Endocrine therapy resistance (ETR) in breast cancer (BC) is a multicausal phenomenon with diverse alterations in the tumor cell interactome. Within these alterations, non-coding RNAs (ncRNAs) such as micro-RNAs (miRNAs) modulate the expression of tumor suppressor genes and proto-oncogenes, such as the ESR1 gene encoding estrogen receptor alpha (ERα). This work aims to review the effects of miRNAs targeting ERα mRNA and their mechanisms related to ETR in BC. A thorough review of the literature and an in silico study were carried out to elucidate the involvement of each miRNA, thus contributing to the understanding of ETR in BC.

Early studies have shown that sex hormone-binding globulin (SHBG) suppresses breast cancer by decreasing estrogen activity. However, the sex hormone-independent role of SHBG in breast cancer has received limited attention. Building on our previous research linking SHBG with tumor-associated macrophage (TYRO3, AXL, and MerTK) receptors, we aimed to explore SHBG's sex hormone-independent involvement in breast cancer progression. Analysis of public datasets and tumor slides from patients with breast cancer revealed that invasive breast cancer was associated with a significant decrease in SHBG, and lower SHBG levels correlated with poor cancer prognosis. In the polyomavirus middle T antigen overexpression mouse model (MMTV-PyMT), SHBG-Tg mice exhibited extended survival both under naïve and ovariectomized conditions. Although SHBG-Tg tumors had an estrogenic environment, their growth was suppressed, which correlated with reduced AXL levels. SHBG plasma treatment inhibited proliferation, tumorsphere growth, and invasion in MDA-MB-231 cells, accompanied by a decrease in AXL levels. In subcutaneous allograft models, SHBG-Tg mice showed reduced tumor growth and metastasis, and intraperitoneal injection of SHBG plasma significantly delayed tumor progression in PyMT mice compared with WT plasma. In summary, our study highlights SHBG's inhibitory role in breast cancer growth and metastasis, which may be particularly relevant for estrogen-independent patients with triple-negative breast cancer.NEW & NOTEWORTHY Our study is the first in vivo experiment using polyomavirus middle T antigen-sex hormone-binding globulin (PyMT-SHBG) mouse model to assess the physiological role of SHBG in breast cancer development. We show that SHBG presence in PyMT model restrains breast cancer development and progression in sex hormone-independent manner.

Immunotherapy in clinical application faces numerous challenges pertaining to both effectiveness and safety. Poly(ADP-ribose) polymerases (PARPs) exhibit multifunctional characteristics by transferring ADP-ribose units to target proteins or nucleic acids. In recent years, more and more attention has been paid to the biological function of PARPs in immune response. This article reviews the relationship between PARP family members and immune response. PARP1 and PARP2 inhibit anti-tumor immune activity by regulating immune checkpoint expression and the cGAS/STING signaling pathway. PARP7 and PARP11 play an important role in promoting immunosuppressive tumor microenvironment. PARP9 promotes the production of Type I interferon and the infiltration of macrophages. PARP13 is a key tumor suppressor that promotes anti-tumor immune response. PARP14 plays a crucial role in promoting the differentiation of macrophages towards the M2 pro-tumor phenotype. Summarizing the molecular mechanisms of PARP7, PARP9, PARP11, PARP13 and PARP14 in regulating immune response is helpful to deepen our comprehension of the role of PARPs in immune function regulation. This provides a reference and basis for targeted PARP-based cancer treatment strategies and drug development. PARP1, PARP7 inhibitors or other PARP inhibitors in combination with immune checkpoint inhibitors or other immunotherapy strategies may be a more effective cancer therapy.

Triple-negative breast cancer (TNBC) disproportionately affects Black women. Immunotherapy improves outcomes in early-stage TNBC (esTNBC) and metastatic TNBC (mTNBC). However, racial and ethnic disparities in immunotherapy receipt and its potential association with oncologic outcomes are unknown.

To examine trends and racial and ethnic disparities in immunotherapy receipt and differences in pathologic complete response (pCR) and overall survival (OS) in TNBC.

This retrospective cohort study analyzed the 2019-2021 National Cancer Database. Data were analyzed from April 1 to August 31, 2024. The esTNBC cohort included patients with stage II to III TNBC treated with neoadjuvant therapy in 2021. The mTNBC cohort included patients with stage IV TNBC treated from 2019 to 2021, with all patients having received chemotherapy with or without immunotherapy.

