated the association of MDR1 2677G>T and 3435C>T polymorphisms and their haplotypes with the chemotherapy response in SCLC patients treated with a combination chemotherapy of EP. In the present study, the patients harboring the 2677G–3435C haplotype responded to chemotherapy significantly better than those patients with other haplotypes. These results suggest that the MDR1 2677G>T and 3435C>T polymorphisms and their haplotype could be used to predict treatment response to etoposide-based chemotherapy.
As stated in previous studies (21,22), we also found that the 2677G>T and 3435C>T polymorphisms were in linkage disequilibrium. However, the allele frequencies of both polymorphisms among healthy Koreans [n = 432, the same subjects used as healthy controls in our previous study; Ref. (23)] differed from those among other ethnic populations. The frequency of the 2677T allele among healthy Koreans was 0.34, which was lower than the allele frequency in Chinese and Caucasians [0.44–0.50 and 0.38–0.46, respectively; Ref. (15)]. The frequency of the 3435T allele among healthy Koreans was 0.36, which was also lower than in Chinese and Caucasians [0.40–0.54 and 0.46–0.57, respectively; Ref. (15)] but higher than that in Africans [0.10–0.26; Ref. (15)].
Several studies have reported that the MDR1 2677G>T and 3435C>T polymorphisms are associated with gene expression and function, but the results are inconsistent. Hoffmeyer et al. (16) reported that the 3435C>T polymorphism was associated with duodenal PGP levels in Caucasians. Individuals with the 3435 TT genotype had significantly lower duodenal MDR1 expression and higher plasma digoxin levels than individuals with the 3435 CC genotype. Johne et al. (24) also reported that the 3435 TT genotype was associated with higher digoxin levels. In contrast to these studies, Gerloff et al. (25) reported no differences in digoxin levels among healthy Caucasian subjects carrying the 3435T allele or the 3435C allele. In addition, in a study that quantified the MDR1 mRNA in duodenum, Nakamura et al. (26) showed higher MDR1 mRNA levels in healthy Japanese subjects carrying the 3435T allele as compared with subjects with the 3435C allele. The controversy is not just limited to Asian populations: a study performed by Illmer et al. (27) found that the 3435 CC genotype was associated with lower MDR1 expression in acute myeloid leukemia blast samples. Conflicting data of a similar nature have also been reported for the 2677G>T polymorphism (17,28). Kim et al. (17) reported that the 2677T allele was associated with a 2-fold enhanced efflux of digoxin compared with the 2677C allele. In contrast, Tanabe et al. (28) reported a non-significant opposite trend for PGP expression in placenta in relation to the 2677G>T polymorphism (GG > GT > TT). In the present study, the 2677 GG genotype and the 3435 CC genotype were associated with a better chemotherapy response. Consistent with the results of genotyping analyses, the 2677G–3435C haplotype was significantly associated with a better chemotherapy response. These findings are in agreement with some reports (17,26,27), but disagree with others (16,24,28). The reason for all these discrepant results is currently unclear. It may be either because the regulation of PGP expression may be significantly different in different body tissues or because the methods used to measure PGP expression differed among different studies (15,27). The variations in genetic backgrounds of the study subjects should also be taken into consideration.
MDR1 polymorphisms and their haplotypes can also affect the PGP-mediated biliary or renal clearance of etoposide, which can influence the occurrence of etoposide-related toxicity (29,30). Therefore, the role of MDR1 polymorphisms and their haplotypes in the occurrence of etoposide-related toxicities was investigated. It was found that the 3435 CC genotype and the 2677G–3435C haplotype were associated with a better chemotherapy response, which might be due to the lower PGP expression level. This genotype and/or haplotype might be associated with the reduced PGP-mediated clearance of etoposide and thus also with increased etoposide-related toxicity. However, there was no significant association between the MDR1 polymorphisms and the occurrence of etoposide-related toxicity observed in this study.
MDR1 polymorphism may have an influence on disease risk and/or disease progression (31,32). In the present study, however, the frequencies of the 2677T and 3435T alleles among the SCLC cases were not significantly different from those among healthy Koreans (0.37 versus 0.34 and 0.39 versus 0.36, respectively). Moreover, no significant difference was observed in the genotype distributions of both polymorphisms between the patients with LD and with ED.
In conclusion, we found that the MDR1 2677G>T and 3435C>T polymorphisms and their haplotypes are associated with the response to EP combination chemotherapy in SCLC patients. Our finding suggests that these polymorphisms could be used as genetic markers for predicting treatment response to etoposide-based combination chemotherapy in SCLC patients, although additional studies with a larger sample size are required to confirm our results. Future studies for other MDR1 sequence variants and their biological function are also needed to understand the role of MDR1 polymorphisms in determining the response to chemotherapy. Moreover, since genetic polymorphisms often vary significantly between different ethnic groups, further studies are warranted to clarify the association of MDR1 polymorphisms with chemotherapy response in diverse ethnic populations.
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Acknowledgments |
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This study was supported in part by grant no. RTI04-01-01 from the Regional Technology Innovation Program of the Ministry of Commerce, Industry and Energy (MOCIE).
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References |
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