Metastatic Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a heterogeneous disease group with a known aggressive phenotype and poor prognosis. To date, it remains a challenging disease given its lack of oncogenic targets as seen in hormone receptor + or HER2 + breast cancers, and limited efficacy with traditional chemotherapy. This article is a review of the latest key literature in the management of metastatic TNBC and offers a glimpse of ongoing drug development. Recent paradigm-shifting trials led to the incorporation of immune checkpoint inhibitors with chemotherapy in the frontline setting for TNBC with positive PDL1-expression. Novel antibody–drug conjugates with new targets (Trop2, HER2) now offer additional treatment options for metastatic TNBC. There have been significant strides in understanding the tumor-immune microenvironment and molecular vulnerabilities in TNBC. As the treatment of metastatic TNBC evolves rapidly, novel combination therapies and therapeutic strategies will continue to improve patient outcomes.


Introduction
In 2022, there is an estimated 287,850 new breast cancer cases in the USA.Hormone receptor-positive and human epidermal growth factor-negative (HER2 negative) breast cancer is the most common subtype.In contrast, triple-negative breast cancer (TNBC), defined by the lack of estrogen receptors, progesterone receptor, and HER2, accounts for about 15% of all breast cancer cases [1].TNBC is a biologically diverse disease group associated with an aggressive phenotype and poor prognosis.It remains a challenge to clinicians given its short duration of response to traditional chemotherapeutics and lack of targetable oncogenic pathways.For patients with metastatic (stage IV) TNBC, 5-year relative survival is around 4-20% in Western countries.For these reasons, better understanding the heterogeneity of tumor microenvironment and expansion of therapy options, including novel targets for treatment, for TNBC have been pressing areas of research interest over the recent years.Practice-changing advancements in the treatment landscape of TNBC include immune checkpoint inhibitors, targeted therapies such as PARP inhibitors, antibody-drug conjugates (ADCs), and emerging novel agents.This article is a review of up-to-date literature on these efforts.

Molecular Landscape and Tumor Microenvironment of TNBC
Notable strides in molecular profiling and genomic sequencing over the past decade have shed valuable insight into the phenotypic heterogeneity behind the clinical diagnosis of TNBC.Although labeled as a single entity in clinical guidelines, pivotal studies have shown that there are distinct subtypes of TNBC based on gene expression: basal-like 1 (BL1), basal-like 2 (BL2), luminal androgen receptor (LAR), and mesenchymal [2].The majority of TNBCs are classified as basal-like (80.6%).The LAR subtype is characterized by the expression of the androgen receptor and thus could be treated with targeted agents toward AR [3].Each of these molecular subtypes has been associated with unique tumor microenvironments, thus impacting response to therapies.
In metastatic TNBC, features such as increased tumor mutation burden, clonal diversity, and germline and somatic mutations (i.e., genes related to homologous recombination DNA repair) make for a promising but challenging landscape for targeted therapies.Mutations in BRCA 1/BRCA 2 are associated with an increased incidence of all breast cancers but are most commonly found in patients with TNBC.Approximately 20% of patients with TNBC may contain the BRCA1/BRCA2 germline mutation, which is a reason why genetic screening is now recommended in all patients, regardless of age, who are diagnosed with TNBC [4].
The unique tumor microenvironment of TNBC sets it aside from other subtypes of breast cancer.In TNBC, higher expression of tumor-infiltrating lymphocytes (TILs), vascular endothelial-like growth factor, and tumor-associated macrophages (TAMs) are found [5].The prognostic importance of TILs is well established in localized or early-stage TNBC: high TILs are associated with a better prognosis with regards to both disease-free survival (DFS) and overall survival (OS) in early-stage disease.In contrast, the presence of TAMs, which facilitate immune escape, is a negative prognostic factor for TNBC: increased TAM expression is correlated to an increased likelihood of distant metastases, and decreased DFS and OS.In metastatic TNBC, relative immune depletion is often observed, with decreased presence of TILs compared to localized or early-stage disease [6].TNBC also harbors higher levels of programmed cell death ligand (PDL1) expression compared to other breast cancer subtypes, underscoring the utility of immune checkpoint inhibitors in TNBC [7].

