Breast cancer is a heterogeneous disease routinely classified by distinct clinical–pathological features on the basis of assays for the estrogen receptor and progesterone receptor as well as the human epidermal growth factor receptor 2 (HER2). The application of microarray-based gene expression analyses for further classification identified at least four intrinsic molecular breast cancer subtypes with prognostic value: luminal A and B, HER2 and basal-like  with the presence of a normal-like subtype still under debate. More recently, another poor prognostic subtype – Claudin-low – has been added to this list. It appears enriched for mesenchymal and stem cell features and often presents with an intense immune cell infiltrate . Defined by the lack of estrogen receptor, progesterone receptor and HER2 expression in the tumor, triple-negative breast cancer (TNBC) consists largely of the basal-like and Claudin-low molecular subtypes and has generated growing interest in recent years despite accounting for only 15–20% of breast cancers. Constituting a clinically important challenge, these aggressive tumors do not respond to endocrine therapy or HER2-targeted therapies with systemic treatment options limited to cytotoxic chemotherapy.
TNBC typically expresses epidermal growth factor receptor (EGFR), basal cytokeratins 5/6, 14, and 17, low cyclin D1, high Ki67 and cyclin E levels and more than 50% of the tumors harbour p53 mutations [3–5]. Also associated with TNBC is a variable incidence of BRCA mutations ranging from 16 to 42% [6,7]. In fact, an array comparative genomic hybridization (aCGH) profile present in BRCA1 mutation carriers is also frequently present in TNBC and results in features referred to as ‘BRCAness’ . TNBCs classified as BRCA1-like are postulated to harbor deficiencies in homologous recombination, which may guide therapeutic options . Gene expression arrays have now identified at least six molecular TNBC subtypes, including two basal-like subtypes 1 and 2, an immunomodulatory, a mesenchymal, a mesenchymal stem-like and a luminal androgen receptor (AR) subtype [10▪▪]. Although considered synonymous with basal-like breast cancer (BLBC) on the basis of the considerable overlap (70–90% concordance) identified by gene expression profiling, some BLBCs express HER2 and estrogen receptor [11▪,12▪▪,13] and should be regarded as distinct but having overlapping features with TNBC. For the purpose of this review, we will refer to the TNBC subtype unless otherwise specified. Further, the recently reported similarities between BLBC and serous ovarian cancers with respect to mutations in TP53 and RB1, BRCA 1 loss and MYC amplification that were identified by the Cancer Genome Atlas Network research indicate shared driving events for these two cancers, suggesting the possibility of a common therapeutic approach . Table 1 lists selected studies targeting both TNBC and ovarian cancer.
Epidemiologically, TNBC is more common in younger women (<50 years old) of African and Hispanic descent with an increased distant recurrence risk that peaks for years 1–3 and a greater propensity for visceral and central nervous system metastases . They demonstrate a marked decrease in survival 3–5 years after the initial diagnosis but have a lesser likelihood of distant relapse at 10 years than estrogen receptor-positive tumors .
The absence of easily identifiable, therapeutically targetable markers in TNBC poses significant treatment challenges. Although chemotherapy remains effective in TNBC, research continues to identify potential targets on the basis of the expression of different biomarkers as well as molecular markers such as EGFR, vascular endothelial growth factor (VEGF) receptor, DNA repair enzymes or members of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Similarities with BLBC and tumors arising in BRCA1 mutation carriers offer additional potential viable therapeutic targets. This review will summarize some of the recently highlighted advances in the treatment of TNBC including some clinical trials in progress.
