Triple Negative Breast Cancer Research Paper

Triple-Negative Breast Cancer: An Unmet Medical Need

  1. Clifford A. Hudisa and
  2. Luca Giannib,c
  1. aBreast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA;
  2. bMedical Oncology and Clinical Pharmacology Laboratory, Istituto Nazionale Tumori of Milan, Milan, Italy;
  3. cFondazione IRCCS, Medical Oncology A, Milan, Italy
  1. Correspondence: Clifford A. Hudis, M.D., Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, Professor of Medicine, Weill Cornell Medical College, New York, New York, USA. Telephone: 646-888-5449; e-mail: hudisc{at}
  • Disclosures: Clifford A. Hudis:Consultant/advisory role: Genentech; Research funding/contracted research: Onyx, Merck; Luca Gianni: None.

    The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.


Triple-negative breast cancer, characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple-negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a shorter median time to relapse and death. One important goal is therefore the identification of prognostic factors and markers to reliably select high and low risk subsets of patients with triple-negative disease for different treatment approaches of subtypes with differential responsiveness to specific agents. However, a reliable prognostic marker has been elusive, and markers have been inconsistently useful. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still a lack of agreement on a standard assay or cutoff for EGFR expression levels with respect to prognosis. Similarly, because triple-negative status is sometimes used as a surrogate for basal-like breast cancer, specific basal markers have been explored. Indeed, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity may provide only an approximation of the triple-negative population and are sometimes reanalyzed using more specific indicators like CK 5/6, EGFR status, and others, again marred by discordances. Chemotherapy remains the mainstay of treatment of triple-negative breast cancer, but important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. Current treatment strategies for triple-negative disease include anthracyclines, taxanes, ixabepilone, platinum agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple-negative breast cancer, again with mixed results. Agents that target poly(ADP-ribose) polymerase and androgen receptors have also been proposed in these patients or subsets of them, and ongoing trials should result in definitive guidance with respect to the value of these agents in triple-negative disease.

Triple-negative breast cancer is clearly a distinct clinical subtype, from the perspective of both ER and HER-2 expression, but further subclassification is needed. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple-negative breast cancer. This article will review the clinical problem of triple-negative disease, potential prognostic factors, demonstrated efficacy of currently available therapeutic options, and new potential therapies.

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Although a good deal is known about available and some experimental agents in triple-negative breast cancer, a number of important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. This discussion will focus on basal-like breast cancer and triple-negative breast cancer, understanding that there is a large degree of overlap between these two terms.

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Epidemiology and Risk Factors for Triple-Negative Breast Cancer

Higher rates of triple-negative breast cancer have been observed in women who are younger, which may be associated with a greater likelihood of BRCA1 expression. Women of African or Hispanic ancestry have been shown to have higher rates of triple-negative breast cancer, as have women in lower socioeconomic groups. It is therefore important to be somewhat skeptical of a few superficial phenotypic characteristics and genes being associated globally with a specific subtype of a malignancy like breast cancer, because some of the incidence may be related to the impact of lower socioeconomic status. A lower proportion of triple-negative breast cancers are discovered by mammography, which is possibly related to the age distribution of these patients [1–4].

From an epidemiologic perspective, the known risk factors for triple-negative disease are modest, suggesting few clear interventions. From a purely histologic point of view, triple-negative breast cancer consists of a collection of subtypes, with some tumors, such as the secretory or adenoid cystic tumors, being relatively less aggressive, even though they are triple-negative, and others being associated with a rapidly progressive course (Fig. 1).

Figure 1.

Triple-negative breast cancer: Range of histology.

The natural history of triple-negative breast cancer has been redefined over the last few years, and it is remarkable how many different clinical data sets provide similar curves. Luminal A metastatic hormone receptor positive breast cancer typically causes late bone metastases, whereas triple-negative breast cancer is more likely to cause early visceral metastases. Fundamentally, in the early-stage setting, triple-negative breast cancer is associated with earlier versus later events, as well as a shorter period from the time of recurrence until death (Fig. 2) [5].

Figure 2.

Triple-negative breast cancer: Recurrence and survival. From Kim K, Lee E, Lee J et al.; Korea Breast Cancer Society. Clinicopathologic signature of TNBC patients with good prognosis. Paper presented at: San Antonio Breast Cancer Symposium (SABCS) 2009; December 15, 2009; San Antonio, Texas; abstract 4065; doi: 10.1158/0008-5472.SABCS-09-4065, with permission.