Immunotherapy use, pCR, and OS with respect to race and ethnicity.

A total of 10 724 patients with TNBC were included (mean [SD] age, 56.1 [13.7] years; 473 [4.4%] Asian or Pacific Islander, 2569 [24.0%] Black, 981 [9.1%] Hispanic, 6465 [60.3%] White, and 236 [2.2%] other). Immunotherapy use increased from 5.5% in 2017 to 38.8% in 2021 for mTNBC and from 4.2% in 2017 to 48.0% in 2021 for esTNBC. Of 7655 cases of esTNBC diagnosed in 2021, immunotherapy use was lower in Black patients (788 of 1715 [45.9%]), but this difference was not significant after adjusting for insurance status, treatment facility type, and other key variables. Among patients with esTNBC receiving immunotherapy, pCR was similar by race and ethnicity. Of 3069 cases of mTNBC diagnosed from 2019 to 2021, immunotherapy use was higher in Asian or Pacific Islander patients (36 of 97 [37.1%]) and lower in Black patients (238 of 848 [28.1%]). Black patients had lower odds of immunotherapy receipt than White patients (adjusted odds ratio, 0.63; 95% CI, 0.49-0.80) even after controlling for confounders. Among patients receiving immunotherapy, OS was similar between Black and White patients (adjusted hazard ratio, 0.92; 95% CI, 0.64-1.32).

In this cohort study of TNBC, Black patients with mTNBC were less likely to have received immunotherapy, even after controlling for socioeconomic factors. In both esTNBC and mTNBC cohorts, patients who received immunotherapy attained similar outcomes across racial and ethnic groups; thus, efforts should be made to ensure equal access to immunotherapy.

Programmed-death-1/ligand-1 inhibitors (PD-1/L1is) have emerged as pivotal treatments for many cancers. A notable feature of this class of medicines is the dichotomous response pattern: A small (but clinically relevant) percentage of patients (5%-20%) benefit from deep and durable responses resembling functional cures (durable responders), while most patients experience only a modest or negligible response. Accurately predicting durable responders remains elusive due to the lack of a reliable biomarker. Another notable feature of these medicines is that different PD-1/L1 is have obtained statistically significant results, leading to marketing approval for some cancer indications but not for others, with no discernible pattern. These puzzling inconsistencies have generated extensive discussions among oncologists. Proposed (but not entirely convincing) explanations include true underlying differences in efficacy for some types of cancer but not others; or subtle differences in trial design. To investigate a less-explored hypothesis-the durable-responder effect: An initially unidentified group of durable responders generates more statistical noise than anticipated, leading to low-powered randomized controlled trials (RCTs) that report randomly variable results.

Employing simulation, this investigation divides participants in PD-(L)1i RCTs into two groups: durable responders and patients with a more modest response. Drawing on published data for melanoma, lung and urothelial cancers, multiple prespecified scenarios are replicated 50,000 times, systematically varying the durable-responder percentage from 5% to 20% and the modest-response hazard ratio for overall survival [HR(OS)] from 0.8 to 1.0. This allowed evaluation of the effect of durable responders on power, point estimates of the treatment effect for OS, and the probability of a misleading signal for harm.

When the treatment effect for the modest responders is similar to the comparator arm, statistical power remains below 80%, limiting the ability to reliably detect durable responders. Conversely, there is a material probability of obtaining a statistically significant result that exaggerates the treatment effect by chance. For instance, with an average HR(OS) of 0.93 (corresponding to 5% durable responders), statistically significant trials (7.2%) show an average HR(OS) of 0.77. Additionally, when 5% are durable responders, there is a 20% probability that the HR(OS) will exceed 1.0-suggesting potential harm when none exists.

This article adds to the possible explanations for the puzzlingly inconsistent results from PD-(L)1i RCTs. Initially, unidentified durable responders introduce features typical of imprecise, low-powered studies: a propensity for false-negative results; estimates of benefit that might not replicate; and misleading signals for harm.