Chemotherapy in Triple-Negative Breast Cancer: Single-Agent Options
To present, cytotoxic chemotherapies remain the backbone of frontline treatment for metastatic TNBC.Single-agent therapies are generally used sequentially.Combination regimens can be considered for patients who are in need of rapid response for visceral crisis [8].Taxanes, which consist of docetaxel, paclitaxel, and nab-paclitaxel, are the most common single-agent chemotherapy options used in metastatic TNBC.Weekly paclitaxel is associated with improved time to progression (HR = 1.43, p < 0.0001) and overall survival (HR = 1.28, p = 0.0092) compared to an every 3-week schedule [9].Docetaxel is administered in a similar weekly versus every 3-week schedule.In a phase III study of docetaxel versus paclitaxel every 3 weeks in metastatic breast cancer patients who progressed after anthracycline therapy, median OS, time to progression, and overall response rate (ORR) were higher for docetaxel compared to paclitaxel [10].Nanoparticle albumin bound-paclitaxel (nabpaclitaxel) has a shorter infusion time and is associated with lower risk of allergic reactions, which enables one to bypass steroid premedication and associated risks such as steroidinduced hyperglycemia.However, nab-paclitaxel is much more expensive than paclitaxel and access to this may be more limited.Nab-paclitaxel was compared with paclitaxel in patients with metastatic breast cancer or locally recurrent breast cancer.While there was no statistically significant difference in OS or PFS, there was a higher rate of grade 3 and 4 toxicities in the nab-paclitaxel arm including peripheral neuropathy as well as hematological toxicities [11].
Anthracyclines comprise the other major chemotherapy class used in breast cancer, although its use in the metastatic setting is limited to those without prior anthracycline exposure given the risk of cumulative, dose-dependent toxicities.This class includes doxorubicin, epirubicin, and pegylated liposomal doxorubicin.In a randomized controlled trial of liposomal doxorubicin versus doxorubicin in patients with metastatic breast cancer, 50% of whom were estrogen receptor negative, doxorubicin resulted in a higher ORR but similar PFS and OS.However, liposomal doxorubicin was also associated with lower rates of cardiotoxicity (7% vs 26%) [12].Liposomal doxorubicin additionally conferred the advantage of an every 4-week infusion, compared to an every 3-week schedule for doxorubicin.To date, there is no direct head-to-head comparison between single-agent anthracycline versus single agent taxanes, but a meta-analysis showed that single-agent taxanes have similar response rates and overall survival compared to single agent anthracyclines [13].
Further agents include classes such as anti-metabolites, including the 5-FU prodrug capecitabine which is administered orally with a 2-week on, 1-week off schedule.It is often used in the first-line setting due to ease of administration and comparable efficacy to other intravenous chemotherapy options.Capecitabine can be used in settings of hepatic dysfunction.However, it can cause unique side effects including hand foot syndrome, as well as diarrhea.Gemcitabine, a pyrimidine anti-metabolite, also has demonstrated efficacy in metastatic cancer in pretreated patients with progression on doxorubicin and taxane therapy, with a response rate of 20%, median response duration of 9 months, and OS of 11 months [14].In patients 60 years or older with metastatic breast cancer randomized to gemcitabine or epirubicin, epirubicin demonstrated statistically significant superiority in time to progression (6.1 vs 3.4 months, p = 0.0001), OS (19.1 vs 11.8 months, p = 0.0004), and response rate (40.3% vs 16.4%, p < 0.001) [15].The microtubule inhibitor, eribulin, has been FDA approved for use in metastatic TNBC in patients who have progressed after two lines of systemic therapies.Eribulin is associated with low risk for peripheral neuropathy and could be dose adjusted for renal and hepatic toxicities.In the phase III EMBRACE trial of 762 patients randomly assigned to eribulin versus another chemotherapy agent based on physician's choice, eribulin is associated with significantly improved OS (13.1 months vs 10.6 months), although it was also associated with all-grade neutropenia in 45% of the patients [16].

