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Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Unveiling Novel Therapeutic Drug Targets and Prognostic Markers of Triple Negative Breast Cancer

Author(s): Acharya Balkrishna, Rashmi Mittal and Vedpriya Arya*

Volume 21, Issue 11, 2021

Published on: 26 November, 2021

Page: [907 - 918] Pages: 12

DOI: 10.2174/1568009621666210908113010

Price: $65

Abstract

Triple negative breast cancer represents multiple genomic and transcriptomic heterogeneities. Genetic and epigenetic changes emerging in TNBC help it in acquiring resistance against immunological response. Distant metastasis, lack of clinically targeted therapies and prognostic markers make it the most aggressive form of breast cancer. In this review, we showed that driver alterations in targeted genes AR, ERR, TIL, TAM, miRNA, mTOR and immunosuppressive cytokines are predominantly involved in complicating TNBC by inducing cell proliferation, invasion and metastasis, and by inhibiting apoptosis. The role of node status, cathepsin-D, Ki-67 index, CD3+TIL, BRCA1 promoter methylation value and p53 as an efficient prognostic factor have also been studied to predict the disease free and overall survival rate in TNBC patients. The present review article is an attempt to gain an insight with a new vision on the etiology of TNBC, its treatment strategies and prognostic marker to identify the outcome of standard therapies and to re-design future treatment strategies to provide maximum benefit to patients.

Keywords: AR, microRNAs, TAM, TNBC, TILs, treatment, prognosis.

