Triple-negative breast cancer central nervous system metastases from the laboratory to the clinic

Abstract

Triple-negative breast cancer accounts for 15-20% of breast cancers and has an incidence as high as 50% of brain metastases once patients develop advanced disease. The lack of targeted and effective therapies, characteristic of this subtype of breast cancer, is especially evident once CNS metastases occur. Compared to other subtypes of breast cancer, TNBC patients have the shorter interval from diagnosis to development of brain metastases and the shorter overall survival once they occur, a median of 4-6months. Preclinical studies of TNBC and CNS microenvironment are actively ongoing, clarifying mechanisms and orienting more effective approaches to therapy. While the first drugs have been specifically approved for use in metastatic TNBC, data on their CNS effect is still awaited.

Introduction

Breast cancer is the most prevalent cancer among women and the second most common cause of brain metastases ¹. Up to 30% of breast cancer patients develop brain metastases and the risk is subtype specific, being higher in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC) ^2,3. TNBC subtype is defined as hormone-receptor and HER2-negative, and accounts for 15-20% of breast cancers overall. In the genomic or molecular classification analysis, TNBC overlaps ~80% with the basal-like subtype ⁴. Once metastatic, half of the patients in this subgroup will develop brain metastases ⁵. Moreover, the overall incidence of breast cancer brain metastases is reportedly increasing, likely due to multiple factors such as better imaging techniques, increased screening and enhanced long term survival with improved cancer therapy ^6,7. While in the HER2-positive subtype several options of targeted therapy provide a good systemic control and progressive improvement in overall survival (OS) despite brain metastases, in the TNBC subtype, the aggressiveness and difficult systemic control of the metastatic disease are possibly related to the high incidence of central nervous system (CNS) involvement. Consequently, understanding the pathology and improving treatment of brain metastases in TNBC is of utmost importance.

Epidemiology and natural history

TNBC has appeared in medical literature as a new entity since around 2005, characterized by its overall aggressiveness and lack of available targeted therapy, and accounting for 12-17% of breast cancer cases ⁸. Soon, cohort evaluations and comparative studies identified a different profile in terms first recurrence sites and metastatic disease for TNBC, with 40% of cases involving lungs and 30% involving CNS ^9-11. A single center analysis of 116 patients with metastatic TNBC, treated between 2000 and 2006, showed that up to 46% developed CNS metastases at some point before death, with 14% (16/116) presenting CNS metastases as first site of metastatic disease ⁵. Evaluating a larger group of patients, an analysis of the Surveillance, Epidemiology, and End Results (SEER) 18 registry selected 206,913 breast cancer patients from 2010 to 2014, with 11.8% characterized as TNBC, and confirmed an incidence of 30.8% brain metastases in TNBC patients with advanced disease, associated to a poorer median overall survival of 6 months (p<0.001) when compared to other subtypes ¹². A possible correlation with stage at diagnosis and brain metastases as first site of metastatic disease was demonstrated in a retrospective analysis of 2448 TNBC patients diagnosed with early stage breast cancer and followed between 1990 and 2010 ¹³. Patients with stage III disease had a significant increase in the risk of developing brain metastases as a first site of recurrence (hazards ratio = 3.51; 95% CI = 1.85 – 6.67; p =.0001) compared to patients with stage I disease, in a multivariate analysis.

When compared to other subtypes in various retrospective analysis, TNBC seems to have typically a shorter interval between initial breast cancer diagnosis and development of brain metastases than other subtypes of breast cancer ^14-17. The shorter timeline is also corroborated by the smaller number of lines of therapy TNBC patients received before their first diagnosis of brain metastases in comparison to other subtypes ¹⁸.

Multiple retrospective analysis have repeatedly reported the median OS after diagnosis of TNBC brain metastases to be dismal, mostly around 4-6 months ^5,17,19-21, with two publications showing extremes of 2.9 in one²² and 8.4 months in other ²³. The final cause of death was directly related to brain metastases in more than half of those patients ^16-19,22,24. Importantly, in all breast cancer subtypes, the OS after brain metastases diagnosis was better in patients that received systemic therapy as opposed to those who did not, even if slightly so in TNBC ^19,23.

