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Predictive value of ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype in small cell lung cancer patients treated with chemotherapy

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Abstract

Purpose

Multiple drug resistance limits the efficacy of numerous cytotoxic drugs used in the treatment of small cell lung cancer (SCLC). The drug efflux protein ATP-binding cassette transporter B1 (ABCB1) has an important role in this process, and its gene variability may affect chemotherapy outcomes.

Patients and methods

This study aimed to evaluate the associations between ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype with progression-free survival (PFS) and overall survival (OS) in 177 SCLC patients treated with cisplatin–etoposide or cyclophosphamide–epirubicin–vincristine chemotherapy. To determine the ABCB1 genotype, allelic specific TaqMan® probes were used in a RT-PCR .

Results

Patients carrying the G2677T/A TT + TA + AA genotypes (24 %) or the C3435T CT + TT genotypes (72 %) or the 2677T/A-3435T haplotype (40 %) had a longer PFS (Cox regression, P = 0.052, 0.037 and 0.037, respectively); these associations persisted also in multivariate analyses (Cox regression, P = 0.028, 0.037 and 0.030, respectively). Moreover, patients with the C3435T CT + TT genotypes had a longer OS both in univariate and multivariate analysis (Cox regression, P = 0.022 and 0.028, respectively). A trend toward longer OS was noted for the 2677T/A-3435T haplotype (Cox regression, P = 0.051), but its independent value was not confirmed (Cox regression, P = 0.071).

Conclusions

Our study reported a possible predictive value of ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype for longer PFS and OS in Caucasian SCLC patients treated with chemotherapy. However, to be implemented into routine clinical practice, ABCB1 polymorphisms require further validation.

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References

  • Arvelo F, Poupon MF, Goguel AF, Lizard G, Burgeois Y, Arriagada R et al (1993) Response of a multidrug-resistant human small-cell lung cancer xenograft to chemotherapy. J Canc Res Clin Oncol 120:17–23

    Article  CAS  Google Scholar 

  • Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D et al (2010) Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 102:1003–1009

    Article  PubMed  CAS  Google Scholar 

  • Buda G, Maggini V, Galimberti S, Martino A, Giuliani N, Morabito F et al (2007) MDR1 polymorphism influences the outcome of multiple myeloma patients. Br J Haematol 137:454–456

    Article  PubMed  CAS  Google Scholar 

  • Buda G, Ricci D, Huang CC, Favis R, Cohen N, Zhuang SH et al (2010) Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin. Ann Hematol 89:1133–1140

    Article  PubMed  CAS  Google Scholar 

  • Chang H, Rha SY, Jeung HC, Im CK, Ahn JB, Kwon WS et al (2009) Association of the ABCB1 gene polymorphisms 2677G > T/A and 3435C > T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients. Ann Oncol 20:272–277

    Article  PubMed  CAS  Google Scholar 

  • Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373–383

    Article  PubMed  CAS  Google Scholar 

  • Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2008) GLOBOCAN 2008, cancer incidence and mortality worldwide: IARC cancer base no. 10. International Agency for Research on Cancer, Lyon

  • Fung KL, Gottesman MM (2009) A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 1794:860–871

    Article  PubMed  CAS  Google Scholar 

  • Green H, Söderkvist P, Rosenberg P, Horvath G, Peterson C (2006) mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy. Clin Cancer Res 12:854–859

    Article  PubMed  CAS  Google Scholar 

  • Han JY, Lim HS, Yoo YK, Shin ES, Park YH, Lee SY et al (2007) Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer 110:138–147

    Article  PubMed  Google Scholar 

  • Huang MY, Huang ML, Chen MJ, Lu CY, Chen CF, Tsai PC et al (2010) Multiple genetic polymorphisms in the prediction of clinical outcome of metastatic colorectal cancer patients treated with first-line FOLFOX-4 chemotherapy. Pharmacogenet Genomics 21:18–25

    Article  Google Scholar 

  • Hüebener C, Petermann I, Browning BL, Shelling AN, Ferguson LR (2007) Triallelic single nucleotide polymorphisms and genotyping error in genetic epidemiology studies: MDR1 (ABCB1) G2677T/A as an example. Cancer Epidemiol Biomarkers Prev 16:1185–1192

    Article  Google Scholar 

  • Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S et al (2002) MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 62:4955–4962

    PubMed  CAS  Google Scholar 

  • Isla D, Sarries C, Rosell R, Alonso G, Domine M, Taron M et al (2004) Single nucleotide polymorphisms and outcome n docetaxel–cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol 15:1194–1203

    Article  PubMed  CAS  Google Scholar 

  • Johnatty SE, Beesley J, Paul J, Fereday S, Spurdle AB, Webb PM et al (2008) ABCB1 (MDR1) polymorphisms and progression-free survival among women with ovarian cancer following paclitaxel/carboplatin chemotherapy. Clin Cancer Res 14:5594–5601