Systemic chemotherapy remains the mainstay for treatment of TNBC with third-generation (taxane containing) adjuvant or neoadjuvant regimens effective in early-stage disease. The addition of taxanes to anthracycline-based regimens has improved rates of pathologic complete response (pCR) and increased disease-free survival (DFS) in this poor prognosis group [15–18]. Intrinsic molecular breast cancer profiling further refines identifying subtypes with a higher likelihood of achieving a pCR to anthracycline and taxane-based neoadjuvant therapy. The highest pCR rates of 45% were seen in basal-like and HER2-positive tumors as compared with only 6% in luminal tumors . Neoadjuvant pCR rates, as a surrogate for long-term survival, have been examined by Carey et al.. Despite high pCR rates noted in basal-like and HER2-positive tumors (27 and 36%, respectively) relative to luminal tumors (7%), the 4-year distant DFS irrespective of response was 84% for the luminal subgroups compared with 71% for the basal-like and 51% for the HER2-positive subgroup in the absence of trastuzumab . Likewise, minimal residual disease was also the highest among BLBC reflecting this subtype's chemosensitivity.
Liedtke et al. also noted higher pCR rates in TNBC relative to non-TNBC, and the findings of a pCR in TNBC correlated with a survival benefit. In contrast, TNBC patients with residual disease after neoadjuvant therapy had significantly worse survival when compared with patients with non-TNBC, especially in the first 3 years . Thus, this paradox of higher sensitivity to neoadjuvant chemotherapy but poorer overall outcomes in TNBC is largely explained by the high rate of relapse among TNBC with residual disease. With the U.S. Food and Drugs Administration (FDA's) newly released draft guidance on pCR as a surrogate endpoint, more promising drugs may move into early-stage disease, fulfilling an ‘unmet’ need for TNBC and other aggressive breast cancers, which typically only enrol in advanced stage trials .
Although a variety of combination regimens and single agents have been used in treating TNBC, none are recommended specifically for TNBC. On the basis of both preclinical and clinical data, the epothilone ixabepilone, a microtubule stabilizing agent, has been explored in TNBC. As a single agent, ixabepilone yielded a 22% pCR . In combination with capecitabine, benefit was seen for the doublet in TNBC in several phase II and III trials spurring early-stage disease evaluations . The PACS08 and the TITAN (A Randomized Trial of Ixempra vs. Taxol in Adjuvant Therapy of Triple-Negative Breast Cancer) trial focused on ixabepilone in early-stage breast cancer, with interest in exploring the role of beta tubulin III expression, a feature commonly seen in TNBC and associated with taxane resistance, with ixabepilone efficacy [25,26]. Despite the premature closure of these trials evaluating ixabepilone versus paclitaxel (TITAN) or docetaxel (PACS08) following anthracycline-based chemotherapy, future study updates are awaited.
The addition of capecitabine to standard adjuvant therapy in the FinXX trial showed improved relapse-free survival in the TNBC subgroup, but not in the overall population . A similar trend for capecitabine benefit with docetaxel following doxorubicin/cyclophosphamide (AC) chemotherapy was observed in the adjuvant USON 01062 study  for the TNBC subset; however, only modest activity was evident for this doublet in a separate smaller preoperative study .
DNA DAMAGING AGENTS
On the basis of the many shared histopathologic features between sporadic TNBC and the germ-line BRCA1 mutation carriers including DNA repair defects, it has been hypothesized that DNA alkylating agents may be particularly effective in the TNBC subset. In-vitro and preclinical studies have shown that tumors with aberrations in the BRCA1 gene are extremely sensitive to platinum-based therapies. The platinum-mediated DNA cross-links result in DNA double-strand breaks that are typically repaired by BRCA1/2-mediated homologous recombination, which is deficient in these tumors. Accordingly, TNBC exhibiting these features of ‘BRCAness’ has demonstrated high pCR rates to single-agent and platinum-based regimens [6,30,31]. The GEICAM 2006-03 study, however, reported no improvement in the pCR rates with the addition of carboplatin to anthracycline/taxane-based therapy in BLBC . In metastatic breast cancer (MBC), a durable overall response rate (ORR) of 30% with either cisplatin or carboplatin as first or second-line therapy was noted , and a study with cisplatin in BRCA-positive MBC patients reported a complete response in seven of the 14 TNBC patients . A larger randomized trial (TNT) of 400 metastatic TNBC (mTNBC) patients comparing carboplatin versus docetaxel is underway in the UK. Thus, ongoing studies will continue to help define the role and optimal tumor profile most likely to benefit from these various agents.