Particular issues with CNS metastases

Historically, the general effect of systemic therapy has been unimpressive in breast cancer brain metastases (BCBM). More often than not, intracranial metastases present in setting of active extracranial disease and responses to systemic treatment are frequently different in those sites. Understanding the unique aspects of CNS metastases has been target of active research and has corroborated clear obstacles to an effective therapy.

One of the anticipated issues reside in the known protective effect and very particular structure of blood-brain barrier (BBB). Yet, once a brain metastases forms, the BBB is modified and becomes what is called the blood-tumor barrier (BBT) ²⁵. The BBT presents some, but still very heterogeneous permeability to drugs. This was well demonstrated by preclinical evaluation of marked paclitaxel and doxorubicin uptake in breast cancer mice models, and then confirmed clinically by the heterogeneous uptake of capecitabine and lapatinib administered to patients before the surgical resection of their BCBM ^26,27.

Brain metastases cells have to change and adapt to the CNS microenvironment to establish and grow. An analysis of gene expression in mice models of brain metastases showed that the brain microenvironment induces complete reprogramming of metastasized cancer cells and leads to gain of neuronal cell characteristics ²⁸. In the same lines, analysis of resected TNBC and HER2-positive BCBM from patients found that breast-to-brain metastatic tissue and cells presented an acquired GABAergic phenotype similar to the neuronal cells ²⁹. In fact, whole exome analysis of different primary tumor types and their matched brain metastases, which included BCBM, revealed the clear presence of a genomic evolution pattern in the brain metastases ³⁰. Importantly, clinically actionable mutations were found in those brain metastases that would not otherwise been demonstrated by sole analysis of extracranial metastases.

Furthermore, an issue very specific to BCBM is the subtype discordance or switching between primary tumor and the brain metastases. Most BCBM are not biopsied or resected given the specific risk-benefit of a CNS surgical intervention. Consequently, comparative studies are limited mostly by sample size. In spite of that, several groups have now repeatedly confirmed the existence of discordance of subtypes ^31-34.The largest analysis involved 219 patients and showed an overall 36.3% incidence of discordance for estrogen receptor (ER), progesterone receptor (PR) or HER2, leading to a change of subtype in 22.8% of cases as a result of receptor alteration. Gain in HER2 expression in the brain metastases was more common than loss (8.0% vs 2.5%, respectively), while loss of ER or PR was more common in the brain metastases than gain (14.8% vs 1.9% and 22.4% vs 2.9%, respectively). Generally, cases with discordance between the primary tumor and brain metastases also had discordances between intra- and extracranial metastases ³⁴.

All these findings indicate the need for organ-specific therapy, considering the tumor specific CNS metastases characteristics, and the need for validation of non-invasive methods to improve precision diagnosis with minimal risk.

Preclinical data

Genomics

In TNBC, tumor biology and brain metastases connection still needs elucidation. A couple of different analysis of paired primary breast cancer samples with respective metastases, showed that the overall gene expression phenotype was mostly maintained in the metastases, even in brain lesions ^35,36. Nevertheless, clear presence of genetic branching evolution has also been demonstrated in whole-exome sequencing analysis of paired tumors and brain metastases, including breast cancer cases ³⁰. While brain metastases shared common genetic ancestry aspects with the primary tumor, they also presented new potentially oncogenic alterations that could contribute to a divergence in response to therapy frequently seen in brain metastases versus other areas of disease. Moreover, genetic selection pressure applied by the effect of previous lines of treatment has to be also taken into account when comparing different studies.

In a deep genomic profiling integrating gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases, basal-like tumors were one of the most commonly represented subtypes in brain metastases cohorts ³⁷. Independent of subtypes, brain metastases were associated with frequent large chromosomal gains (1q, 5p, 8q, 11q, and 20q), deletions (8p, 17p, 21p and Xq), amplifications and overexpressed genes (ATAD2, BRAF, DERL1, DNMTRB and NEK2A), and enrichment in cell cycle and G2/M transition pathways (AURKA, AURKB and FOXM1) was also demonstrated ³⁷. However, while overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation, which tends to lead to defects in cell migration and adhesion and contributes to a more metastatic pattern.

Looking for a specific genetic profile linked to brain metastases predisposition inside TNBC, a retrospective analysis investigated expression of 29,369 gene transcripts in primary TNBC tumor samples from 119 patients, including patients with symptomatic brain metastases ³⁸. No gene expression was found to be associated with the occurrence of symptomatic brain metastases, but there were many valid criticisms to the study, including the lack of brain metastases samples limiting subtypes classification and genetic analysis only of primary breast tumor, the possible “contamination” of the non-brain metastases pool by asymptomatic brain metastases patients and limitation of utilized technique.