Chemotherapy in Triple-Negative Breast Cancer: Combination Options
Although used less frequently, combination chemotherapy is useful in patients with high tumor burden and who need a rapid response for visceral crisis.A recent meta-analysis of 9742 patients with metastatic breast cancer, 45% of whom were treatment naïve, showed that the combination of anthracycline and/or taxanes improved OS compared with single-agent therapy (HR 0.88, 95% confidence interval (CI) 0.83-0.93,p < 0.00001) but also at the cost of increased toxicities including a 32% greater risk of neutropenic fever [17].In patients who are not candidates for anthracyclines, taxane-based combination therapies are the preferred treatments, such as gemcitabine with docetaxel or paclitaxel.Choice between taxanes is often driven by toxicity profiles.
A meta-analysis evaluating the benefit of platinumbased chemotherapy in metastatic TNBC showed no progression-free survival (PFS) advantage compared to those treated with non-platinum-based regimens (HR 1.16, 95% CI 0.90-1.49;p = 0.24) [18].However, the benefit of platinum-based chemotherapy is shown to be context dependent.Specifically, platinum-based regimens have shown efficacy for patients with BRCA1/BRCA2 mutant TNBC and other deficiencies in homologous recombination.The phase III TNT trial showed that in patients with BRCA-mutated breast cancer, carboplatin had double the ORR compared to docetaxel (68% vs 33%, respectively) [19].The same was not found in the overall population.The reason for this is felt in part to be driven by the sensitization to platinum-based chemotherapies of tumors with impaired DNA repair mechanisms such as homologous recombination repair deficiency.The outcomes from chemotherapy over the recent years have been improved by the incorporation of immunotherapy, targeted therapy as well as novel agents.

Developments in Immunotherapy
The programmed cell death ligand 1 (PD-L1) combined positive score (CPS), which indicates the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total viable cells multiplied by 100, became a standard-of-care evaluation in the stratification and management of TNBC over recent years.Multiple early-phase trials have shown the benefit of PD-L1 inhibitors in patients with a higher PD-L1 expression.In 2016, the KEYNOTE-012 phase Ib trial showed a benefit of the immune checkpoint inhibitor, pembrolizumab, in patients with pretreated, advanced TNBC, as part of a larger basket trial.A modest response rate of 18% was observed in the patients, with those with higher PD-L1 scores having a greater likelihood of response (p = 0.028) [20].Atezolizumab is another PD-L1 inhibitor also reported to be effective in the treatment of metastatic TNBC.Patients with PD-L1 expression of at least 1% in TILs had higher ORR (12% vs 0%) and longer OS (10.1 vs 6 months), respectively [21].A higher level of PDL1 expression in TILs (> 10%) was independently associated with higher ORRs and longer OS.While early-phase studies have shown the promise of single-agent immunotherapy in TNBC, it is more effective in combination with chemotherapy.Immunotherapy has been shown to prime the anti-tumor immune response by enhancing tumor antigen release and further sensitizing the tumor to chemotherapy effects.In KEYNOTE 355, patients with untreated, advanced, or metastatic TNBC had a modest improvement in median PFS with the addition of pembrolizumab to the investigator's choice of chemotherapy (nanoparticle albuminbound paclitaxel, paclitaxel, or gemcitabine-carboplatin) (7.5 vs 5.6 months; HR 0.82, 95% CI 0.69-0.97).Notably, patients with CPS ≥ 10 had the most benefit (9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86).The addition of pembrolizumab improved OS among patients with a CPS ≥ 10 (23.0 vs 16.1 months; HR 0.73, 95% CI 0.55-0.95)[22].However, in KEYNOTE-119, pembrolizumab did not improve median OS in previously treated metastatic TNBC regardless of CPS.This highlighted the importance of incorporating immunotherapy in early lines of therapy for patients with metastatic TNBC [23].IMpassion-130 study was another pivotal study looking at the combination of atezolizumab versus placebo with nab-paclitaxel in patients with advanced TNBC.While the intention-to-treat group analysis favored the atezolizumab arm, again the greatest benefit was seen in those who had PD-L1-positive disease (PD-L1 > 1%), with a median PFS benefit of 7.5 months versus 5 months (p < 0.001).The median OS in the PD-L1-positive group reached 25.4 months in the atezolizumab arm versus 17.9 months in the control arm [24].The same outcome was interestingly not seen when paclitaxel (instead of nab-paclitaxel) was used as the chemotherapy partner with atezolizumab.Based on the IMPASSION-131 study, patients who received paclitaxel with atezolizumab were not found to have improved PFS compared to those who had paclitaxel with a placebo.This was seen both in the overall population and the subset of patients who were PDL-1 positive [25].Although unclear, the lack of difference in the study and control arm was felt potentially to be driven by the immunosuppressive effects of dexamethasone used with paclitaxel in IMPASSION-131, which could have blunted the efficacy of atezolizumab.Although further work needs to be undertaken to understand the underlying mechanistic reason for this difference, these set the basis for the recommendation in favor of atezolizumab with nabpaclitaxel, rather than paclitaxel.