    Article  PubMed  CAS  Google Scholar 

  • Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199

    Article  PubMed  CAS  Google Scholar 

  • Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528

    Article  PubMed  CAS  Google Scholar 

  • Knez L, Sodja E, Kern I, Košnik M, Cufer T (2011) Predictive value of multidrug resistance proteins, topoisomerase II and ERCC1 in small cell lung cancer: a systematic review. Lung Cancer 72:271–279

    Article  PubMed  Google Scholar 

  • Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ et al (2003) Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 13:481–494

    Article  PubMed  CAS  Google Scholar 

  • Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE et al (2009) Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27:2530–2535

    Article  PubMed  CAS  Google Scholar 

  • Marsh S, Paul J, King CR, Gifford G, McLeod HL, Brown R (2007) Pharmacogenetic assessment of toxicity and outcome after platinum plus taxanes chemotherapy in ovarian cancer: the Scottish randomised trial in ovarian cancer. J Clin Oncol 25:4528–4535

    Article  PubMed  CAS  Google Scholar 

  • Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655

    Article  PubMed  CAS  Google Scholar 

  • Pan JH, Han JX, Wu JM, Sheng LJ, Huang HN, Yu QZ (2008) MDR1 single nucleotide polymorphisms predict response to vinorelbine-based chemotherapy in patients with non-small cell lung cancer. Respiration 75:380–385

    Article  PubMed  CAS  Google Scholar 

  • Pan JH, Han JX, Wu JM, Huang HN, Yu QZ, Sheng LJ (2009) MDR1 single nucleotide polymorphism G2677T/A and haplotype are correlated with response to docetaxel–cisplatin chemotherapy in patients with non-small-cell lung cancer. Respiration 78:49–55

    Article  PubMed  CAS  Google Scholar 

  • Shitara K, Matsuo K, Ito S, Sawaki A, Kawai H, Yokota T et al (2010) Effects of genetic polymorphisms in the ABCB1 gene on clinical outcomes in patients with gastric cancer treated by second-line chemotherapy. Asian Pac J Cancer Prev 11:447–452

    PubMed  Google Scholar 

  • Sissung TM, Baum CE, Deeken J, Price DK, Aragon-Ching J, Steinberg SM et al (2008) ABCB1 genetic variation influences the toxicity and clinical outcome of patients with androgen independent prostate cancer treated with docteaxel. Clin Cancer Res 14:4543–4549

    Article  PubMed  CAS  Google Scholar 

  • Sohn JW, Lee SY, Lee SJ, Kim EJ, Cha SI, Kim CH et al (2006) MDR1 polymorphisms predict the response to etoposide-cisplatin combination chemotherapy in small cell lung cancer. Jpn J Clin Oncol 36:137–141

    Article  PubMed  Google Scholar 

  • Sørensen M, Pijls-Johannesma M, Felip E, ESMO Guidelines Working Group (2010) Small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v120–v125

    Article  PubMed  Google Scholar 

  • Stewart DJ (2010) Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol 75:173–234

    Article  PubMed  Google Scholar 

  • Tang K, Wong LP, Lee EJ, Chong SS, Lee CG (2004) Genomic evidence for recent positive selection at the human MDR1 gene locus. Hum Mol Genet 13:783–797

    Article  PubMed  CAS  Google Scholar 

  • Tregouet DA, Tiret L (2004) Cox proportional hazards survival regression in haplotype-based association analysis using the stochastic-EM algorithm. Eur J Hum Genet 12:971–974

    Article  PubMed  CAS  Google Scholar 

  • van den Heuvel-Eibrink MM, Wiemer EA, de Boevere MJ, van der Holt B, Vossebeld PJ, Pieters R et al (2001) MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. Blood 97:3605–3611

    Article  PubMed  Google Scholar 

  • Viñolas N, Provencio M, Reguart N, Cardenal F, Alberola V, Sánchez-Torres JM et al (2011) Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine. Lung Cancer 71:191–198

    Article  PubMed  Google Scholar 

  • Zhou J (2010) Multi-drug resistance in cancer, 1st edn. Humana Press, New York

    Book  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Matija Rijavec for his advice in planning the laboratory analysis.

Conflict of interest

None.

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Authors and Affiliations

  1. University Hospital Golnik, Golnik 36, 4204, Golnik, Slovenia

    L. Knez, M. Košnik, E. Sodja, I. Kern & T. Cufer

  2. University Clinic Maribor, Ljubljanska ulica 5, 2000, Maribor, Slovenia

    T. Ovčariček

  3. Faculty of Computer and Information Sciences, University of Ljubljana, Tržaška cesta 25, 1000, Ljubljana, Slovenia

    A. Sadikov

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  1. L. Knez
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  2. M. Košnik
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  3. T. Ovčariček
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  5. E. Sodja
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  6. I. Kern
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  7. T. Cufer
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Correspondence to L. Knez.

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Knez, L., Košnik, M., Ovčariček, T. et al. Predictive value of ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype in small cell lung cancer patients treated with chemotherapy. J Cancer Res Clin Oncol 138, 1551–1560 (2012). https://doi.org/10.1007/s00432-012-1231-1

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  • DOI: https://doi.org/10.1007/s00432-012-1231-1

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