Graphical Abstract
[1]
Arnedos, M.; Bihan, C.; Delaloge, S.; Andre, F. Triple-negative breast cancer: are we making headway at least? Ther. Adv. Med. Oncol., 2012, 4(4), 195-210.
[http://dx.doi.org/10.1177/1758834012444711] [PMID: 22754593]
[2]
Schmadeka, R.; Harmon, B.E.; Singh, M. Triple-negative breast carcinoma: current and emerging concepts. Amer. Clin. Path., 2014, 141(4), 462-477.
[http://dx.doi.org/10.1309/AJCPQN8GZ8SILKGN] [PMID: 24619745]
[3]
Lehmann, B.D.; Bauer, J.A.; Chen, X.; Sanders, M.E.; Chakravarthy, A.B.; Shyr, Y.; Pietenpol, J.A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest., 2011, 121(7), 2750-2767.
[http://dx.doi.org/10.1172/JCI45014] [PMID: 21633166]
[4]
Barton, V.N.; D’Amato, N.C.; Gordon, M.A.; Lind, H.T.; Spoelstra, N.S.; Babbs, B.L.; Heinz, R.E.; Elias, A.; Jedlicka, P.; Jacobsen, B.M.; Richer, J.K. Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo. Mol. Cancer Ther., 2015, 14(3), 769-778.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0926] [PMID: 25713333]
[5]
Stagg, J.; Allard, B. Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects. Ther. Adv. Med. Oncol., 2013, 5(3), 169-181.
[http://dx.doi.org/10.1177/1758834012475152] [PMID: 23634195]
[6]
Balkrishna, A.; Mittal, R.; Arya, V. Unveiling role of MicroRNAs as treatment strategy and prognostic markers in triple negative breast cancer. Curr. Pharm. Biotechnol., 2020, 21(15), 1569-1575.
[http://dx.doi.org/10.2174/1389201021666200627201535] [PMID: 32593278]
[7]
Treeck, O.; Schüler-Toprak, S.; Ortmann, O. Estrogen actions in triple-negative breast cancer. Cells, 2020, 9(11), 2358.
[http://dx.doi.org/10.3390/cells9112358] [PMID: 33114740]
[8]
Maniscalco, L.; Millán, Y.; Iussich, S.; Denina, M.; Sánchez-Céspedes, R.; Gattino, F.; Biolatti, B.; Sasaki, N.; Nakagawa, T.; Di Renzo, M.F.; de Las Mulas, J.M.; De Maria, R. Activation of mammalian target of rapamycin (mTOR) in triple negative feline mammary carcinomas. BMC Vet. Res., 2013, 9(1), 80.
[http://dx.doi.org/10.1186/1746-6148-9-80] [PMID: 23587222]
[9]
Kim, J.Y.; Jung, H.H.; Ahn, S.; Bae, S.; Lee, S.K.; Kim, S.W.; Lee, J.E.; Nam, S.J.; Ahn, J.S.; Im, Y.H.; Park, Y.H. The relationship between nuclear factor (NF)-κB family gene expression and prognosis in triple-negative breast cancer (TNBC) patients receiving adjuvant doxorubicin treatment. Sci. Rep., 2016.
[http://dx.doi.org/10.1038/srep31804]
[10]
Kwon, J.; Eom, K.Y.; Koo, T.R.; Kim, B.H.; Kang, E.; Kim, S.W.; Kim, Y.J.; Park, S.Y.; Kim, I.A. A prognostic model for patients with triple-negative breast cancer: importance of the modified nottingham prognostic index and age. J. Breast Cancer, 2017, 20(1), 65-73.
[http://dx.doi.org/10.4048/jbc.2017.20.1.65] [PMID: 28382096]
[11]
Yao, L.; Liu, Y.; Cao, Z.; Li, J.; Huang, Y.; Hu, X.; Shao, Z. MicroRNA-493 is a prognostic factor in triple-negative breast cancer. Cancer Sci., 2018, 109(7), 2294-2301.
[http://dx.doi.org/10.1111/cas.13644] [PMID: 29777630]
[12]
Chen, X.; Li, J.; Gray, W.H.; Lehmann, B.D.; Bauer, J.A.; Shyr, Y.; Pietenpol, J.A. TNBC type: a subtyping tool for triple-negative breast cancer. Cancer Inform., 2012, 11, 147-156.
[http://dx.doi.org/10.4137/CIN.S9983] [PMID: 22872785]
[13]
Bauer, J.A.; Chakravarthy, A.B.; Rosenbluth, J.M.; Mi, D.; Seeley, E.H.; De Matos Granja-Ingram, N.; Olivares, M.G.; Kelley, M.C.; Mayer, I.A.; Meszoely, I.M.; Means-Powell, J.A.; Johnson, K.N.; Tsai, C.J.; Ayers, G.D.; Sanders, M.E.; Schneider, R.J.; Formenti, S.C.; Caprioli, R.M.; Pietenpol, J.A. Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation. Clin. Cancer Res., 2010, 16(2), 681-690.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1091] [PMID: 20068102]
[14]