The DNA repair defects observed in TNBC may also render them more sensitive to pharmacological inhibition of polyadenosine diphosphate-ribose polymerases (PARPs). PARP is an important regulator of the DNA base excision pathway and PARP inhibition demonstrated activity and enhanced the cytotoxic effects of chemotherapy in preclinical studies. A recent phase II trial in mTNBC demonstrated that the addition of the PARP inhibitor iniparib to a doublet of gemcitabine/carboplatin resulted in a nearly 5-month increase in overall survival (OS) from 7.7 to 12.3 months (P = 0.014) . Disappointingly, the subsequent phase III trial exploring this same study design did not meet its prespecified coprimary endpoints of OS and progression-free survival (PFS). However, subset analyses demonstrated benefit in TNBC patients not receiving this triplet as first-line [36▪▪]. The neoadjuvant addition of iniparib to weekly paclitaxel in the SOLTI-neoPARP study was feasible; however, it did not translate to improved pCR rates . Subsequent in-vitro studies [38▪▪,39▪▪] have shown that iniparib acts by a mechanism unrelated to direct competitive inhibition of PARP, and hence, its role and further development in TNBC is unclear. Other studies exploring PARP inhibitors have focused on BRCA-related breast cancers. Olaparib, a potent oral PARP inhibitor, was evaluated in combination with weekly paclitaxel in BRCA mutant tumors in which impressive response rates were seen, but due to neutropenia, an acceptable dose intensity was not achieved . So far, the data for PARP inhibition appear more promising in BRCA-related TNBC than for sporadic TNBC as evidenced by the lack of objective responses with olaparib in 16 sporadic cases of advanced TNBC leading to closure of that study arm . Although no RECIST confirmed responses were seen, some tumor shrinkage and stable disease for greater than 8 weeks was seen in 63% of the BRCA1/2 carriers as compared with only 13% of sporadic tumors demonstrating any degree of tumor shrinkage. Other PARP inhibitors such as veliparib are also being evaluated in combination with various chemotherapy agents in TNBC as well as other solid tumors. An ongoing adjuvant trial is recruiting TNBC patients with BRCA1/2 mutations demonstrating residual disease following nonplatinum-based neoadjuvant chemotherapy and surgery to receive treatment with cisplatin with or without rucaparib (a PARP inhibitor). However, given the lack of a clear efficacy signal of the PARP agents in sporadic TNBC, the developmental strategy of these agents in TNBC remains unclear.
Irinotecan is an inhibitor of topoisomerase I, an enzyme essential for DNA replication. Its active metabolite SN38 binds the topo I–DNA complex, preventing resealing of the DNA during replication and transcription causing DNA breaks and leading to apoptosis. This drug was evaluated in anthracycline and/or taxane-pretreated MBC with an ORR of 23% . NKTR-102 (etirinotecan pegol) is a novel polymer conjugate that provides a slow release of irinotecan that is converted to SN38, the active metabolite. The half-life of NKTR-102 is around 50 days compared with 5 days for irinotecan, and this continuous dosing exposure throughout the dosing intervals may translate into improved antitumor effects. In support of this are mouse xenograft findings of increased concentration of SN38 in the tumors treated with NKTR-102 . In a study of anthracycline and taxane-pretreated mTNBC, a high ORR of 32% was reported for NKTR-102 . A clinical benefit rate (CBR) of 36.7% for TNBC was reported with EZN-2208 (a pegylated conjugate of SN38), including a 26.1% CBR in the subset of platinum progressors . Additional studies are underway evaluating the compound NK-012 (a micelle formulation of irinotecan) in mTNBC.