The metastatic potential of all subtypes of breast cancers is ultimately similar, but the growth rates and tumor distributions vary so that the natural history and clinical course can appear divergent, especially over the short run. Once a metastatic triple-negative breast cancer is present, there is a much shorter median time from relapse to death [6]. This represents a key challenge, as clinicians try to palliate an incurable disease and extend life when possible. Although prognostic markers indicative of poor outcome have been identified, these factors come up in any series of metastatic breast cancers, and some of them are not particularly well categorized. For example, as already described, there is still no agreement on standard assay or expression levels for epidermal growth factor receptor (EGFR). Nevertheless, this is often listed as a poor prognostic factor in triple-negative disease.

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Limitations of Current Treatment Strategies for Triple-Negative Breast Cancer

Current treatment strategies include many chemotherapy agents, such as the anthracyclines, taxanes, ixabepilone, and platinum agents, as well as selected biologic agents and possibly anti-EGFR drugs.

Platinum therapy in particular requires close scrutiny, because preclinical evidence suggests that it may be especially useful in triple-negative breast cancer and BRCA mutation-associated malignancy in particular. However, assessing its effectiveness is challenging because focused trials have not been performed. Notably, triple-negative breast tumors can have higher response rates to a variety of chemotherapy agents despite being associated with poorer outcomes. This may limit the utility of response rates as indicators of superiority.

A related challenge, from a drug approval or regulatory perspective, is utility of the widely accepted surrogate endpoint of progression-free survival (PFS). It has been demonstrated that regimens based on anthracyclines or taxanes, such as the taxane-fluorouracil-doxorubicin-cyclophosphamide (T-FAC) regimen used at MD Anderson or doxorubicin-cyclophosphamide-taxane used in the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials, in relatively small series of patients treated in the preoperative setting, are effective with high in-breast response rates [7, 8]. In the triple-negative breast cancers, as opposed to especially the luminal As or Bs, there is a markedly higher response rate. However, despite this higher response rate, this subtype has a far shorter disease-free survival and overall survival (OS). If accrual to a trial is not limited to one subtype of breast cancer, clinicians should exercise caution when using in-breast response as a surrogate for outcomes. There is no doubt that, in a defined subset, an in-breast response yields a better disease-free and overall survival, but if the patient population is not selected appropriately, one may observe a paradox of high in-breast activity and worse overall outcomes, compared to other groups.

For example, a larger T-FAC series compared outcomes in patients with triple-negative and non–triple-negative breast cancer. This study demonstrated a paradoxical doubling of the pathological complete response (CR) rate but a shortening of both PFS and OS [9].

A meta-analysis by Di Leo et al., as well as smaller phase II and phase III trials with anthracyclines, have shown variable results for individual agents and regimens in this subtype of breast cancer (Table 1) [10–12]. From these studies, we can say that these drugs have activity in triple-negative breast cancer but their relative merit, compared to other available agents, cannot be established.

Continuing to focus on the taxanes, Hayes and colleagues retrospectively studied a subset of patients enrolled in the Cancer and Leukemia Group B (CALGB) 9344 study for whom paraffin samples were available. Patients were classified into one of four groups, as shown in Figure 3. Critically, the largest group is the HER-2-negative, estrogen receptor (ER)-positive cohort, and despite the overall positive findings in the 9344 trial with the addition of the paclitaxel, that subgroup does not appear to get a large benefit. However, clinicians should note that these results have not been uniformly consistent across other trials, such as those from the GEICAM (Grupo Español de Investigación del Cáncer de Mama) investigators. Turning specifically to triple-negative disease, as shown in Figure 3, there is a large benefit for paclitaxel. These data and others are consistent with the hypothesis that the taxanes are effective in triple-negative breast cancer. Paclitaxel was also useful in HER-2 positive breast cancer, regardless of receptor status, in the pre-trastuzumab era (Fig. 3) [13].

Figure 3.

C9344 disease-free survival for paclitaxel by ER and HER-2 status. From Hayes DF, Thor AD, Dressler LG et al. HER-2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 2007;357:1496–1506, with permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved.

Other studies have investigated the use of adjuvant anthracycline plus taxane in triple-negative breast cancer (Fig. 4A). The Breast Cancer International Research Group (BCIRG) 001 trial compared docetaxel-doxorubicin-cyclophosphamide versus fluorouracil-doxorubicin-taxane (FAC). The addition of the taxane yielded an advantage in the triple-negative cohort, as was true for the overall trial [14]. In a slightly more difficult-to-interpret trial that investigated additional cycles of paclitaxel instead of cyclophosphamide, the addition of more, versus less, paclitaxel was associated with a benefit in the triple-negative cohort (Fig. 4B) [15]. These three data sets all consistently suggest that, in triple-negative disease, there is a benefit for taxanes.