In a different approach, transcription factors highly and specifically expressed in primary TNBCs were selected and analyzed ³⁹. Among those, engrailed 1 (EN1) was of specific interest because of its known roles in brain and dermomyotome development ^40,41. Preclinical evaluation showed that genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance were direct EN1 transcriptional targets. Additionally, expression analysis was performed on METABRIC dataset where high expression of EN1 correlated with increased risk of developing brain metastases in TNBC patients, as well, as with shorter overall survival ³⁹.

Preclinical models

Preclinical models are essential to elucidate the complexity of CNS metastases and perform initial tests of new therapies. Different models to study brain metastases in laboratory include cell lines and mice models. Several TNBC cell lines and models are available. The models, methods of development and analysis are extensively reviewed in references ⁴² and ⁴³.

Microenvironment and molecular pathways

Tumor microenvironment has an important role in metastases establishment and growth. Evaluation of the microenvironment in TNBC brain metastases are mostly limited to preclinical models with the function of generating hypothesis that need validation in the clinical setting.

Brain-derived neurotrophic factor (BDNF), for example, is widely expressed in the brain and has the function to stimulate neurons growth and synapses ^44,45. In TNBC brain metastases models, BDNF was demonstrated to perform autocrinal regulation of BDNF-tumor cell tropomyosin kinase receptor B (TrkB) gene expression with consequent increase in cell migratory activity, which is important for metastases development. Extending the analysis to protein expression levels in tumor tissue arrays, a correlation was found with patient prognosis and TrkB expression, but not of BDNF ⁴⁶. Furthermore, a more detailed evaluation identified estradiol (E2) as causing upregulation of BDNF in estrogen receptor positive astrocytes ⁴⁷, which activated TrkB signaling and increased invasiveness and tumor initiating capacity of TNBC cells in vitro ⁴⁸. These findings provide and interesting basis for the clinical evaluation of estrogen depletion therapy and/or TrkB inhibitors in the prevention of brain metastases.

The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathway also seems to be activated in TNBC and brain metastases, promoting tumor colonization, survival, and growth ^49,50. Utilizing clinically available brain-penetrant inhibitors in intracranial TNBC tumors mice models, treatment with MEK, PI3K, or platelet derived growth factor receptor (PDGFR) inhibitors was evaluated. Combination treatments with selumetinib (MEK inhibitor) and buparlisib (PIK3 inhibitor) or selumetinib and pazopanib (PDGFR inhibitor) were synergistic in vitro but improved survival only in in two of the four TNBC intracranial metastases models ⁵¹. Though these represent rational combinations for treatment of TNBC brain metastases, its clinical development needs to be carefully considered in view of the significant toxicity observed both in this preclinical setting and also known from experiences in the context of other tumors clinical treatment.

Current management

Local therapy

The current treatment of brain metastases is multidisciplinary, although mainly based on combination of local therapeutics including surgical resection, stereotactic radiosurgery (SRS) and/or whole brain radiation (WBRT) ⁵². Notably, the fundamental trials establishing local therapy for brain metastases evaluated cohorts mainly composed of patients with non-small cell lung cancer and with smaller proportions of breast cancer patients. Overall, the addition of WBRT to surgery or SRS improves local progression free survival but does not affect OS ^53-55. However, worsening quality of life and neurocognitive decline have been demonstrated with WBRT ^56-58. Therefore, SRS is the preferred treatment for limited number of brain metastases ⁵⁹, while WBRT tends to be mainly indicated for treatment of diffuse brain metastases. In cases with solitary brain lesion and controlled systemic disease, the combination of surgical resection and postoperative SRS has reportedly improved survival and should be the preferred approach ^60,61.

Systemic therapy

Systemic therapy has been generally less effective in treatment of BCBM than of non-CNS metastatic disease, as documented by several clinical trials ^62-66. Nevertheless, retrospective analysis repeatedly demonstrate improvement of overall survival when systemic therapy is offered to brain metastases patients as opposed to no systemic therapy at all ²¹. Contrasting with the HER2-positive subtype, in which anti-HER2 agents have generated some intra-cranial response ^67-70, TNBC treatment has been mostly based on the systemic chemotherapy agents reaching very limited effect in CNS.