Juul, N.; Szallasi, Z.; Eklund, A.C.; Li, Q.; Burrell, R.A.; Gerlinger, M.; Valero, V.; Andreopoulou, E.; Esteva, F.J.; Symmans, W.F.; Desmedt, C.; Haibe-Kains, B.; Sotiriou, C.; Pusztai, L.; Swanton, C. Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials. Lancet Oncol., 2010, 11(4), 358-365.
[http://dx.doi.org/10.1016/S1470-2045(10)70018-8] [PMID: 20189874]
[15]
Mayer, I.A. A phase II newoadjuvant negative (TN) locally advanced breast cancer (BC). J. Clin. Oncol., 2010, 28(1), 15.
[PMID: 19933920]
[16]
Bertucci, F.; Finetti, P.; Cervera, N.; Charafe-Jauffret, E.; Mamessier, E.; Adélaïde, J.; Debono, S.; Houvenaeghel, G.; Maraninchi, D.; Viens, P.; Charpin, C.; Jacquemier, J.; Birnbaum, D. Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. Cancer Res., 2006, 66(9), 4636-4644.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0031] [PMID: 16651414]
[17]
Gibson, G.R.; Qian, D.; Ku, J.K.; Lai, L.L. Metaplastic breast cancer: clinical features and outcomes. Am. Surg., 2005, 71(9), 725-730.
[http://dx.doi.org/10.1177/000313480507100906] [PMID: 16468506]
[18]
Prat, A.; Parker, J.S.; Karginova, O.; Fan, C.; Livasy, C.; Herschkowitz, J.I.; He, X.; Perou, C.M. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res., 2010, 12(5), R68.
[http://dx.doi.org/10.1186/bcr2635] [PMID: 20813035]
[19]
Hayes, M.J.; Thomas, D.; Emmons, A.; Giordano, T.J.; Kleer, C.G. Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin. Cancer Res., 2008, 14(13), 4038-4044.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-4379] [PMID: 18593979]
[20]
Chen, C.D.; Welsbie, D.S.; Tran, C.; Baek, S.H.; Chen, R.; Vessella, R.; Rosenfeld, M.G.; Sawyers, C.L. Molecular determinants of resistance to antiandrogen therapy. Nat. Med., 2004, 10(1), 33-39.
[http://dx.doi.org/10.1038/nm972] [PMID: 14702632]
[21]
Farmer, P.; Bonnefoi, H.; Becette, V.; Tubiana-Hulin, M.; Fumoleau, P.; Larsimont, D.; Macgrogan, G.; Bergh, J.; Cameron, D.; Goldstein, D.; Duss, S.; Nicoulaz, A.L.; Brisken, C.; Fiche, M.; Delorenzi, M.; Iggo, R. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene, 2005, 24(29), 4660-4671.
[http://dx.doi.org/10.1038/sj.onc.1208561] [PMID: 15897907]
[22]
Ring, BZ.; Hout, DR.; Morris, SW.; Lawrence, K.; Schweitzer, BL.; Bailey, DB.; Lehmann, BD.; Pietenpol, JA.; Seitz, RS. Generation of an algorithm based on minimal gene sets to clinically subtype triple negative breast cancer patients. BMC Cancer, 2016, 16(1), 143.
[23]
Rampurwala, M.; Wisinski, K.B.; O’Regan, R. Role of the androgen receptor in triple-negative breast cancer. Clin. Adv. Hematol. Oncol., 2016, 14(3), 186-193.
[PMID: 27058032]
[24]
Bonnefoi, H.; Grellety, T.; Tredan, O.; Saghatchian, M.; Dalenc, F.; Mailliez, A.; L’Haridon, T.; Cottu, P.; Abadie-Lacourtoisie, S.; You, B.; Mousseau, M.; Dauba, J.; Del Piano, F.; Desmoulins, I.; Coussy, F.; Madranges, N.; Grenier, J.; Bidard, F.C.; Proudhon, C.; MacGrogan, G.; Orsini, C.; Pulido, M.; Gonçalves, A. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann. Oncol., 2016, 27(5), 812-818.
[http://dx.doi.org/10.1093/annonc/mdw067] [PMID: 27052658]
[25]
Zhu, A.; Li, Y.; Song, W.; Xu, Y.; Yang, F.; Zhang, W.; Yin, Y.; Guan, X. Antiproliferative effect of androgen receptor inhibition in mesenchymal stem-like triple-negative breast cancer. Cell. Physiol. Biochem., 2016, 38(3), 1003-1014.
[http://dx.doi.org/10.1159/000443052] [PMID: 26938985]
[26]
Caiazza, F.; Murray, A.; Madden, S.F.; Synnott, N.C.; Ryan, E.J.; O’Donovan, N.; Crown, J.; Duffy, M.J. Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells. End. Rel. Cancer, 2016, 23(4), 323-334.
[http://dx.doi.org/10.1530/ERC-16-0068] [PMID: 26932782]
[27]
Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer, 2012, 12(4), 252-264.
[http://dx.doi.org/10.1038/nrc3239] [PMID: 22437870]
[28]
Qiao, Y.; He, H.; Jonsson, P.; Sinha, I.; Zhao, C.; Dahlman-Wright, K. AP-1 is a key regulator of proinflammatory cytokine TNFα-mediated triple-negative breast cancer progression. J. Biol. Chem., 2016, 291(10), 5068-5079.