Figure 4.

Adjuvant anthracycline plus taxane for triple-negative breast cancer. (A) From 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 2009;27:1168–1176. Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved. (B) From Loesch DM, Greco F, O'Shaughnessy J et al. A randomized, multicenter phase III trial comparing doxorubicin + cyclophosphamide followed by paclitaxel or doxorubicin + paclitaxel followed by weekly paclitaxel as adjuvant therapy for high-risk breast cancer. J Clin Oncol 2007;25(suppl 18);abstract 517. Reprinted with permission. © 2007 American Society of Clinical Oncology. All rights reserved.

A newer agent, ixabepilone, has been evaluated in subsets of patients with triple-negative metastatic breast cancer, in phase II and phase III studies [16, 17]. Like the other agents discussed, there is evidence of activity, but it is difficult to assess the relative value of this drug compared with the others in this cohort beyond stating simply that it is active (Table 2).

Table 1.

Anthracyclines for triple-negative breast cancer

Table 2.

Ixabepilone for triple-negative breast cancer

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Platinum Salts in Triple-Negative Breast Cancer

A key issue is the role of platinum salts because of their specific mechanism of action, in that they cause DNA cross-link strand breaks. In cells that lack homologous repair, such as BRCA mutants, and possibly in BRCA-deficient cells, this could be a particularly effective treatment approach. However, determining whether they actually have clinically distinct activity in triple-negative disease has been challenging.

Although platinum salts have been investigated for a century and a half, clinical trials with platinum salts in cancer did not begin until the early 1970s. The FDA approval was specifically in ovarian and testicular cancer in 1978. Then in 1989, replacing cisplatin in many centers, carboplatin became available. Although it too forms DNA cross-breaks, it appears to be cross-resistant in some cases. A number of platinum agents were subsequently developed in an attempt to provide a greater therapeutic index, but randomized data to address the role of platinums have been limited. A rigorous meta-analysis of chemotherapy agents performed in 1998 by Fossati and colleagues included one randomized trial with a platinum agent [18].

The available data with platinum agents is further confounded by the inclusion of asymmetric comparator arms. For instance, one study compared cisplatin plus doxorubicin versus a non–doxorubicin-containing regimen, which also omitted the platinum. In this trial, the combination of these two active drugs—platinum and doxorubicin—was actually associated with a reduction in benefit. Another small, randomized trial compared epirubicin alone versus epirubicin plus cisplatin in metastatic disease and showed at least a borderline advantage for the addition of platinum in a completely unselected cohort of 139 randomized patients [19]. More recently, there have been a series of phase II studies, some of them modest in size and others reported retrospectively in the preoperative or metastatic setting, using both carboplatin and cisplatin, and also confounded by the addition of other agents. These data continue to show pathologic complete response rates in the range seen in other clinical trials with non–platin-containing regimens (Table 3) [20–25].

One phase II study (NCT00148694) in particular received attention, because it was prospectively conducted and enrolled a specifically defined cohort of triple-negative patients. In the neoadjuvant setting at Dana Farber Cancer Institute, 14 of 28 patients who were given single-agent cisplatin responded including six CRs. However, there was a relatively high incidence of BRCA mutation carriers in this patient population. When two patients who were known to be BRCA mutation carriers were excluded from the analysis, leaving behind the patients who were known not to have those mutations, the CR rate was 4 patients of 26. That is a 15% CR rate to a single agent in a prospectively conducted study at a large cancer center, which may be viewed as impressive results [22].

However, in comparison, a non–platinum-containing regimen reported in 2002, looking at neoadjuvant cyclophosphamide-vincristine-doxorubicin-prednisolone (CVAP) followed after four cycles by randomization in the responders to docetaxel or more of the CVAP, showed a 15% increment in the CR rate with the taxane [26]. This suggests that CRs in triple-negative breast cancer, apart from the BRCA mutation subset, may not be particularly greater with platinums than they are with other regimens.

Similar results have been seen in trials conducted at MD Anderson, where the CR rate was 27% for the paclitaxel-FAC regimen [23]. Importantly, these data included the diluting effects of a large number of patients who had ER positive disease. Consequently, there is no clear answer in the unselected triple-negative population as to whether or not the platinums represent a special agent. This is a question that still remains under careful study, as will be discussed.

Table 3.