PARP Inhibitors in BRCA Mutated Diseases
Germline BRCA1/2 mutations can be found in approximately 20% of patients with TNBC, and are sensitive to cytotoxic agents including platinum-based chemotherapy, as well as poly(ADP-ribose) polymerase (PARP) inhibitors [26].Two major trials have cemented the role of PARP inhibitors in the management of BRCA mutated metastatic TNBC, the OlympiAD and the EMBRACA studies.In OlympiAD, patients with germline BRCA1/2 mutation and metastatic HER2-negative (HER2 −) breast cancer (hormone receptor positive or TNBC) who have received no more than two prior lines of chemotherapy were randomized to receive olaparib or physician's choice of single-agent chemotherapy (vinorelbine, capecitabine, and eribulin).Olaparib improved median PFS by 2.8 months (7.0 vs 4.2 months) with a hazard ratio for disease progression or death of 0.58 (95% CI 0.43-0.80;p < 0.001).In the subgroup analysis of patients with TNBC, the benefit of olaparib was similarly observed, with an HR of 0.43 (95% CI 0.29-0.63)[27].Whether this translates to an OS benefit remains to be seen.The EMBRACA trial similarly investigated talazoparib in patients with germline BRCA1/2 mutations and metastatic HER2 -breast cancer who had received a median of two prior lines of therapy.Median PFS was 8.6 months in the talazoparib group versus 5.6 months in the control group (hazard ratio for disease progression or death, 0.54; 95% CI 0.41-0.71;p < 0.001).This benefit was similar in the hormone receptor (HR)-positive patients as well as the HR-negative (TNBC) patients [28].However, a follow-up analysis of the EMBRACA trial showed that OS with talazoparib versus chemotherapy was not significantly different, a result that may have been impacted by subsequent treatments the patients received [29].An additional important measure for patients-a delay in time to definitive clinically meaningful deterioration in global health status and quality of life-was found to favor talazoparib versus chemotherapy (p < 0.01).Veliparib, another PARP inhibitor, was investigated in combination with carboplatin and paclitaxel in germline BRCA mutated HER2 -metastatic breast cancer in the phase III BROCADE3 trial.The addition of veliparib to platinum doublet therapy resulted in statistically significant PFS; median PFS was 14•5 months (95% CI 12.5-17.7)in the veliparib group versus 12.6 months (10.6-14.4) in the control group (hazard ratio 0.71, 95% CI 0•57-0•88, p = 0•0016) [30].