TNBCs are highly proliferative tumors that display enhanced angiogenesis supporting rapid growth and early metastases characteristic of this breast cancer subtype. The high levels of intratumoral VEGF noted in TNBC underlie the rationale for the use of antiangiogenic agents in these tumors . The addition of bevacizumab, a monoclonal antibody (mAb) targeted against VEGF, to chemotherapy in the first-line treatment of MBC was evaluated in three randomized phase III trials (ECOG 2100, AVADO and RIBBON-1) [47–49]. A meta-analysis of the TNBC subgroup treated with bevacizumab (N = 621) from these studies revealed a median PFS benefit of 2.7 months (P < 0.0001) versus chemotherapy alone . In the second-line setting, RIBBON-2 examined the addition of bevacizumab to physician's choice chemotherapy in 684 HER2-negative locally advanced or MBC patients. An exploratory subgroup analysis for TNBC demonstrated a median PFS of 6.0 months for bevacizumab in TNBC compared with 2.7 months for chemotherapy alone . This translated into a risk reduction of 51% with an ORR of 41% with a recently updated continued trend towards improved survival [median OS of 17.8 versus 13.5 months; hazard ratio 0.85; 95% confidence interval (95% CI) 0.58–1.26] .
Bevacizumab was also evaluated in the ATHENA study, a prospective registry of 2251 MBC patients treated with various first-line chemotherapy regimens in combination with bevacizumab. An exploratory subgroup analysis of 585 TNBC patients revealed a median time to progression (TTP) of 7.2 versus 10.6 months in the non-TNBC patients . At the time of data cut-off, the median OS was 18.3 months for TNBC and 27.3 months in the non-TNBC subset. Although there is no nonbevacizumab control arm in this study, these results highlight the poor prognosis and shorter DFS associated with TNBC. Consistent findings were evident from another study  in which 154 TNBC patients receiving first-line bevacizumab with paclitaxel demonstrated a median PFS of 8 months, an ORR of 51% and median OS of 16 months.
However, despite the statistically significant median PFS benefit demonstrated with the addition of bevacizumab to chemotherapy especially in the first-line MBC setting, the FDA has withdrawn the accelerated approval of bevacizumab for MBC citing the lack of OS improvement and the modest risk–benefit ratio. This lack of OS benefit in the first-line setting has been attributed to the unselected patient population enrolled on these trials potentially diminishing bevacizumab's benefit. Unfortunately, to date, no specific biomarker for bevacizumab efficacy has emerged. The MERiDiAN trial hopes to identify a prospective predictive biomarker by its focus on VEGF-A. This randomized trial evaluates paclitaxel with bevacizumab or placebo as first-line therapy for HER2-negative MBC. Patients will be stratified on the basis of their hormone receptor status as well as plasma VEGF-A levels, and outcomes between the two treatment arms in regard to plasma VEGF-A levels will be evaluated. Additional first-line bevacizumab combinations of either paclitaxel (BATMAN trial); paclitaxel/capecitabine (GINECO-TAXEL trial); or gemcitabine/carboplatin (ML25420 study) in TNBC are ongoing.
In the neoadjuvant setting, no differences were reported in the NSABP-B40 study evaluating the addition of bevacizumab and/or antimetabolites to docetaxel/AC-based neoadjuvant therapy in HER2-negative breast cancer. Although 41% of the tumors were TNBC, the addition of bevacizumab only showed benefit in the hormone receptor-positive subgroup . This contradicts the neoadjuvant Geparquinto study reporting that bevacizumab benefit was confined to the TNBC cohort (N = 684) with a pCR rate of 44.6 versus 36.5% in the absence of bevacizumab . It is unlikely that the ongoing randomized phase III neoadjuvant ARTemis trial will clarify the conflicting results seen to date with bevacizumab in early-stage breast cancer . Disappointingly, at the first interim analysis, the phase III BEATRICE study (NCT00528567) evaluating adjuvant bevacizumab in combination with standard chemotherapy in early-stage TNBC did not meet its primary endpoint of invasive DFS, a term selected to exclude in-situ breast cancer events, which were not considered an appropriate measure of the impact of the treatment under study (D.A. Yardley, personal communication).