Platinum agents for triple-negative breast cancer

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The clinical impact of bevacizumab is complicated for all breast cancers and no clearer for triple-negative disease. Across all of the reported prospective clinical trials of bevacizumab, there is no clear signal that this anti-angiogenic agent has any special properties in the triple-negative cohort compared with the broader population (Table 4) [27, 28].

Table 4.

Bevacizumab for triple-negative breast cancer

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EGFR Inhibitors

The potential of EGFR inhibition in breast cancer has been another interesting story. Modi et al. investigated a regimen of cetuximab plus paclitaxel, and then cetuximab plus doxorubicin, in breast cancer. The cetuximab caused an unacceptable acneiform rash for women with breast cancer and did not appear to have particular activity [29]. In a prospective phase II study by the Translational Breast Cancer Research Consortium (TBCRC), single-agent cetuximab was evaluated alone or in combination with carboplatin. The single-agent cetuximab was deemed not worthy of further study in this trial, and the combination was deemed possibly worthy of further study. However, this was simply a comparison of a regimen with or without a platinum agent, and whether or not the anti-EGFR antibody was contributing at all is difficult to determine [30]. In contrast, another phase II trial was conducted of irinotecan plus carboplatin, alone or in combination with cetuximab. In the triple-negative cohort, an increase in activity was observed with irinotecan (Table 5) [31]. Additional trials are ongoing. Very recently, another randomized phase II study showed modest activity [32].

Table 5.

Epidermal growth factor receptor inhibition for triple-negative breast cancer: Efficacy data from phase II trials

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Other Potential Therapeutic Targets in Triple-Negative Breast Cancer

A variety of other potential targets have been incompletely validated in triple-negative breast cancer [33]. Particular attention should be paid to a number of the vascular endothelial growth factor receptor inhibitors [34], dasatinib (a Src kinase inhibitor) [35], and checkpoint kinase 1 inhibitors currently under development, among many others (Table 6).

Table 6.

Other targets for triple-negative breast cancer

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Poly(ADP-ribose) Polymerase Inhibitors

Although the poly(ADP-ribose) polymerase (PARP) inhibitor story will be thoroughly addressed in other sections of this supplement, it is important to highlight the rapidity of translation from preclinical experiments [36, 37] into a meaningful clinical advance. On the basis of initial findings, preclinical investigators proposed that a PARP inhibitor would be especially useful as a single agent, or in combination regimens in patients with BRCA mutations.

A phase II study was conducted with olaparib, an oral PARP inhibitor, in BRCA-deficient metastatic breast cancer [38]. The patient cohort included those with metastatic disease at multiple sites, extensively pretreated for a median of three prior systemic chemotherapy regimens, having BRCA1 or BRCA2 mutations or an overwhelming family history consistent and suggestive of that mutation. Patients were treated with olaparib 100 mg twice daily (bid) or 400 mg bid, on the basis of preclinical data suggesting that the lower dose would be sufficient to achieve a therapeutic serum level for inhibition of the target.

This may be a bit of a peril as investigators move away from dosing in drug development trials based on maximum tolerated dose and toward known target inhibition. In 27 patients, the 100-mg bid dose (which was believed to be effective at target inhibition) achieved a 22% response rate, an impressive result in the setting of salvage therapy for these patients. However, the higher dose of 400 mg bid resulted in an apparent almost doubling of response rate to 41%. This high response rate with a single-agent, relatively nontoxic oral therapy in an extensively pretreated patient population was remarkable. Both complete and partial response rates were significant, and the time to progression was ∼2 months longer in this nonrandomized intrastudy comparison. These findings led to investigators dropping the 100-mg dose arm and allowing some of the patients to cross over to the higher dose. The toxicity associated with this single agent was modest, with grade 3 or 4 toxicity rates reported in single-digit percentages [38].

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Androgen Receptor Targeted Therapy

Recent research focusing on the androgen receptor (AR) is an example of taking an old story and making it new. One investigation processed 99 specimens through tissue microarray (TMA), with cluster analysis. In Figure 5, ER positive cancers are shown in blue and ER negative cancers are shown in red. In a small sliver of the specimens shown on the left, a number of the ER negatives, by cluster analysis, were grouped with the ER positives. While determining the reasons for these results using principal component analysis, the investigators found that there was a series of additional genes that were upregulated here that were similar to what is seen in ER positive breast cancer. Investigators then painstakingly went back through these specimens and identified by mRNA and repeat immunohistochemistry that they lacked ER [39].

Figure 5.

Unsupervised cluster analysis of 99 primary breast carcinomas. Reprinted by permission from Macmillan Publishers Ltd: Oncogene. Doane AS, Danso M, Lal P et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 2006;25:3994–4008, copyright 2006.