Antibody-Drug Conjugates
While targeted therapies remain limited in the setting of TNBC, key advances have been made over the recent few years.One such pivotal advance has been the emergence of ADCs, which have yielded clinically meaningful improvements in outcomes.ADC harnesses the specificity of the antibody with the cytotoxicity of a payload.For example, sacituzumab govitecan is an ADC composed of a topoisomerase I inhibitor coupled to the humanized antibody against the trophoblast cell-surface antigen 2 (Trop-2), a transmembrane calcium signal transducer overexpressed in many epithelial cancer cells, including in over 85% of TNBC tumors.The IMMU-132-01 is a phase I/II basket design, open-label, multicenter trial involving patients with metastatic TNBC with prior taxane-or anthracyclinebased chemotherapy.Patients treated with the sacituzumab govitecan experienced a response rate of 33.3%, with a median duration of response of 7.7 months.The median PFS was 5.5 months with a median OS of 13 months.The most common adverse events of grade 3 or higher (> 5% incidence) included neutropenia, anemia, and leukopenia [31].The ASCENT trial further investigated the role of sacituzumab govitecan in a phase III, randomized control trial, as compared with single-agent chemotherapy of the physician's choice in patients with relapsed or refractory metastatic TNBC.Patients in the study, all of whom had prior taxanes, had a median PFS of 5.6 months in the study arm, as compared to 1.7 months in the control arm (95% CI 4.3-6.3;166 events).The median OS was about double with sacituzumab at 12.1 months versus 6.7 months in the control group (95% CI 5.8-to 7.7).The objective response rate was seen at 35% compared to 5% with chemotherapy [32].Multiple studies of sacituzumab govitecan are still underway, including evaluation of the agent in the neoadjuvant setting, adjuvant setting in resectable TNBC (NCT04230109, GBG102-SASCIA), as well as in combination with immunotherapies or PARP inhibitors in advanced TNBC (NCT03424005, NCT04468061).

HER2-Low Triple-Negative Breast Cancer
Among patients who had historically been characterized as HER2 -via fluorescence in situ hybridization, about 60% express low levels of HER2, defined as a score of 1 + or 2 + on immunohistochemical analysis [33].This re-stratifying of HER2 -disease has shifted the paradigm of targeted therapies for this subset of patients.Although HER2-low tumors have not been shown to respond to conventional HER2-targeted therapy, the newer generation of HER2-directed ADCs has been shown to have efficacy in this patient population.Trastuzumab deruxtecan (T-Dxd), composed of trastuzumab, a humanized anti-HER2 monoclonal antibody, linked to topoisomerase I inhibitor payload, is one such therapy previously approved for the treatment of patients with metastatic HER2-positive breast cancer.Unlike other approved HER2-targeted therapies, it effectively targets even tumor cells that express low levels of HER2.With a drug-to-antibody ratio of 8:1, it has an important bystander cytotoxic effect on neighboring tumor cells.In phase I and II studies, the ORR for patients with HER2-low TNBC ranged around 37%, with a median PFS of anywhere from 6.3 to 11.1 months [34,35].The DESTINY-Breast04 trial is a landmark randomized, open-label, phase III trial involving patients with HER2-low, unresectable, or metastatic breast cancer.Patients were randomized 2:1 to T-Dxd and to the physician's choice of chemotherapy.The median PFS in the hormone receptor-negative cohort was 8.5 months in the T-Dxd arm compared to 2.9 months in the control arm (p < 0.001).The median OS was 18.2 months in the T-Dxd arm versus 8.3 months in the chemotherapy arm (p = 0.001) [36].
Important challenges remain to be tackled in the use of ADCs in TNBC.One such challenge is the heterogeneity with which HER2-low disease is determined via IHC.Results from the College of American Pathologists Proficiency Testing Surveys showed that 52 of the 80 cores evaluated (65%) had a 90% or greater concordance agreement, and 15 (25%) had a concordance agreement of less than 70% [37].Additional analysis showed that among samples that were read by at least one pathologist as IHC 3 + , 58% had a concordance rate of 90% or greater.However, among samples read as IHC 0 by at least one pathologist, only 26% had a concordance rate of 90% or higher [38].This carries inevitable implications for patients with HER2-low disease and underscores an area for necessary improvement for a precise and predictive biomarker necessary for new therapy such as T-Dxd.With the availability of ADCs also emerges the questions regarding the optimal sequence of therapy selection for eligible patients.To date, there is no direct comparison of sacituzumab govitecan with T-Dxd in patients who may be eligible for both.Therefore, therapy options are dependent on the availability of clinical trials and the shared decision of individual patients and providers.Nevertheless, ADCs have greatly expanded the options for patients with TNBC and serve as an important direction for future studies.