Programmed-death-1/ligand-1 (PD-1(L)1) inhibitors are crucial cancer treatments, with global spending expected to surpass $75 billion by 2026. Multiple versions of these medicines are available, all designed to boost the immune system to fight cancer. We would expect them all to work similarly, but clinical trials show mixed results-some seem effective for certain cancers but not others, without a clear pattern. This article uses simulations (virtual trials) to suggest that these inconsistent results may be due to chance, caused by a small group of patients who respond very well to the treatment. Larger trials or specific analysis methods could help reduce the chance effects and provide more robust data for clinician and patient decision-making.

Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, is characterized by the non-appearance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Clinically, TNBC is marked by its low survival rate, poor therapeutic outcomes, high aggressiveness, and lack of targeted therapies. Over the past few decades, many clinical trials have been ongoing for targeted therapies in TNBC. Although some classes, such as Poly (ADP Ribose) Polymerase (PARP) inhibitors and immunotherapies, have shown positive therapeutic outcomes, however, clinical effects are not much satisfiable. Moreover, the development of drug resistance is the major pattern observed in many targeted monotherapies. The heterogeneity of TNBC might be the cause for limited clinical benefits. Hence,, there is a need for the potential identification of new therapeutic targets to address the above limitations. In this context, some novel targets that can address the above-mentioned concerns are emerging in the era of TNBC therapy, which include Hypoxia Inducible Factor (HIF-1α), Matrix Metalloproteinase 9 (MMP-9), Tumour Necrosis Factor-α (TNF-α), β-Adrenergic Receptor (β-AR), Voltage Gated Sodium Channels (VGSCs), and Cell Cycle Regulators. Currently, we summarize the ongoing clinical trials and discuss the novel therapeutic targets in the management of TNBC.

Breast cancer is one of the most common malignancies in women, with rare subtypes presenting unique clinical challenges. This review provides a comprehensive analysis of rare breast cancers, including both epithelial and non-epithelial subtypes, and explores their epidemiology, pathology, prognosis, and treatment approaches.

A systematic review was conducted focusing on recent advancements in the treatment of rare breast cancer subtypes. Articles were selected based on criteria emphasizing studies from the past five years, with older foundational studies included where necessary. The analysis incorporated molecular profiling, clinical trials, and advancements in targeted and immunotherapies, where possible.

Rare epithelial subtypes, such as tubular, mucinous, and medullary carcinomas, demonstrate distinct clinical and pathological features, with generally favorable prognoses compared to invasive ductal carcinoma (IDC). Non-epithelial cancers, including sarcomas and primary breast lymphomas, require individualized treatment due to aggressive behavior and poor prognosis in certain cases. Recent advancements in targeted therapies (e.g., HER2 inhibitors, PI3K inhibitors, and PARP inhibitors) and immunotherapies (e.g., PD-1 inhibitors) have shown promise in improving outcomes for specific molecularly characterized subtypes.

While the management of common breast cancers has become increasingly sophisticated, rare subtypes continue to pose challenges due to limited research and small patient populations. Advances in molecular profiling and next-generation sequencing are pivotal in identifying actionable mutations and expanding personalized treatment options. Future research should focus on clinical trials and collaborative efforts to refine treatment strategies and improve outcomes for these rare subtypes.

Breast cancer, particularly triple-negative (TNBC), is a leading malignancy with aggressive traits and high metastasis rates. Clinical trial is an important tool for optimizing therapeutic strategies in the evaluation of the safety and efficacy for TNBC. Our bibliometric study of TNBC clinical trials aims to assess therapeutic strategies, identify trends, and explore advancements in treatment. We focus on mapping knowledge development, including key research entities and topics, and analyzing research trends and emerging methods. This analysis intends to inform future research, especially in personalized and precision medicine for TNBC.

We selected publications on clinical trials for the treatment of TNBC from 1997 to 2024 in the Web of Science Core Collection (WoSCC). After an initial screening, we downloaded key data including titles, publication years, authors, countries, institutional affiliations, journals, keywords, and abstracts, and saved them in BibTex format. We then conducted a bibliometric analysis using Bibliometrix in R and VOSviewer to illustrate the prospects, highlights, and trends of TNBC treatment options. Furthermore, to emphasize the hot topics in TNBC treatment strategies, we performed a bibliometric analysis of immunotherapy using the same approach.