In further analyses of these ER negative tumors, investigators noted that what actually defined them is that, despite the lack of ER and progesterone receptor (PR) negativity, this downstream expression analysis suggested that they were, in fact, similar to ER positives. However, these patients exhibited AR expression as opposed to ER. [39]. The role of AR has therefore been rediscovered, in this regard. Although it has been known for some time that AR is widely expressed in breast cancer, it has not been a focus of interest in triple-negative breast cancer until recently.

Although the incidence of AR positivity is lower in triple-negative disease than in ER positives, it is perhaps more important, because there are few proven, effective, nontoxic therapies as discussed above for these patients. To transition these initial findings into a clinically meaningful result, a phase II trial (NCT00468715) is now underway in the Translational Breast Cancer Consortium with bicalutamide, an AR antagonist and widely available prostate cancer drug, in triple-negative breast cancer. The trial aims to accrue 28 patients who are triple-negative but AR positive. A challenge has been the rarity of AR positivity in the clinic, estimated to be 20% in triple-negative disease in the TMA previously discussed [39]. In anecdotal clinical practice, the rate has been closer to 10% among triple-negative patients.

The challenge in using AR targeted drugs is that, if triple-negative breast cancer represents 20% of the disease, and if 10% of that is AR positive, then this represents only 2% of overall breast cancer cases. If the AR was a new target, and a new drug was under development, substantial business and regulatory challenges would exist in demonstrating efficacy and moving forward.

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Addressing Current Unmet Needs in Clinical Practice

Clinicians have been challenged with a lack of guidelines that specifically address the management of patients with triple-negative disease. Although the St. Gallen guidelines briefly mention triple-negative disease, the National Comprehensive Cancer Network (NCCN) is nonspecific in terms of drugs and agents but includes triple-negative disease in its overall guidelines. Guidelines from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) are also nondirective on the subject of managing triple-negative breast cancer.

There are, therefore, a variety of ongoing prospective trials to explore a range of therapeutic options for these patients, and more than 61 trials are currently listed at To highlight a few current clinical trials, the BEATRICE study is testing the activity of bevacizumab, and there are trials in the metastatic setting looking at various chemotherapy combinations, as well as neoadjuvant studies, including one in the CALGB that is prospectively evaluating the roles of carboplatin and bevacizumab as well, with correlative signs (Table 7).

Table 7.

Questions being asked in ongoing trials

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Triple-negative breast cancer is clearly a distinct subtype, from the perspective of both ER and HER-2, and there may yet be further distinct subclassifications. This disease presentation clearly represents an important clinical challenge. Triple-negative breast cancer is also a surrogate of basal-like breast cancer. Therefore, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity provide an approximation of the triple-negative population, but, as described in the introduction, there is some discordance, including some HER-2 positives and some ER positives among the basals. At present, there is not a clear, proven effective single agent that targets a driving vulnerability in triple-negative breast cancer. However, there are a number of potential therapies currently under investigation that may eventually improve outcomes in these patients.

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Triple negative breast cancer (TNBC) is a subtype of breast cancer (BC) with a heterogeneous nature that stains negatively for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) during immunohistochemistry. Approximately 15–20% of all cases of breast cancer are triple negative phenotypes. Compared to patients with hormone receptor-positive cancer, TNBC patients are typically younger (<50 years), African American, and have a high incidence of mutations in BRCA1/2 genes. To date, not a single targeted therapy has been approved for TNBC treatment, and cytotoxic chemotherapy remains as the standard systemic treatment, meaning that TNBC is an aggressive subtype of breast cancer with a poor prognosis. In this review, the literature search was done up to date on which gene expression profile of TNBC has been analyzed in order to identify the consensus on molecular mechanisms involved in carcinogenesis and/or the prognostic markers of the disease. In conclusion, these studies have reported that TNBC is composed of several clusters or genomic signatures as basal keratins. They have also reported on their proliferation, luminal/basal apocrine, regulatory interferon, immune cells/immunoglobulin related to stem cells, epithelial-mesenchymal, androgen receptor and angiogenesis. However, not all research groups have reported reproducible results. This confirms the heterogeneous nature of TNBC and the need for research on uniform selection criteria. However, these discoveries have led to the proposal of new treatments, such as the addition of platinum salts, new combinations of therapeutic agents, some targeted therapies such as PARP inhibitors, and PI3K and androgen antagonists. There is no doubt that a better understanding of the nature of TNBC will allow individualized and more effective therapies.

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