In recent years, at least three classes of drugs or regimens have shown more targeted benefits in the treatment of subgroups of metastatic TNBC: immune checkpoint inhibitors (ICI), poly (ADP-ribose) polymerase (PARP) inhibitors, and an antibody drug conjugate (ADC) targeting Trop-2 ^71-74.

PARP inhibitors

BRCA1/2 mutation carriers have an elevated risk of developing breast cancer. Overall, up to 20% of TNBC have a germline BRCA mutation, and BRCA1 carriers most likely will develop TNBC ^75,76. Analysis of different cohorts of breast cancer patients with germline BRCA mutation have demonstrated high incidences of brain metastases (44%-53%) in the BRCA1 carriers, most of them with TNBC (84%-73%) ^77,78; and the risk of brain metastases seems to be more strongly associated with tumor subtype than with the mutation ⁷⁷.

PARP inhibitors (PARPi) are a class of drugs that inhibit double-stranded DNA repair. This repair mechanism is already deficient in BRCA mutated cells, which makes PARPi an effective therapy in breast cancer patients affected by BRCA mutation ⁷⁹. Two PARPi are currently approved for treatment of metastatic BRCA1/2 mutated breast cancer based on PFS improvement when compared to chemotherapy, olaparib (7.0 versus 4.2 months; 0.58, 95% CI 0.43-0.80; p<0.001), and talazoparib (8.6 versus 5.6 months; HR 0.54, 95% CI 0.41-0.71; p<0.001) ^72,80-82. In the phase III trial evaluating talazoparib, patients with treated and stable CNS disease were enrolled ⁸⁰, but no patient with active CNS disease or evaluation of CNS endpoints was performed in both trials. Nevertheless, the PARPi veliparib presented CNS penetrance and survival benefit when combined to carboplatin for treatment of BRCA mutated TNBC in preclinical models of intracranial metastases ⁸³. A phase II trial (NCT02595905) is currently ongoing and evaluating the use of cisplatin plus or minus veliparib in TNBC metastatic breast cancer patients with or without BRCA mutation, also including patients with brain metastases. Initial results of the study showed significant benefit in PFS with the addition of veliparib only in the BRCA-like TNBC cohort (5.9 versus 4.2 months, HR, 0.53; 95% CI 0.34-0.83; p=0 .006), and CNS endpoints are yet to be reported ⁸⁴.

Immune checkpoint inhibitors (ICI)

TNBC are very immunogenic tumors, presenting high number of tumor mutations, more tumor infiltrating lymphocytes (TIL), and high PDL-1 expression both in in tumor and immune cells around them ^85-88. Immune checkpoints are proteins, such as PDL-1, produced by some of the immune cells and tumor cells and control negatively the immune response. ICI are agents that block those immune checkpoints and enhance the immune response. Two of those agents, atezolizumab (anti-PDL1) and pembrolizumab (anti-PD1) are currently approved for initial treatment of PDL1 positive TNBC in combination with chemotherapy ⁸⁹.

The Impassion130 trial randomized 902 previously untreated metastatic TNBC patients between nab-paclitaxel plus or minus atezolizumab and showed progression free survival (PFS) benefit with addition of atezolizumab (7.2 versus 5.5 months, HR 0.80, 95% CI 0.69–0.92, p=0.0021). An OS benefit, however, was observed only in the TNBC subgroup presenting PDL1 positive immune cells, in an exploratory analysis (25 versus 18 months, HR 0.71, 95% CI 0.54 – 0.94). Only 61 patients with treated and asymptomatic CNS disease were enrolled and presented the same PFS benefit as the overall trial population ⁸⁹. No specific CNS endpoints were evaluated.

In the Keynote355 trial, 847 previously untreated metastatic TNBC patients were randomized between chemotherapy plus or minus pembrolizumab. Adding pembrolizumab improved PFS (9.7 versus 5.6 months, HR 0.65, 95% CI 0.49 – 0.86, p=0.0012) in patients with PDL1 combined positive score (CPS) ≥ 10 ⁹⁰. Once more, only patients with treated and stable brain metastases were enrolled and no specific CNS endpoints were reported.