1907 publications were included, most of which were from China, Italy, and the United States. The number of annual publications has increased dramatically since 2010. The focus of TNBC clinical trial research has shifted from understanding the biology, such as breast cancer subtyping and genotyping, to novel therapeutic approaches. The major advancement in clinical trials is the switch from late-stage palliative treatment to early preoperative neoadjuvant therapy, as more TNBC cases are discovered at an early stage. Immunotherapy is also highlighted with additional alternatives for advanced or metastasized TNBC, such as targeted inhibitors with unusual mutation rates and antibody drug conjugates (ADC).

This investigation made it apparent how immunotherapy has recently made major advancements in TNBC treatment plans and how ADCs, or targeted therapies, are currently popular for TNBC. By identifying significant papers, comprehending trending topics, and collaborating across multiple disciplines, this study may accelerate research on TNBC therapy options.

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC's aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival.

In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab plus chemotherapy and then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522.

Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel plus carboplatin and then 4 cycles of doxorubicin (or epirubicin) plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23) were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1 of cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with at least 60% completion and at least 80% compliance were assessed using a longitudinal model (no alpha error assigned).

Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab plus chemotherapy [n = 762] vs placebo plus chemotherapy [n = 383]) in LS mean change from baseline to week 21 in QLQ-C30 global health status/quality of life (GHS/QoL), emotional functioning, and physical functioning were -1.04 (95% confidence interval = -3.46 to 1.38), -0.69 (95% CI = -3.13 to 1.75), and -2.85 (95% CI = -5.11 to -0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [n = 539] vs placebo [n = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI = -2.60 to 1.77), -0.60 (95% CI = -2.99 to 1.79), and -1.57 (95% CI = -3.36 to 0.21).

No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo plus chemotherapy in early-stage TNBC.

ClinicalTrials.gov, NCT03036488.

Adding pembrolizumab to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) improves pathologic complete response (pCR) rates and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes is unknown. This study compares 90-day post-surgical complications (PSCs) and time to adjuvant treatment among patients undergoing NAC for TNBC with and without immunotherapy.

Patients treated with NAC alone or with immunotherapy (NAC-I) for stage I-III TNBC between 2018 and 2022 were retrospectively identified at a single academic institution. Kruskal-Wallis rank sum and Fisher's exact tests compared patient sociodemographic and clinical characteristics. Multivariable logistic regression determined odds ratios (OR) predicting PSCs.

Of 54 patients, 29 received NAC alone and 25 received NAC-I. Compared to NAC patients, NAC-I patients had more advanced stage tumors (p = 0.038), and had slightly higher rates of mastectomy with reconstruction (p = 0.193). 72.0% of NAC-I patients experienced a pCR, compared with 44.8% of NAC patients (p = 0.193). There were 10 PSCs (34.5%) in NAC patients compared to 9 PSCs (36.0%) in NAC-I patients (p > 0.99). Regression analysis demonstrated no association of PSCs with NAC-I (OR 0.83, 95% CI 0.19-3.60). Time to adjuvant therapy was shorter for NAC-I patients (28 days vs 36 days, p = 0.013).

Patients with TNBC receiving NAC-I have higher pCR rates and do not appear to have added 90-day PSCs or delays to adjuvant therapy despite trending toward more extensive surgical procedures compared to NAC alone. Larger studies are needed to further evaluate the surgical safety of immunotherapy.

Robust molecular subtyping of triple-negative breast cancer (TNBC) is a prerequisite for the success of precision medicine. Today, there is a clear consensus on three TNBC molecular subtypes: luminal androgen receptor (LAR), basal-like immune-activated (BLIA), and basal-like immune-suppressed (BLIS). However, the debate about the robustness of other subtypes is still open.

An unprecedented number (n = 1942) of TNBC patient data was collected. Microarray- and RNAseq-based cohorts were independently investigated. Unsupervised analyses were conducted using k-means consensus clustering. Clusters of patients were then functionally annotated using different approaches. Prediction of response to chemotherapy and targeted therapies, immune checkpoint blockade, and radiotherapy were also screened for each TNBC subtype.

Four TNBC subtypes were identified in the cohort: LAR (19.36%); mesenchymal stem-like (MSL/MES) (17.35%); BLIA (31.06%); and BLIS (32.23%). Regarding the MSL/MES subtype, we suggest renaming it to mesenchymal-like immune-altered (MLIA) to emphasize its specific histological background and nature of immune response. Treatment response prediction results show, among other things, that despite immune activation, immune checkpoint blockade is probably less or completely ineffective in MLIA, possibly caused by mesenchymal background and/or an enrichment in dysfunctional cytotoxic T lymphocytes. TNBC subtyping results were included in the bc-GenExMiner v5.0 webtool ( http://bcgenex.ico.unicancer.fr ).