[http://dx.doi.org/10.1074/jbc.M115.702571] [PMID: 26792858]
[29]
Wang, J.; Chen, H.; Chen, X.; Lin, H. Expression of Tumor-Related Macrophages and Cytokines After Surgery of Triple-Negative Breast Cancer Patients and its Implications. Med. Sci. Monit., 2016, 22, 115-120.
[http://dx.doi.org/10.12659/MSM.895386] [PMID: 26752006]
[30]
García-Teijido, P.; Cabal, M.L.; Fernández, I.P.; Pérez, Y.F. Tumor-infiltrating lymphocytes in triple negative breast cancer: The future of immune targeting. Clin. Med. Ins. Oncol, 2016.
[31]
Browne, G.; Dragon, J.A.; Hong, D.; Messier, T.L.; Gordon, J.A.; Farina, N.H.; Boyd, J.R.; VanOudenhove, J.J.; Perez, A.W.; Zaidi, S.K.; Stein, J.L.; Stein, G.S.; Lian, J.B. MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells. Tumour Biol., 2016, 37(7), 8825-8839.
[http://dx.doi.org/10.1007/s13277-015-4710-6] [PMID: 26749280]
[32]
Adams, B.D.; Wali, V.B.; Cheng, C.J.; Inukai, S.; Booth, C.J.; Agarwal, S.; Rimm, D.L.; Győrffy, B.; Santarpia, L.; Pusztai, L.; Saltzman, W.M.; Slack, F.J. MiR-34a silences c-SRC to attenuate tumor growth in triple-negative breast cancer. Cancer Res., 2016, 76(4), 927-939.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-2321] [PMID: 26676753]
[33]
Phan, B.; Majid, S.; Ursu, S.; de Semir, D.; Nosrati, M.; Bezrookove, V.; Kashani-Sabet, M.; Dar, A.A. Tumor suppressor role of microRNA-1296 in triple-negative breast cancer. Oncotarget, 2016, 7(15), 19519-19530.
[http://dx.doi.org/10.18632/oncotarget.6961] [PMID: 26799586]
[34]
Yan, M.; Li, X.; Tong, D.; Han, C.; Zhao, R.; He, Y.; Jin, X. miR-136 suppresses tumor invasion and metastasis by targeting RASAL2 in triple-negative breast cancer. Oncol. Rep., 2016, 36(1), 65-71.
[http://dx.doi.org/10.3892/or.2016.4767] [PMID: 27108696]
[35]
Wu, Y.M.; Chen, Z.J.; Jiang, G.M.; Zhang, K.S.; Liu, Q.; Liang, S.W.; Zhou, Y.; Huang, H.B.; Du, J.; Wang, H.S. Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways. Oncotarget, 2016, 7(11), 12568-12581.
[http://dx.doi.org/10.18632/oncotarget.7276] [PMID: 26871469]
[36]
Pikarsky, E.; Porat, R.M.; Stein, I.; Abramovitch, R.; Amit, S.; Kasem, S.; Gutkovich-Pyest, E.; Urieli-Shoval, S.; Galun, E.; Ben-Neriah, Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature, 2004, 431(7007), 461-466.
[http://dx.doi.org/10.1038/nature02924] [PMID: 15329734]
[37]
Wang, C.Y.; Mayo, M.W.; Baldwin, A.S., Jr TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kB. Science, 1996.
[http://dx.doi.org/10.1126/science.274.5288.784]
[38]
Chen, YJ.; Yeh, MH.; Yu, MC.; Wei, YL.; Chen, WS.; Chen, JY.; Shih, CY.; Tu, CY.; Chen, CH.; Hsia, TC.; Chien, PH. Lapatinib–induced NF-kappaB activation sensitizes triple-negative breast cancer cells to proteasome inhibitors. Breast Cancer Res., 2013, 15(6), 1.
[http://dx.doi.org/10.1186/bcr3575]
[39]
Manning, BD.; Cantley, LC. AKT/PKB signaling: navigating downstream. Cell, 2007, 129(7), 1261-1274.
[40]
Rubio-Viqueira, B.; Hidalgo, M. Targeting mTOR for cancer treatment. In: New trends in cancer for the 21st century; Springer: Netherlands, 2006; pp. 309-327.
[http://dx.doi.org/10.1007/978-1-4020-5133-3_24]
[41]
Zhang, H.; Cohen, AL.; Krishnakumar, S.; Wapnir, IL.; Veeriah, S.; Deng, G.; Coram, MA.; Piskun, CM.; Longacre, TA.; Herrler, M.; Frimannsson, DO. Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition. Breast Cancer Res., 2014, 16(2), R36.
[http://dx.doi.org/10.1186/bcr3640]
[42]
Singh, J.; Novik, Y.; Stein, S.; Volm, M.; Meyers, M.; Smith, J.; Omene, C.; Speyer, J.; Schneider, R.; Jhaveri, K.; Formenti, S.; Kyriakou, V.; Joseph, B.; Goldberg, J.D.; Li, X.; Adams, S.; Tiersten, A. Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Res., 2014, 16(2), R32.
[http://dx.doi.org/10.1186/bcr3634] [PMID: 24684785]
[43]