Much remains to be understood regarding the CNS and brain metastases immunological environment. The CNS used to be considered as having an absolute immune privilege, but that assumption has been questioned and studies demonstrate changes in blood-brain barrier and environment once primary or metastatic tumors are present ⁹¹. ICI therapy has even led to intracranial responses in melanoma and non-small cell lung cancer ^92,93. In melanoma, selected aspects of brain metastases environment such as immune infiltrate, hemorrhage, necrosis have prognostic significance ⁹⁴. An analysis of 203 BCBM tissue biobank looked into these same histologic aspects. Necrosis was higher in TNBC in comparison to other subtypes and associated with worse prognosis. Meanwhile, gliosis was linked to a better prognosis in TNBC ⁹⁵. The analysis, however, was not made in relation to a specific therapy.

In a retrospective evaluation of 84 breast cancer brain metastases, PD-L1 and PD-L2 were analyzed by immunohistochemistry and found to be present in 53 % and 36 % of cases, respectively, and not related to the brain metastasis phenotype ⁹⁶. In the same analysis, PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs. Overall, these findings suggest a promising landscape for use of immune checkpoint inhibitors, if we assume immune functions in CNS mimic the systemic ones. Conversely, in an analysis of 46 paired samples from primary breast cancers and respective brain metastases, the percentage of TILs was significantly lower in the metastatic lesions. The numbers of CD4/CD8/Foxp3-positive cells were also significantly higher in primary lesions, but there was no clear difference in PD-L1 positivity between primary tumors and brain metastases ⁹⁷. Clinical trials evaluating immunological therapeutics alone or combined to other systemic agents or radiation are currently ongoing.

Antibody drug conjugates

Antibody drug conjugates (ADCs) are a class of drugs that deliver treatment in a targeted way, combining the active compound to a specific antibody. Sacituzumab-govitecan is an antibody–drug conjugate in which an active metabolite of irinotecan (SN-38) is linked to the humanized antitrophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody ⁹⁸. Trop-2 is detected in triple-negative breast cancer cells amongst other tumors ⁹⁹.

In a phase I/II trial, 108 TNBC patients previously treated with a median of 3 lines for metastatic disease, received treatment with Sacituzumab-govitecan and presented a response rate of 33.3% (95% CI, 24.6 to 43.1), with median duration of response of 7.7 months (95% CI, 4.9 to 10.8), with main adverse events being hematologic toxicity related ⁷⁴. Based on these results, the ADC has been approved for use in metastatic TNBC patients that received at least 2 prior therapies in metastatic setting. The phase III ASCENT trial compared sacituzumab govitecan with single-agent chemotherapy per physician’s choice (capecitabine, eribulin, vinorelbine or gemcitabine) in 468 patients with metastatic TNBC and showed improvement in PFS (5.6 versus 1.7 months; HR 0.41; p<0.0001) and OS (12.1 versus 6.7 months; HR 0.48; p<0.0001) with the use of the ADC ¹⁰⁰. Both trials were non-informative regarding possible CNS effects of the drug since patients with active CNS disease were not eligible. However, in a phase 0 trial (NCT03995706), Sacituzumab-govitecan was given as single pre-operative dose to 19 patients with CNS primary tumors or metastases undergoing resection with continued treatment after surgery until progression. Sacituzumab-govitecan delivered 150-fold (BC brain metastases) and 40-fold (glioblastomas) the 50% inhibitory concentration (IC50) of SN38, and produced partial responses in both cohorts per preliminary reports ¹⁰¹. These are stimulating results and should lead to further investigation of this ADC activity in TNBC brain metastases. A phase II trial with Sacituzumab-govitecan in patients with HER2-negative BCBM is expected to be launched by the Southwestern Oncology Group (SWOG) soon.

Table 1 presents currently available clinical trials for TNBC with CNS metastases.

Table 1.

