Triple Negative Breast Cancer: Molecular Classification, Prognostic Markers and Targeted Therapies

Jafarzadeh, Narges; Ashraf, Hami; Khoshroo, Fahimeh; Sepehri Shamloo, Alireza; Bidouei, Farzad; Ghaffarzadehgan, Kamran

doi:10.30483/rijm.2015.118321

Triple Negative Breast Cancer: Molecular Classification, Prognostic Markers and Targeted Therapies

Authors

¹ Department of Research and Education, Razavi Hospital, Mashhad, IR Iran

² Student Research Committee, Mashhad University of Medical Sciences, Mashhad, IR Iran

10.30483/rijm.2015.118321

Abstract

Background: Triple negative breast cancer (TNBC) is a heterogeneous group of diseases that is negative for esterogen receptor (ER) progesteron receptor (PR) and human epidermal growth factor receptor 2 (HER2). This type of breast cancer is typically high-grade carcinomas, although low-grade tumors occur. The aim of this review is to focus on molecular classification and features, prognostic markers and targeted therapies of triple negative breast cancer.

Evidence Acquisition: We searched using electronic databases Pubmed/Medline, Dare, Scopus, Embase, and Cochrane Database of Systematic Reviews with terms of ‘Triple negative breast cancer’, ‘Breast cancer’, ‘Molecular classification’, ‘Immunohistochemical markers’, ‘Molecular features, ‘Targeted therapy’, and ‘Prognostic marker’.

Results: It seems that TNBC itself can be subdivided into immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor, and distinct basal-like subtypes that differ substantially from basal-like tumors. There are several prognostic makers for TNBC including EGFR and ALDH1, Lysyl Oxidase-Like 2 protein (LOXL2), Synuclein gamma (SNCG), LDHB (Lactate Dehydrogenase B). The antiangiogenic agents, EGFR inhibitors, and PARP inhibitors are new therapeutic Implications and potent factors to targeted therapies of TNBC.

Conclusions: Only a few clinical trials are performed on TNBC patients because this disease has a low incidence. Therefore, it seems larger scale clinical trials are needed to be conducted in the future.

Keywords

Open Access Policy: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/

References

1. Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med. 2013;274(2):113-26. https://doi.org/10.1111/joim.12084 PMid:23844915 PMCid:PMC3711134

2. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4):207. 3. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492-502. https://doi.org/10.1001/jama.295.21.2492 PMid:16757721

3. Oakman C, Viale G, Di Leo A. Management of triple negative breast cancer. Breast. 2010;19(5):312-21. https://doi.org/10.1016/j.breast.2010.03.026 PMid:20382530

4. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429-34. https://doi.org/10.1158/1078-0432.CCR-06-3045 PMid:17671126

5. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 2010;15 Suppl 5:39-48. https://doi.org/10.1634/theoncologist.2010-S5-39 PMid:21138954

6. Dawood S. Triple-negative breast cancer: epidemiology and management options. Drugs. 2010;70(17):2247-58. https://doi.org/10.2165/11538150-000000000-00000 PMid:21080741

7. Lara-Medina F, Perez-Sanchez V, Saavedra-Perez D, Blake-Cerda M, Arce C, Motola-Kuba D, et al. Triple-negative breast cancer in Hispanic patients: high prevalence, poor prognosis, and association with menopausal status, body mass index, and parity. Cancer. 2011;117(16):3658-69. https://doi.org/10.1002/cncr.25961 PMid:21387260

8. Brady-West DC, McGrowder DA. Triple negative breast cancer: therapeutic and prognostic implications. Asian Pac J Cancer Prev. 2011;12(8):2139-43.

9. Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, et al. Risk factors for triple-negative breast cancer in women under the age of 45 years. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1157-66. https://doi.org/10.1158/1055-9965.EPI-08-1005 PMid:19336554 PMCid:PMC2754710

10. Bosch A, Eroles P, Zaragoza R, Vina JR, Lluch A. Triple-negative breast cancer: molecular features, pathogenesis, treatment and current lines of research. Cancer Treat Rev. 2010;36(3):206-15. https://doi.org/10.1016/j.ctrv.2009.12.002 PMid:20060649

11. Carey L, Winer E, Viale G, Cameron D, Gianni L. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol. 2010;7(12):683-92. https://doi.org/10.1038/nrclinonc.2010.154 PMid:20877296

12. Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, Benitez J, et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res. 2006;12(5):1533-9. https://doi.org/10.1158/1078-0432.CCR-05-2281 PMid:16533778

13. Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2003;95(19):1482-5. 15. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12(5):R68. https://doi.org/10.1186/bcr2635 PMid:20813035 PMCid:PMC3096954

14. Turner N, Lambros MB, Horlings HM, Pearson A, Sharpe R, Natrajan R, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;29(14):2013-23. https://doi.org/10.1038/onc.2009.489 PMid:20101236 PMCid:PMC2852518

15. Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, et al. Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res. 2009;15(2):441-51. https://doi.org/10.1158/1078-0432.CCR-08-1791 PMid:19147748

16. Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E, Hanker L, et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res. 2011;13(5):R97. https://doi.org/10.1186/bcr3035 PMid:21978456 PMCid:PMC3262210

17. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-67. https://doi.org/10.1172/JCI45014 PMid:21633166 PMCid:PMC3127435

18. Linn SC, Van 't Veer LJ. Clinical relevance of the triple-negative breast cancer concept: genetic basis and clinical utility of the concept. Eur J Cancer. 2009;45 Suppl 1:11-26. https://doi.org/10.1016/S0959-8049(09)70012-7 PMid:19775601

19. Turner N, Moretti E, Siclari O, Migliaccio I, Santarpia L, D'Incalci M, et al. Targeting triple negative breast cancer: is p53 the answer? Cancer Treat Rev. 2013;39(5):541-50. https://doi.org/10.1016/j.ctrv.2012.12.001 PMid:23321033

20. Purrington KS, Slager S, Eccles D, Yannoukakos D, Fasching PA, Miron P, et al. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triplenegative breast cancer. Carcinogenesis. 2014;35(5):1012-9. https://doi.org/10.1093/carcin/bgt404 PMid:24325915 PMCid:PMC4004200

21. Radojicic J, Zaravinos A, Vrekoussis T, Kafousi M, Spandidos DA, Stathopoulos EN. MicroRNA expression analysis in triple-negative (ER, PR and Her2/neu) breast cancer. Cell Cycle. 2011;10(3):507-17. https://doi.org/10.4161/cc.10.3.14754 PMid:21270527

22. de Rinaldis E, Gazinska P, Mera A, Modrusan Z, Fedorowicz GM, Burford B, et al. Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control. BMC Genomics. 2013;14:643. https://doi.org/10.1186/1471-2164-14-643 PMid:24059244 PMCid:PMC4008358

23. Chen JQ , Russo J. ERalpha-negative and triple negative breast cancer: molecular features and potential therapeutic approaches. Biochim Biophys Acta. 2009;1796(2):162-75. https://doi.org/10.1016/j.bbcan.2009.06.003 PMid:19527773 PMCid:PMC2937358

24. Lowery AJ, Miller N, Devaney A, McNeill RE, Davoren PA, Lemetre C, et al. MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neu receptor status in breast cancer. Breast Cancer Res. 2009;11(3):R27. https://doi.org/10.1186/bcr2257 PMid:19432961 PMCid:PMC2716495

25. Bernardi R, Gianni L. Hallmarks of triple negative breast cancer emerging at last? Cell Res. 2014;24(8):904-5. https://doi.org/10.1038/cr.2014.61 PMid:24810303 PMCid:PMC4123289

26. Chen X, Iliopoulos D, Zhang Q , Tang Q, Greenblatt MB, Hatziapostolou M, et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1alpha pathway. Nature. 2014;508(7494):103-7. 29. Criscitiello C, Sotiriou C, Ignatiadis M. Circulating tumor cells and emerging blood biomarkers in breast cancer. Curr Opin Oncol. 2010;22(6):552-8. https://doi.org/10.1097/CCO.0b013e32833de186 PMid:20706122

27. Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Newell J, Kerin MJ. Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg. 2010;251(3):499-505. https://doi.org/10.1097/SLA.0b013e3181cc939f PMid:20134314

28. Shiu KK, Tan DS, Reis-Filho JS. Development of therapeutic approaches to 'triple negative' phenotype breast cancer. Expert Opin Ther Targets. 2008;12(9):1123-37. https://doi.org/10.1517/14728222.12.9.1123 PMid:18694379

29. Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, Nebert DW, et al. Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 2011;5(4):283-303. https://doi.org/10.1186/1479-7364-5-4-283 PMid:21712190 PMCid:PMC3392178

30. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555-67. https://doi.org/10.1016/j.stem.2007.08.014 PMid:18371393 PMCid:PMC2423808

31. Ohi Y, Umekita Y, Yoshioka T, Souda M, Rai Y, Sagara Y, et al. Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer. Histopathology. 2011;59(4):776-80. https://doi.org/10.1111/j.1365-2559.2011.03884.x PMid:22014057

32. Csiszar K. Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol. 2001;70:1-32. https://doi.org/10.1016/S0079-6603(01)70012-8 PMid:11642359

33. Jiao Q , Wu A, Shao G, Peng H, Wang M, Ji S, et al. The latest progress in research on triple negative breast cancer (TNBC): risk factors, possible therapeutic targets and prognostic markers. J Thorac Dis. 2014;6(9):1329-35.

34. Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer--current status and future directions. Ann Oncol. 2009;20(12):1913-27. https://doi.org/10.1093/annonc/mdp492 PMid:19901010

35. Wu K, Huang S, Zhu M, Lu Y, Chen J, Wang Y, et al. Expression of synuclein gamma indicates poor prognosis of triple-negative breast cancer. Med Oncol. 2013;30(3):612. https://doi.org/10.1007/s12032-013-0612-x PMid:23696021

36. McCleland ML, Adler AS, Shang Y, Hunsaker T, Truong T, Peterson D, et al. An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer. Cancer Res. 2012;72(22):5812-23. https://doi.org/10.1158/0008-5472.CAN-12-1098 PMid:23139210

37. Dennison JB, Molina JR, Mitra S, Gonzalez-Angulo AM, Balko JM, Kuba MG, et al. Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res. 2013;19(13):3703-13. https://doi.org/10.1158/1078-0432.CCR-13-0623 PMid:23697991 PMCid:PMC3727144

38. Singh-Ranger G, Salhab M, Mokbel K. The role of cyclooxygenase-2 in breast cancer: review. Breast Cancer Res Treat. 2008;109(2):189-98. https://doi.org/10.1007/s10549-007-9641-5 PMid:17624587

39. Hoellen F, Kelling K, Dittmer C, Diedrich K, Friedrich M, Thill M. Impact of cyclooxygenase-2 in breast cancer. Anticancer Res. 2011;31(12):4359-67.

40. Mosalpuria K, Hall C, Krishnamurthy S, Lodhi A, Hallman DM, Baraniuk MS, et al. Cyclooxygenase-2 expression in non-metastatic triple-negative breast cancer patients. Mol Clin Oncol. 2014;2(5):845-50. https://doi.org/10.3892/mco.2014.327 PMid:25054056 PMCid:PMC4106732

41. Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol. 2005;23(28):7212-20. https://doi.org/10.1200/JCO.2005.07.501 PMid:16192605

42. Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, et al. Com- Jafarzadeh N et al. Razavi Int J Med. 2015;3(2):e24992 7 parative value of tumour grade, hormonal receptors, Ki-67, HER2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracyclinebased chemotherapy. Euro J of Cancer. 2004;40(2):205-11. https://doi.org/10.1016/S0959-8049(03)00675-0 PMid:14728934

43. Rhee J, Han SW, Oh DY, Kim JH, Im SA, Han W, et al. The clinicopathologic characteristics and prognostic significance of triplenegativity in node-negative breast cancer. BMC Cancer. 2008;8:307. 47. Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, et al. Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res. 2011;13(2):R22. https://doi.org/10.1186/bcr2834 PMid:21366896 PMCid:PMC3219180

44. Siziopikou KP, Ariga R, Proussaloglou KE, Gattuso P, Cobleigh M. The challenging estrogen receptor-negative/ progesterone receptor-negative/HER-2-negative patient: a promising candidate for epidermal growth factor receptor-targeted therapy? Breast J. 2006;12(4):360-2. https://doi.org/10.1111/j.1075-122X.2006.00276.x PMid:16848847

45. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329-34. https://doi.org/10.1158/1078-0432.CCR-06-1109 PMid:17438091

46. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26(15):2568-81. https://doi.org/10.1200/JCO.2007.13.1748 PMid:18487574

47. Populo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. 2012;13(2):1886-918. https://doi.org/10.3390/ijms13021886 PMid:22408430 PMCid:PMC3291999