Modulation of the PI3K/AKT/PTEN Pathway
Among the promising targetable pathways within TNBC, the PI3K/AKT pathway has long been a focus of research given its central role in regulating the hallmarks of cancer biology.Different alterations along the pathway lead to dysregulation of cell growth, proliferation, metabolism, and survival.The PI3K/AKT pathway is frequently activated in TNBC, through activating mutations in PIK3K or AKT1 and/or inactivating alterations in the tumor suppressor, PTEN.Selective PI3Kα inhibitors have shown promising antitumor activity in TNBC, particularly in combination with other systemic therapies.The LOTUS trial is a randomized, double-blind phase II study looking at the impact of the oral AKT inhibitor, ipatasertib, in patients with previously untreated, advanced TNBC who were randomized to either paclitaxel with ipatasertib or placebo.Ipatasertib with paclitaxel prolonged PFS compared to paclitaxel with placebo, with median PFS being 6.2 months versus 4.9 months, respectively.The study also examined patients who had a deficient expression of the PTEN, which was present in approximately half of the patients.Among patients with low PTEN expression, the median PFS was 6.2 versus 3.7 months with ipatasertib compared to placebo [39].Key adverse events in the LOTUS trial included diarrhea (23%), leading to discontinuation of therapy in about 3% of patients in the ipatasertib arm.Building off the LOTUS trial, the first to support AKT-targeted therapy for triple-negative breast cancer, the IPATunity130 is a phase III trial that looked at patients with unresectable or metastatic breast cancer who were naïve to chemotherapy.Patients were split into two cohorts, TNBC (cohort A) and hormone receptor-positive patients (cohort B), randomized 2:1 to paclitaxel with ipatasertib versus placebo until disease progression.For the TNBC cohort, investigator-assessed PFS was not different for those who received ipatasertib versus placebo, at 7.4 months for the ipatasertib arm versus 6.1 months for the placebo arm (hazard ratio = 1.02, 95% CI 0.71-1.45).The investigator-assessed objective response rate was similar: 39% with ipatasertib versus 35% with placebo [40].While a negative study, a few potential factors may have impacted the outcomes.Of note, there were more dose reductions in the ipatasertib plus paclitaxel arm compared to the placebo arm (46% vs 27%) due to increased adverse events.The lack of PFS and OS benefits seen may also underscore the importance of a better understanding of the right population to select for this targeted therapy, or perhaps the need for use of a more potent AKT inhibitor.
Other AKT inhibitors have also been studied in metastatic TNBC, stemming from promising results in preclinical studies.Capivasertib is one such drug that held promise in preclinical studies and was subsequently investigated in the PAKT trial, a double-blind, placebo-controlled, randomized phase II trial in patients with untreated metastatic TNBC.Patients were randomized 1:1 to paclitaxel plus capivasertib versus placebo.The median PFS, the primary endpoint, was 5.9 months with capivasertib versus 4.2 months with placebo (p = 0.06).Median OS was 19.1 months in the capivasertib versus 12.6 months with placebo (p = 0.04).In the subgroup of patients with genomic evidence of PI3K/AKT/PTEN alterations, the median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (p = 0.01).Overall, this suggests that capivasertib, when added to paclitaxel, improves OS in metastatic, untreated TNBC patients and, notably, may have an augmented effect for the subset of patients who have mutations in the PI3K/ AKT/PTEN pathway [41].The phase III trial, CAPItello-290, further evaluating the efficacy of capivasertib with paclitaxel versus placebo is currently ongoing [42].

