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.
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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
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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.
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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.
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38▪▪. Patel AG, De Lorenzo SB, Flatten KS, et al. Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res
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