Other antiangiogenesis inhibitors such as sorafenib and sunitinib have been evaluated in HER2-negative MBC. Subset analyses of these studies revealed a benefit for the TNBC patients prompting their further evaluation in the neoadjuvant setting. Pazopanib, another multikinase VEGF inhibitor, was evaluated in combination with weekly paclitaxel following AC as neoadjuvant therapy for HER2-negative breast cancer. Results from this single arm, phase II trial reported pCR rates of 42% in the TNBC cohort (27% of patients) versus 9% in the estrogen receptor-positive cohort .
EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS
EGFR is expressed in 27–57% of BLBC and TNBC on the basis of immunohistochemistry assays and has therefore been explored as a potential target for the disease . The data indicate that EGFR inhibitors such as cetuximab have low efficacy as single agents but led to modest improvements when combined with other cytotoxic agents . The phase II randomized BALI-1 trial in TNBC reported that the addition of cetuximab to cisplatin resulted in a significantly longer PFS of 3.7 versus 1.5 months with cisplatin only (hazard ratio 0.67; P = 0.032) . The TBCRC001 trial examined cetuximab alone and in combination with carboplatin for patients with mTNBC who had received up to three prior regimens. The cetuximab/carboplatin regimen was well tolerated, but TTP and OS were short at 2.1 and 10.4 months, respectively [62▪]. Correlative analysis performed with tissue collected from serial biopsies of patients on the study revealed that cetuximab inhibited the EGFR pathway only in a minority of the patients indicating the existence of alternative mechanisms for EGFR pathway activation.
Nabholtz et al. reported that neoadjuvant explorations in TNBC with panitumumab (another mAb against EGFR) in combination with 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel resulted in a pCR rate of 57%. Other ongoing studies with cetuximab in early and advanced disease settings and with panitumumab combined with gemcitabine/carboplatin in first and second-line TNBC may help further define the role of the EGFR inhibitors in TNBC.
OTHER TARGETED AGENTS AND NOVEL APPROACHES
Preclinical studies indicated that BLBC cell lines were sensitive to Src kinase inhibitor, dasatinib . However, dasatinib, when administered for 3–4 weeks as neoadjuvant therapy for TNBC, resulted in only a 9% clinical response rate following an interim analysis, and the trial was terminated due to futility . A study with single agent dasatinib also demonstrated limited activity in unselected patients with mTNBC .
Met and its ligand hepatocyte growth factor (HGF) are expressed to a higher degree in TNBC relative to other breast cancer subtypes, and mouse models have implicated a role for the Met pathway in the development of TNBC. MetMAb is a humanized monovalent mAb against Met that binds and blocks its extracellular domain from ligand binding and subsequent downstream signaling by HGF. It is under evaluation in combination with paclitaxel and bevacizumab in a randomized, blinded phase II study for mTNBC. ARQ 197, an oral c-Met inhibitor, is also being tested as a single agent in a phase II trial of mTNBC.
The PI3K/Akt/mTOR pathway is a key regulatory pathway for tumor growth and survival, and agents such as everolimus, temsirolimus and BEZ 235 are being evaluated in clinical trials for TNBC. Novel drugs targeting other biological pathways including tigatuzumab (mAb targeting TRAIL-R2/DR-5), P276 00 (HIF-1 inhibitor) and foretinib (dual c-Met/VEGF inhibitor) are being tested in ongoing studies. More recently, the expression of the AR in triple-negative tumors has prompted the evaluation of drugs such as bicalutamide (an antiandrogen) in clinical trials for AR-positive, estrogen receptor/progestrone receptor-negative breast cancer with encouraging preliminary results . With the recent approval of the AR inhibitor enzalutamide in prostate cancer, new studies evaluating this agent in breast cancer are being planned. Table 2 lists some ongoing studies with select targeted agents in TNBC.
Table 2-a List of se...Image Tools
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).
Table 2-b List of se...Image Tools
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.
Conflicts of interest
The authors have no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 85–86).
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