Moestue, S.A.; Dam, C.G.; Gorad, S.S.; Kristian, A.; Bofin, A.; Mælandsmo, G.M.; Engebråten, O.; Gribbestad, I.S.; Bjørkøy, G. Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer. Breast Cancer Res., 2013, 15(1), R16.
[http://dx.doi.org/10.1186/bcr3391] [PMID: 23448424]
[44]
Ellard, S.L.; Clemons, M.; Gelmon, K.A.; Norris, B.; Kennecke, H.; Chia, S.; Pritchard, K.; Eisen, A.; Vandenberg, T.; Taylor, M.; Sauerbrei, E.; Mishaeli, M.; Huntsman, D.; Walsh, W.; Olivo, M.; McIntosh, L.; Seymour, L. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J. Clin. Oncol., 2009, 27(27), 4536-4541.
[http://dx.doi.org/10.1200/JCO.2008.21.3033] [PMID: 19687332]
[45]
Hart, S.; Novotny-Diermayr, V.; Goh, K.C.; Williams, M.; Tan, Y.C.; Ong, L.C.; Cheong, A.; Ng, B.K.; Amalini, C.; Madan, B.; Nagaraj, H.; Jayaraman, R.; Pasha, K.M.; Ethirajulu, K.; Chng, W.J.; Mustafa, N.; Goh, B.C.; Benes, C.; McDermott, U.; Garnett, M.; Dymock, B.; Wood, J.M. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol. Cancer Ther., 2013, 12(2), 151-161.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0466] [PMID: 23270925]
[46]
Liang, D.H.; Choi, D.S.; Ensor, J.E.; Kaipparettu, B.A.; Bass, B.L.; Chang, J.C. The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair. Cancer Lett., 2016, 376(2), 249-258.
[http://dx.doi.org/10.1016/j.canlet.2016.04.002] [PMID: 27060208]
[47]
Zhou, X.; Jiao, D.; Dou, M.; Zhang, W.; Lv, L.; Chen, J.; Li, L.; Wang, L.; Han, X. Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression. J. Cell. Mol. Med., 2020, 24(18), 10648-10662.
[http://dx.doi.org/10.1111/jcmm.15683] [PMID: 32725802]
[48]
Huang, L.; Liu, Z.; Chen, S.; Liu, Y.; Shao, Z. A prognostic model for triple-negative breast cancer patients based on node status, cathepsin-D and Ki-67 index. PLoS One, 2013, 8(12), e83081.
[http://dx.doi.org/10.1371/journal.pone.0083081] [PMID: 24340082]
[49]
Rathore, A.S.; Goel, M.M.; Makker, A.; Kumar, S.; Srivastava, V. Prognostic impact of CD3 tumor infiltrating lymphocytes in triple-negative breast cancer. Oncology, 2013, CD3.
[50]
Fulford, L.G.; Reis-Filho, J.S.; Ryder, K.; Jones, C.; Gillett, C.E.; Hanby, A.; Easton, D.; Lakhani, S.R. Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res., 2007, 9(1), R4.
[http://dx.doi.org/10.1186/bcr1636] [PMID: 17217540]
[51]
Rodríguez-Pinilla, S.M.; Sarrió, D.; Honrado, E.; Hardisson, D.; Calero, F.; Benitez, J.; Palacios, J. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin. Cancer Res., 2006, 12(5), 1533-1539.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2281] [PMID: 16533778]
[52]
Guo, X.; Fan, Y.; Lang, R.; Gu, F.; Chen, L.; Cui, L.; Pringle, G.A.; Zhang, X.; Fu, L. Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast. Mod. Pathol., 2008, 21(9), 1101-1107.
[http://dx.doi.org/10.1038/modpathol.2008.72] [PMID: 18469794]
[53]
Rabinowich, H.; Cohen, R.; Bruderman, I.; Steiner, Z.; Klajman, A. Functional analysis of mononuclear cells infiltrating into tumors: lysis of autologous human tumor cells by cultured infiltrating lymphocytes. Cancer Res., 1987, 47(1), 173-177.
[PMID: 3491673]
[54]
Topalian, S.L.; Solomon, D.; Rosenberg, S.A. Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J. Immunol., 1989, 142(10), 3714-3725.
[PMID: 2785562]
[55]
Sharma, P.; Stecklein, S.R.; Kimler, B.F.; Sethi, G.; Petroff, B.K.; Phillips, T.A.; Tawfik, O.W.; Godwin, A.K.; Jensen, R.A. The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer. J. Cancer Ther. Res., 2014, 3(2), 1-11.
[http://dx.doi.org/10.7243/2049-7962-3-2] [PMID: 25177489]
[56]
Chae, B.J.; Bae, J.S.; Lee, A.; Park, W.C.; Seo, Y.J.; Song, B.J.; Kim, J.S.; Jung, S.S. p53 as a specific prognostic factor in triple-negative breast cancer. Jpn. J. Clin. Oncol., 2009, 39(4), 217-224.
[http://dx.doi.org/10.1093/jjco/hyp007] [PMID: 19304743]

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