Androgen Receptor Targeted Therapies
There is a high degree of variability in the reported literature on androgen receptor (AR) expression in TBNC, in part due to the heterogeneity in AR expression measurement methodology and cutoffs used in literature.In a systematic review of 7693 breast cancer patients, AR expression was noted in 74.8% in ER + tumors and 31.8% in ER-negative tumors [43].Several studies have shown that in TNBC, positivity for AR by immunohistochemistry is associated with a favorable prognosis, as well as favorable features including lower clinical stage, histological grade, and mitotic score [44][45][46].Although more than one TNBC subtype expresses AR, the luminal androgen receptor subtype is known to be most enriched in AR expression [47].The earliest clinical studies investigating AR as a therapeutic target in breast cancer were conducted in the 1980s using flutamide as the antiandrogen drug of choice and did not show any meaningful benefit in patients.However, the lack of benefit was potentially in part due to the small size of the studies and the lack of stratification of patients by AR expression status.More recently, a single-arm, multi-center, non-randomized phase II clinical trial showed the efficacy of bicalutamide in AR + , ER/PR -metastatic breast cancer [48,49].Among 424 patients with ER/PR -disease screened, 51 patients (12%) were positive for AR based on preselected criteria (AR > 10% by IHC).The trial showed a clinical benefit rate (defined as complete response, partial response, or stable disease > 6 months) of 19% at 24 weeks with median PFS of 12 weeks [50].Patients who derived benefit were treated in the first-line or second-line setting.Notably, bicalutamide was well tolerated, with no grade 4 or 5 adverse events reported in the study.Enzalutamide has also been studied in a phase II trial in advanced AR + TNBC.A total of 118 patients was enrolled in the trial, of whom 50% were treated in the first and second setting [51].The study showed a clinical benefit rate of 25% at 16 weeks and 20% at 24 weeks in patients who are AR + by IHC.Those whose AR positivity is > 10% had an even improved clinical benefit rate of 35% and 29% at 24 weeks [51].Novel AR targeted therapies, such as AR degraders and second-generation AR antagonists, which have been used for metastatic prostate cancer, are emerging which may also be potential therapeutics in this subset of TNBC patients.

Conclusion and Future Perspectives
Marked strides have been made in the realm of therapeutic approaches to TNBC, which has historically largely been treated with chemotherapy regimens.These advances have included the incorporation of immunotherapy based on CPS status and the emergence of targeted therapies, ranging from the use of PARP inhibitors to ADCs, to emerging therapies such as modulators of the PI3K/AKT pathway.Figure 1 summarizes the treatment algorithm that incorporates these key studies.Table 1 summarizes the key findings of the landmark or key phase III trials that encompass these recent developments.
The future treatment landscape of TNBC is fast evolving with novel combinations of known pathways and new targeted treatments.For instance, early promising results have come out of studies combining AKT inhibitors with immunotherapy, such as ipatasertib and atezolizumab [52], as well as PARP inhibitors olaparib and immunotherapy durvalumab [53].
Combination ADCs and immunotherapy studies such as the BEGONIA phase Ib/II study showing promising efficacy with using T-DXd and durvalumab, as well as datopotamab-DXd (Trop2 ADC) and durvalumab in first-line HER2low advanced TNBC [54].Phase III studies evaluating the combination of sacituzumab and immunotherapy are ongoing (NCT05382286).In addition, there are numerous studies using combination immunotherapies beyond PD-1/PD-L1 immune checkpoint inhibitors, such as agents that modulate the tumorimmune microenvironment or macrophage reprogramming, i.e., eganelisib in Mario-3 study [55], oncolytic viruses, adaptive cellular (T or NK cells) therapy, and cancer vaccine.Finally, the wave of ADCs renewed the efforts of targeted delivery of molecules to replace standard chemotherapy, and to target other cancer antigens such as HER3 [56], LIV1 (NCT04032704), and Nectin-4 (NCT04225117).It will be important to understand which therapy should be used in whom and when, with the help of more precise predictive biomarkers for each drug, akin to the microbial culture sensitivity table.Furthermore, in silico antigen maps of tumors may further identify novel molecular targets for ADCs [57,58].Other major developments in ADCs are also aiming to go beyond chemotherapeutical payloads.Studies using Yttrium-90 conjugated radionuclide [59], immune-stimulant molecules such as STING agonists or Toll-like receptor agonists [60], or dual distinct chemotherapy payloads are ongoing [61].Management of metastatic TNBC remains a moving target.As breast oncologists and our patients contend with this devastating diagnosis and the molecular heterogeneity of this disease, we celebrate the small victories in basic, translational, and clinical research.The persistence in tackling this disease from a wide variety of approaches has been and will continue to pave the way for therapies that revolutionize the treatment landscape of TNBC as well as other cancer types.

Fig. 1
Fig. 1 Representative treatment algorithm for metastatic TNBC based on current phase III evidence available

Table 1
Landmark phase III trials in metastatic TNBC (bolded trials reflect FDA-approved therapy options)