Abstract
Several studies have investigated the effects of polymorphisms in the GSTP1, GSTT1, and GSTM1 genes on responsiveness to chemotherapy in breast cancer, but the results have been inconsistent. The aim of this study was to determine the association between polymorphisms of GSTP1, GSTT1, and GSTM1 genes and response to chemotherapy in patients with breast cancer. The relevant studies were retrieved from PubMed, Embase, ISI Web of Knowledge, China National Knowledge Infrastructure, and Wanfang databases. The articles evaluating the correlations between response to chemotherapy and GSTP1, GSTT1, and GSTM1 polymorphisms in breast cancer patients were comprehensively reviewed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to measure the strength of the associations. These associations were assessed with the χ 2 test in this meta-analysis. Subgroup analysis by chemotherapy protocol and ethnicity were conducted to explore the source of heterogeneity among studies. A total of 14 articles with 31 studies involving GSTP1, GSTT1, and GSTM1 polymorphisms with response to chemotherapy were identified in the final meta-analysis. In the overall analysis, a significant association of GSTM1-present/GSTM1-null polymorphism with responsiveness to chemotherapy was observed in breast cancer patients (OR 0.74, CI 0.60–0.92, P = 0.006), whereas the GSTT1-present/GSTT1-null and GSTP1rs1695 polymorphisms were not significantly associated with clinical response to chemotherapy. The subgroup analysis by chemotherapy protocol indicated that the patients who harboring GSTP1rs1695 AA or AG variant had a higher response rate to anthracycline-based chemotherapy than those carrying GSTP1rs1695 GG variant [AA vs. GG: OR 0.48, CI 0.29–0.80, P < 0.05; AA vs. AG: OR 0.60, CI 0.43–0.83, P < 0.05; A vs. G: OR 0.60, CI 0.47–0.77, P < 0.05; AA vs. (AG + GG): OR 0.56, CI 0.42–0.76, P < 0.05; (AA + AG) vs. GG: OR 0.57, CI 0.34–0.94, P < 0.05]. In addition, the heterogeneity existed among studies for GSTP1 polymorphism, while no obvious heterogeneity was detected for GSTT1 and GSTM1 polymorphisms. And the heterogeneity present in different studies, evaluating the association of GSTP1 polymorphism with response to anthracycline-based chemotherapy, disappeared in breast cancer patients after subgroup analysis by chemotherapy regimen was performed. In conclusion, this meta-analysis suggested that GSTP1rs1695 and GSTM1-present/GSTM1-null polymorphisms could be considered as reliable predictors of response to anthracycline-based chemotherapy in patients with breast cancer.
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References
Jemal A, Siegel R, Ward E et al (2009) Cancer statistics. CA Cancer J Clin 59(4):225–249
Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386
Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108
Ibrahim NI, Dahlui M, Aina EN et al (2012) Who are the breast cancer survivors in Malaysia? Asian Pac J Cancer Prev 13(5):2213–2218
Yao S, Barlow WE, Albain KS et al (2010) Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer. Clin Cancer Res 16(24):6169–6176
Zurrida S, Veronesi U (2015) Milestones in breast cancer treatment. Breast J 21(1):3–12
Roche H, Fumoleau P, Spielmann M et al (2006) Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol 24(36):5664–5671
Afsar NA, Haenisch S, Mateen A et al (2010) Genotype frequencies of selected drug metabolizing enzymes and ABC drug transporters among breast cancer patients on FAC chemotherapy. Basic Clin Pharmacol Toxicol 107(1):570–576
Ji M, Tang J, Zhao J et al (2012) Polymorphisms in genes involved in drug detoxification and clinical outcomes of anthracycline-based neoadjuvant chemotherapy in Chinese Han breast cancer patients. Cancer Biol Ther 13(5):264–271
Davidson A, Gelmon K (2011) Do anthracyclines still have a role in adjuvant chemotherapy of breast cancer? Future Oncol 7(1):37–55
Huang MY, Wang YH, Chen FM et al (2008) Multiple genetic polymorphisms of GSTP1 313AG, MDR1 3435CC, and MTHFR 677CC highly correlated with early relapse of breast cancer patients in Taiwan. Ann Surg Oncol 15(3):872–880
Armstrong RN (1997) Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem Res Toxicol 10(1):2–18
Zhong S, Huang M, Yang X et al (2006) Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus. Br J Clin Pharmacol 62(4):457–472
Hayes JD, McLellan LI (1999) Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic Res 31(4):273–300
Srivastava SK, Singhal SS, Hu X et al (1999) Differential catalytic efficiency of allelic variants of human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys 366(1):89–94
