Exploiting epigenetic modifications in tumor cells is another novel approach to treating TNBC. A recent study  on whole genome methylation analysis noted that TNBCs have a methylation pattern distinct from hormone receptor-positive breast cancer. In further support of this, the Cancer Genome Atlas Network's research using DNA methylation arrays in primary breast tumors showed that basal-like mRNA breast cancer subtype exhibited the lowest level of methylation . Preliminary evidence of BRCA1 inactivation by promoter methylation was reported supporting the hypothesis that epigenetic silencing may drive tumor progression towards BLBC . Panobinostat, an epigenetic modifier inhibiting histone deacetylase (HDAC), was shown to inhibit the growth of TNBC cell lines and decrease tumorigenesis in vivo . Thus, the use of methylation or acetylation inhibitors in TNBC may lead to reactivation of genes in the endocrine pathway resulting in subsequent sensitivity to hormonal therapies. This approach has been validated by the demonstration of the re-expression of estrogen receptor and progesterone receptor in TNBC after treatment with LBH589 (panobinostat) and decitabine, a hypomethylating agent . Entinostat, a novel class I specific HDAC inhibitor, which has already demonstrated benefit in postmenopausal hormone receptor-positive MBC progressing on an aromatase inhibitor, is also being evaluated in the treatment of TNBC (D.A. Yardley, R.R. Ismail-Khan, B. Melichar, et al., in preparation).
TNBC remains a heterogeneous disease currently defined by clinical assays demonstrating the lack of estrogen receptor, progesterone receptor and HER2 expression in the tumor. Molecularly, the majority of TNBC segregate out with the basal-like and Claudin-low molecular subtypes. TNBC is chemosensitive, and at present, treatment is limited to cytotoxic compounds with third-generation chemotherapy regimens being quite effective in early-stage disease. Regardless, the prognosis is poor and based on the usual variables of tumor size and grade, as well as the degree of nodal involvement. PARP inhibitors remain promising in targeting BRCA mutant tumors, although their role in TNBC remains unclear. Shared ‘BRCAness’ characteristics such as high tumor grade, mitotic indices and chromosomal instability in sporadic TNBC and BLBC may open the door to other potential targets. Although VEGF expression is the highest in TNBC, bevacizumab trials have demonstrated conflicting results. Addressing the heterogeneity of TNBC and targeting its molecularly defined distinct groups will be necessary to impact outcomes for this disease.
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 85–86).
1. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490:61–70.
2. Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res
3. Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res
4. Viale G, Rotmensz N, Maisonneuve P, et al. Invasive ductal carcinoma of the breast with the ‘triple-negative’ phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat
5. Gluz O, Liedtke C, Gottschalk N, et al. Triple-negative breast cancer-current status and future directions. Ann Oncol
6. Gelmon K, Dent R, Mackey JR, et al. Targeting triple-negative breast cancer: optimising therapeutic outcomes. Ann Oncol
7. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res
8. Vollebergh MA, Lips EH, Nederlof PM, et al. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol
9. Oonk AMM, van Rijn C, Smits MM, et al. Clinical correlates of ‘BRCAness’ in triple-negative breast cancer of patients receiving adjuvant chemotherapy. Ann Oncol
10▪▪. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest
The authors of this study identified six TNBC subtypes with unique gene expression profiles and ontologies. They used representative TNBC cell lines and demonstrated that the various subtypes exhibited differing sensitivities to agents currently under investigation.
11▪. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol
This study discusses the clinical characteristics of the various intrinsic subtypes of breast cancer including their developmental origin, with a special emphasis on the Claudin-low subtype.
12▪▪. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist
2011; 16 (Suppl 1):61–70.
This article describes the molecular classification of the TNBCs and the implications for treatment based on this classification.
13. Lachapelle J, Foulkes WD. Triple-negative and basal-like breast cancer: implications for oncologists. Curr Oncol
14. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med
15. Arnedos M, Bihan C, Delaloge S, Andre F. Triple-negative breast cancer: are we making headway at least? Ther Adv Med Oncol
16. Hugh J, Hanson J, Cheang MC, et al. Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol
17. Huober J, von Minckwitz G, Denkert C, et al. Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat
18. Martin M, Segui MA, Anton A, et al. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med
19. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res
20. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res
21. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol
22. Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med
23. Baselga J, Zambetti M, Llombart-Cussac A, et al. Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer. J Clin Oncol
24. Perez EA, Patel T, Moreno-Aspitia A. Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer. Breast Cancer Res Treat
25. Dumontet C, Jordan MA, Lee FFY. Ixabepilone: targeting βIII-tubulin expression in taxane-resistant malignancies. Mol Cancer Ther
26. Horak CE, Lee FY, Xu L, et al
. High beta-III tubulin expression in triple-negative (TN) breast cancer (BC) subtype and correlation to ixabepilone response: a retrospective analysis. ASCO Meeting Abstracts; 8 June 2009; 27(15S):3587.
27. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol
28. O'Shaughnessy J, Devchand P, Stokoe C. First efficacy results of a randomized, open-label, phase III study of adjuvant doxorubicin plus cyclophosphamide followed by docetaxel with or without capecitabine in high-risk early breast cancer. SABCS 2010; 2010:Abstract S4–S2.
29. Zelnak AB, Harichand-Herdt S, StybloTM, et al.
Final results from randomized phase II trial of preoperative docetaxel (D) and capecitabine (C) given sequentially or concurrently for HER2-negative breast cancers. J Clin Oncol 2011; 29(Suppl):abstr 1118.
30. Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol
31. Sirohi B, Arnedos M, Popat S, et al. Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol
32. Alba E, Chacon JI, Lluch A, et al.
Chemotherapy (CT) with or without carboplatin as neoadjuvant treatment in patients with basal-like breast cancer: GEICAM 2006-03-A multicenter, randomized phase II study. J Clin Oncol 2011; 29(Suppl):abstr 1015.
33. Isakoff SJ, Goss PE, Mayer EL, et al.
TBCRC009: a multicenter phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response. J Clin Oncol 2011; 29(Suppl):abstr 1025.
34. Byrski T, Dent R, Blecharz P, et al. Results of a phase II open-label, nonrandomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res
35. O'Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med
36▪▪. O'Shaughnessy J, Schwartzberg LS, Danso MA, et al.
A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol 2011; 29(Suppl):abstr 1007.
This study did not meet the prespecified criteria for the coprimary endpoints PFS and OS, prompting re-exploration of the role of iniparib and PARP inhibitors in the treatment of TNBC.
37. Llombart A, Lluch A, Villanueva C, et al.
SOLTI NeoPARP: a phase II, randomized study of two schedules of iniparib plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC). J Clin Oncol 2012; 30(Suppl):abstr 1011.
38▪▪. Patel AG, De Lorenzo SB, Flatten KS, et al. Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res
This study showed that iniparib failed to inhibit PARP in vitro and hence caution should be exercised while interpreting the clinical significance of its efficacy and mechanism of action.
39▪▪. Liu X, Shi Y, Maag DX, et al. Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a bona fide PARP inhibitor. Clin Cancer Res
The publication demonstrated that iniparib is not a true PARP inhibitor such as olaparib, indicating that the clinical results obtained with iniparib may not be extrapolated across all PARP inhibitors and vice versa.
40. Dent RA, Lindeman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the first- or second-line treatment of patients with metastatic triple-negative breast cancer: Results from the safety cohort of a phase I/II multicenter trial. J Clin Oncol
2010; 28 (Suppl 15):1018.
41. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, nonrandomised study. Lancet Oncol
42. Perez EA, Hillman DW, Mailliard JA, et al. Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol
43. von Hoff DD, Jameson GS, Borad MJ, et al.
First phase 1 trial of NKTR-102 (Peg-Irinotecan) reveals early evidence of broad antitumor activity in three different schedules. EORTC-NCI-AACR Symposium on ‘Molecular Targets and Cancer Therapeutics’ Meeting; 21–24 October 2008; Geneva, Switzerland. Poster no. 595.
44. Awada A, Chan S, Jerusalem GHM, et al.
Significant antitumor activity in a randomized phase 2 study comparing 2 schedules of Nktr-102 in patients (Pts) with metastatic breast cancer (MBC). Ann Oncol 2012; 23(Suppl 2):abstract 101P.
45. Cynthia RC, Osborne JOS, Holmes FA, et al.
Final analysis of phase II study of EZN-2208 (PEG-SN38) in metastatic breast cancer (MBC). J Clin Oncol 2012; 30(Suppl):abstr 1017.
46. Linderholm BK, Hellborg H, Johansson U, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol
47. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med
48. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol
49. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol
50. O'Shaughnessy J, Romieu G, Dieras V, et al.
Meta-analysis of patients with triple-negative breast cancer (TNBC) from three randomized trials of first-line bevacizumab (BV) and chemotherapy treatment for metastatic breast cancer (MBC). Cancer Res 2011; 70(Suppl 24):P6-12-03.