Available clinical trials for TNBC with brain metastases

NCT	Title	Intervention	Eligibility
03994796 (Phase II)	Genomically-Guided Treatment Trial in Brain Metastases	Palbociclib or GDC-0084 or entrectinib, pending on presence of gene mutation	clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K pathway at least one prior TNBC directed therapy in the metastatic setting
03449238 (Phase I/II)	Pembrolizumab and Stereotactic Radiosurgery (SRS) of Selected Brain Metastases in Breast Cancer Patients	Pembrolizumab plus SRS	at least 2 intracranial untreated metastases exclusion: current systemic therapy, previous WBRT or anti-PD1/PD1 or PDL2 agents
03483012 (Phase II)	Atezolizumab and Stereotactic Radiation in Triple-negative Breast Cancer and Brain Metastasis	Atezolizumab plus SRS	up to 5 intracranial untreated metastases with indication for SRS exclusion: previous treatment with anti-PD1/PD1 or PDL2 agents
02886585 (Phase II)	Pembrolizumab In Central Nervous System Metastases	Pembrolizumab	measurable CNS metastases
04434560 (Phase II)	Neoadjuvant Immunotherapy in Brain Metastases	Nivolumab and Ipilimumab	1 to 3 previously untreated CNS metastases, at least one resectable, plan for SRS TNBC that is PD-L1 positive
03328884 (Phase II)	Evaluation of the Efficacy and Safety of Nal-IRI for Progressing Brain Metastases in Breast Cancer Patients	Irinotecan Hydrochloride	measurable CNS metastases exclusion: previous treatment with irinotecan
04039230 (Phase IB/II)	Phase 1b/2 Study to Evaluate Antibody-Drug Conjugate Sacituzumab Govitecan in Combination with PARP Inhibitor Talazoparib in Patients with Metastatic Breast Cancer	Sacituzumab-govitecan and Talazoparib	only stable CNS disease allowed
03952325 (Phase II)	Tesetaxel Plus 3 Different PD-(L)1 Inhibitors in Patients with Metastatic TNBC and Tesetaxel Monotherapy in Patients with HER2 Negative MBC (CONTESSA TRIO)	Tesetaxel plus either Nivolumab, Pembrolizumab or Atezolizumab	known metastases to the CNS are permitted but not required exclusion: previous treatment with anti-PD1/PD1 or PDL2 agents

Looking forward

Many aspects remain to be clarified to improve the treatment of TNBC brain metastases. While information on CNS effect of the currently therapies specifically approved for TNBC treatment is eagerly awaited, a couple of innovative clinical trials is considering different approaches to the problem.

Based on the demonstrated presence of genomic branched evolution in brain metastases that may generate specific targetable mutations in the brain lesions ³⁰, a genomically guided phase II trial (Alliance A071701; NCT03994796) has been developed. Patients with TNBC and brain metastases are also eligible. Each patient will receive the specific treatment pending on actionable mutations found in their brain metastases: abemaciclib for CDK alterations, dual mTOR/PI3K inhibitor paxalisib/GDC-0084 for mTOR/AKT/PI3K alterations, and entrectinib for NTRK/ROS1 fusions (specific for lung brain metastases). The primary endpoint of the trial is overall CNS response rate. This approach represents the next steps in the precision medicine strategy.

In setting of high-risk for brain metastases development and poor prognosis once they are established, a preventative approach would also make sense. Based on its high CNS penetrance, temozolomide was evaluated in TNBC brain metastases mice models and found to be highly effective in preventing brain metastases development ¹⁰². No effect was seen in treating established brain metastases lesions though. Currently, a phase I/II clinical trial for secondary prevention of brain metastases with temozolomide (NCT03190967) is opened for HER2-positive breast cancer patients ¹⁰³. A phase I/II brain metastases prevention clinical trial with temozolomide for patients with TNBC is currently under development with plans to open in the soon. Eligible patients should have received local therapy for brain metastases close to enrollment and will then receive temozolomide in combination with an active systemic treatment for extracranial TNBC based on physician’s choice.

Conclusion

Brain metastases are frequent and confer an even poorer prognosis to patients with TNBC. Different than HER2-positive breast cancer, systemic therapeutic options have just recently started to be available for patients with metastatic TNBC, and data on specific CNS action of those agents is still unclear. There is, however, an increased awareness of brain metastases being an unmet need in this subtype of breast cancer. CNS biology is knowingly complex and has a distinctive microenvironment that needs to be studied in association with the specific nature of TNBC metastases, guiding the development of brain permeable therapeutic options. Associated with that, clinical trials design has to be reconsidered to include patients with CNS active metastases, mirroring the reality of our clinics and patients’ lives. Effectively connecting laboratory evidences to our clinical research is the only promising pathway to improve the lives of our patients with TNBC and CNS metastases.