Townsend DM, Tew KD (2003) The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 22(47):7369–7375
Hirshfield KM, Rebbeck TR, Levine AJ (2010) Germline mutations and polymorphisms in the origins of cancers in women. J Oncol 2010:297671
Lourenco GJ, Lorand-Metze I, Delamain MT et al (2010) Polymorphisms of glutathione S-transferase mu 1, theta 1, and pi 1 genes and prognosis in Hodgkin lymphoma. Leuk Lymphoma 51(12):2215–2221
Satta T, Isobe K, Yamauchi M et al (1992) Expression of MDR1 and glutathione S transferase-pi genes and chemosensitivities in human gastrointestinal cancer. Cancer Am Cancer Soc 69(4):941–946
Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188
Egger M, Davey SG, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247
Jinhai T, Jianhua Z, Jianzhong W et al (2009) Establishment of a multiplex ligation-dependent SNP genotyping method and its application in the detection of genes related to chemotherapeutic drugs in breast cancer. Chin J Oncol 31(2):0253–3766
Oliveira AL, Rodrigues FF, Santos RE et al (2010) GSTT1, GSTM1, and GSTP1 polymorphisms and chemotherapy response in locally advanced breast cancer. Genet Mol Res 9(2):1045–1053
Shanliang Zhong, Shenggao Jiang, Jinhai Tang et al (2010) Association of GSTs gene polymorphism with response to chemotherapy in breast cancer. Chin J Clin Lab Sci 28(6):438–440
Bai YL, Zhou B, Jing XY et al (2012) Predictive role of GSTs on the prognosis of breast cancer patients with neoadjuvant chemotherapy. Asian Pac J Cancer Prev 13(10):5019–5022
Romero A, Martin M, Oliva B et al (2012) Glutathione S-transferase P1 c.313A>G polymorphism could be useful in the prediction of doxorubicin response in breast cancer patients. Ann Oncol 23(7):1750–1756
Tulsyan S, Chaturvedi P, Agarwal G et al (2013) Pharmacogenetic influence of GST polymorphisms on anthracycline-based chemotherapy responses and toxicity in breast cancer patients: a multi-analytical approach. Mol Diagn Ther 17(6):371–379
Xinlan L, Yanjiao Z, Min J et al (2013) Association of polymorphisms of GSTP1 (rs1695) with the efficacy of paclitaxel/anthracycline—based chemotherapy in stage breast cancer. Acad J Second Mil Med Univ 34(8):0879–0884
Islam MS, Islam MS, Parvin S et al (2015) Effect of GSTP1 and ABCC4 gene polymorphisms on response and toxicity of cyclophosphamide-epirubicin-5-fluorouracil-based chemotherapy in Bangladeshi breast cancer patients. Tumour Biol 36(7):5451–5457
Zhou L, Huang A, Zhang D et al (2015) Genetic variability of glutathione S-transferases influences treatment outcome of breast cancer. Tumour Biol 36(8):5925–5929
Khedhaier A, Remadi S, Corbex M et al (2003) Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma. Br J Cancer 89(8):1502–1507
Mishra A, Chandra R, Mehrotra PK et al (2011) Glutathione S-transferase M1 and T1 polymorphism and response to neoadjuvant chemotherapy (CAF) in breast cancer patients. Surg Today 41(4):471–476
Saadat M, Khalili M, Nasiri M et al (2012) Clinical response to chemotherapy in locally advanced breast cancer was not associated with several polymorphisms in detoxification enzymes and DNA repair genes. Biochem Biophys Res Commun 419(1):117–119
Sivonova M, Waczulikova I, Dobrota D et al (2009) Polymorphisms of glutathione-S-transferase M1, T1, P1 and the risk of prostate cancer: a case-control study. J Exp Clin Cancer Res 28:32
Hershman D, Neugut AI, Jacobson JS et al (2007) Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 99(3):196–205
Ambrosone CB, Ahn J, Singh KK et al (2005) Polymorphisms in genes related to oxidative stress (MPO, MnSOD, CAT) and survival after treatment for breast cancer. Cancer Res 65(3):1105–1111
Bewick MA, Conlon MS, Lafrenie RM (2008) Polymorphisms in manganese superoxide dismutase, myeloperoxidase and glutathione-S-transferase and survival after treatment for metastatic breast cancer. Breast Cancer Res Treat 111(1):93–101
Sau A, Pellizzari TF, Valentino F et al (2010) Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys 500(2):116–122
Arun BK, Granville LA, Yin G et al (2010) Glutathione-s-transferase-pi expression in early breast cancer: association with outcome and response to chemotherapy. Cancer Invest 28(5):554–559
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Kong, X., Li, Z. & Li, X. GSTP1, GSTM1, and GSTT1 polymorphisms as predictors of response to chemotherapy in patients with breast cancer: a meta-analysis. Cancer Chemother Pharmacol 78, 1163–1173 (2016). https://doi.org/10.1007/s00280-016-3173-9
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DOI: https://doi.org/10.1007/s00280-016-3173-9