51. Brufsky A, Valero V, Tiangco B, et al. Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial. Breast Cancer Res Treat
52. Brufsky AM, Hurvitz SA, Perez EA, et al.
Final overall survival (OS) and safety analyses of RIBBON-2, a randomized phase III trial of bevacizumab (BEV) versus placebo (PL) combined with second-line chemotherapy (CT) for HER2-negative BEV-naive metastatic breast cancer (MBC). ASCO Meeting Abstracts; 18 September 2012; 30(Suppl 27):100.
53. Thomssen C, Pierga JY, Pritchard KI, et al. First-line bevacizumab-containing therapy for triple-negative breast cancer: analysis of 585 patients treated in the ATHENA study. Oncology
54. Schneeweiss A, Foerster F, Hollburg W, et al.
Bevacizumab (Bev) combined with paclitaxel (Pac) as first-line therapy for metastatic triple-negative breast cancer (TNBC): analysis of 147 patients (pts) treated in routine oncology practice in Germany. Eur J Cancer 2011; 47 (Suppl 1):S352.
55. Bear HD, Tang G, Rastogi P, et al.
The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. J Clin Oncol 2011; 29(Suppl 18):LBA1005.
56. Gerber B, Eidtmann H, Rezai M, et al. Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapry in 686 triple-negative primary breast cancers: secondary endpoint analysis of the GeparQuinto study (GBG 44). J Clin Oncol
2011; 29 (Suppl 15):1006.
57. Earl HM, Blenkinsop C, Grybowicz L, et al. ARTemis: randomized trial with neoadjuvant chemotherapy for patients with early breast cancer. J Clin Oncol
2012; 30 (Suppl 15):TS1144.
58. Tan AR, Buyse ME, Rastogi P, et al. NSAB FB-6: phase II trial of weekly paclitaxel (WP) and pazopanib following doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for HER2-negative locally advanced breast cancer (LABC). J Clin Oncol
2012; 30 (Suppl 15):1025.
59. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res
60. O'Shaughnessy J, Weckstein D, Vukelja SJ, et al. Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer. Breast Cancer Res Treat
2007; 106 (Suppl 1):S32Abstract 308.
61. Baselga J, Stemmer S, Pego A, et al.
Cetuximab + cisplatin in estrogen receptor-negative, progesterone receptor-negative, HER2-negative (triple-negative) metastatic breast cancer: results of the randomized phase II BALI-1 trial. Cancer Res 2011; 70(Suppl 24):PD01-01.
62▪. Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase ii study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol
This study included a serial biopsy substudy, which revealed that although most of the triple-negative tumors had EGFR pathway expression and activation, inhibition of the EGFR pathway with cetuximab was infrequent and may explain the negative results in the treatment of TNBC.
63. Nabholtz J-M, Weber B, Gligorov J, et al.
Panitumumab in combination with FEC 100 (5-fluorouracile, epirubicin, cyclophosphamide) followed by docetaxel (T) in patients with operable, triple negative breast cancer (TNBC): final results of a multicentre neoadjuvant pilot phase II study. Cancer Res 2012; 71(Suppl 24):P3-14-01.
64. Finn RS, Dering J, Ginther C, et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/’triple-negative’ breast cancer cell lines growing in vitro. Breast Cancer Res Treat
65. Rimawi M, Rodriguez A, Yang W, et al.
A phase II preoperative study of dasatinib, a multi-targeted tyrosine kinase inhibitor, in locally advanced ‘triple-negative’ breast cancer patients. Cancer Res 2012; 71(Suppl 24):P3-14-09.
66. Finn RS, Bengala C, Ibrahim N, et al. Dasatinib as a single agent in triple-negative breast cancer: results of an open-label phase 2 study. Clin Cancer Res
67. Gucalp A, Tolaney SM, Isakoff SJ, et al.
Targeting the androgen receptor (AR) in women with AR+ ER-/PR- metastatic breast cancer (MBC). ASCO Meeting Abstracts; 30 May 2012; 30(Suppl 15):1006.
68. Dedeurwaerder S, Fumagalli D, Fuks F. Unravelling the epigenomic dimension of breast cancers. Curr Opin Oncol
69. Grushko TA, Nwachukwu C, Charoenthammaraksa S, et al.
Evaluation of BRCA1 inactivation by promoter methylation as a marker of triple-negative and basal-like breast cancers. ASCO Meeting Abstracts; 14 June 2010; 28(Suppl 15):10510.
70. Tate CR, Rhodes LV, Segar HC, et al. Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat. Breast Cancer Res
71. Sharma D, Knight BB, Yacoub R, et al.
Using epigenetic reprogramming to target triple-negative breast cancer. ASCO Meeting Abstracts; 8 June 2009; 27(15S):e14565.