48. Burgess DJ, Doles J, Zender L, Xue W, Ma B, McCombie WR, et al. Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc Natl Acad Sci U S A. 2008;105(26):9053-8. https://doi.org/10.1073/pnas.0803513105 PMid:18574145 PMCid:PMC2435590

49. Sharpe R, Pearson A, Herrera-Abreu MT, Johnson D, Mackay A, Welti JC, et al. FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2011;17(16):5275-86. https://doi.org/10.1158/1078-0432.CCR-10-2727 PMid:21712446 PMCid:PMC3432447

50. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-34. https://doi.org/10.1056/NEJMoa0900212 PMid:19553641

51. O'shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, Monaghan G, et al., editors. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/ carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial.; ASCO Annual Meeting Proceedings.; 2009; p. 3. https://doi.org/10.1200/jco.2009.27.15_suppl.3

52. Chiosis G, Caldas Lopes E, Solit D. Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents. Curr Opin Investig Drugs. 2006;7(6):534-41.

53. Patel HJ, Modi S, Chiosis G, Taldone T. Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert Opin Drug Discov. 2011;6(5):559-87. https://doi.org/10.1517/17460441.2011.563296 PMid:22400044 PMCid:PMC3293194

54. Kim LC, Song L, Haura EB. Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol. 2009;6(10):587-95. https://doi.org/10.1038/nrclinonc.2009.129 PMid:19787002

55. Finn RS, Bengala C, Ibrahim N, Roche H, Sparano J, Strauss LC, et al. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res. 2011;17(21):6905-13. https://doi.org/10.1158/1078-0432.CCR-11-0288 PMid:22028489

56. Tryfonopoulos D, Walsh S, Collins DM, Flanagan L, Quinn C, Corkery B, et al. Src: a potential target for the treatment of triple-negative breast cancer. Ann Oncol. 2011;22(10):2234-40. https://doi.org/10.1093/annonc/mdq757 PMid:21357651

57. Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptorpositive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010;23(2):205-12. https://doi.org/10.1038/modpathol.2009.159 PMid:19898421

58. Shah PD, Gucalp A, Traina TA. The role of the androgen receptor in triple-negative breast cancer. Womens Health (Lond Engl). 2013;9(4):351-60. https://doi.org/10.2217/WHE.13.33 PMid:23826776

59. Modi S, Stopeck A, Linden H, Solit D, Chandarlapaty S, Rosen N, et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2- positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res. 2011;17(15):5132-9. 64. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389(6649):349-52. https://doi.org/10.1038/38664 PMid:9311776

60. Jones RA, Campbell CI, Gunther EJ, Chodosh LA, Petrik JJ, Khokha R, et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene. 2007;26(11):1636-44. https://doi.org/10.1038/sj.onc.1209955 PMid:16953219

61. Bolderson E, Richard DJ, Zhou BB, Khanna KK. Recent advances in cancer therapy targeting proteins involved in DNA doublestrand break repair. Clin Cancer Res. 2009;15(20):6314-20. https://doi.org/10.1158/1078-0432.CCR-09-0096 PMid:19808869

62. Ashwell S, Zabludoff S. DNA damage detection and repair pathways--recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin Cancer Res. 2008;14(13):4032-7. https://doi.org/10.1158/1078-0432.CCR-07-5138 PMid:18593978

63. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085-94. https://doi.org/10.1158/0008-5472.CAN-09-3746 PMid:20179196 PMCid:PMC2832818

64. Sharpe R, Pearson A, Herrera-Abreu MT, Johnson D, Mackay A, Welti JC, et al. FGFR Signaling Promotes the Growth of Triple-Negative and Basal-Like Breast Cancer Cell Lines Both In Vitro and In Vivo. Clinical Cancer Research. 2011;17(16):5275-86. https://doi.org/10.1158/1078-0432.CCR-10-2727 PMid:21712446 PMCid:PMC3432447

Razavi International Journal of Medicine

Triple Negative Breast Cancer: Molecular Classification, Prognostic Markers and Targeted Therapies

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Volume 3, Issue 2
April 2015

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Triple Negative Breast Cancer: Molecular Classification, Prognostic Markers and Targeted Therapies

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Volume 3, Issue 2April 2015

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How to cite

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Volume 3, Issue 2
April 2015