The mesenchymal TNBC subtype is characterized by an exhausted and altered immune response, and resistance to immune checkpoint inhibitors. Consensus for molecular classification of TNBC subtyping and prediction of cancer treatment responses helps usher in the era of precision medicine for TNBC patients.

Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer and is associated with high probability of metastasis and poor prognosis. Chemotherapeutics and surgery remain the most common options for TNBC patients; however, chemotherapeutic resistance and relapse of tumors limit the progression free survival and patient life span. This review provides an overview of recent chemotherapeutics that are in clinical trial, and the combination of drugs that are being investigated to overcome the drug resistance and to improve patient survival in different molecular subtypes of TNBCs. Nanotherapeutics have emerged as a promising platform for TNBC treatment and aim to improve the selectivity and solubility of drugs, reduce systemic side effects, and overcome multi-drug resistance. The study explores the role of nanoparticles for TNBC treatment and summarizes the types of nanoparticles that are in clinical trials. Poly(L-lactide-co-glycolide) (PLGA) is the most studied polymeric carrier for drug delivery and for TNBC treatment in research and in clinics. This review is about providing recent advancements in PLGA nanotherapeutic formulations and their application to help treat TNBC. Some background on current chemotherapies and pathway inhibitors is provided so that the readers are aware of what is currently considered for TNBC. Some of the pathway inhibitors may also be of importance for nanotherapeutics development. SIGNIFICANCE STATEMENT: This minireview summarizes the progress on chemotherapeutics and nanoparticle delivery for treatment of TNBC and specifically highlights the lead compounds that are in clinical trials.

Triple-negative breast cancer (TNBC) comprises 15-20% of all breast cancers (BC). Lacking targeted therapy options, TNBC becomes the focal point of clinical investigations aiming not only to identify drugs with enhanced response potential but also to uncover new immunological and/or metabolic pathways conducive to more effective treatments. Currently, neoadjuvant treatment for TNBC relies on standard chemotherapy in conjunction with immunotherapy, given the improved response observed with this drug combination. This review delves into the latest therapeutic updates in TNBC treatment and explores potential advancements shaping the future landscape of this disease in the neoadjuvant setting.

Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes is critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house and public cohorts, we investigated the expression features and immuno-correlations of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in a mouse model. We also developed a novel classifier combining B7-H3 and PD-L1 expression in TNBC. B7-H3 was revealed to be related to immuno-cold features and accumulated collagen in TNBC. In addition, targeting B7-H3 using the monoclonal antibody significantly suppressed mouse TNBC growth, reversed the armored-cold phenotype, and also boosted anti-PD-1 immunotherapy. In addition, patients with B7-H3 high and PD-L1 low expression showed the lowest anti-tumor immune infiltration, the highest collagen level, and the lowest therapeutic responses to multiple therapies, which mostly belong to armored-cold tumors. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression, which leads to a novel approach for the management of TNBC.

Metastatic Triple-negative Breast Cancer (mTNBC) is the most aggressive form of breast cancer, with a greater risk of metastasis and recurrence. Research studies have published in-depth analyses of the advantages and disadvantages of pembrolizumab, and early data from numerous trials suggests that patients with mTNBC have had remarkable outcomes. This meta-analysis compares the data from numerous relevant studies in order to evaluate the safety and efficacy of pembrolizumab monotherapy or combination therapies for mTNBC.

To identify eligible RCTs, a thorough literature search was carried out using electronic databases. CMA software was utilized to perform heterogeneity tests using fixed and random-effects models.

According to our pooled data, the median Progression-free Survival (PFS) was 2.66 months, and the median overall survival (OS) was 12.26 months. Furthermore, by comparing efficacy indicators between PD-L1-positive and PD-L1-negative groups, a correlation was found between the overexpression of PD-L1 with OS, PFS, and ORR. Patients with PD-L1-positive tumors had a higher response rate, with an ORR of 21.1%, compared to the patients with PD-L1-negative tumors. The ORR for first-line immunotherapy was higher than that of ≥second-line immunotherapy. In addition, pembrolizumab plus combination treatment resulted in a pooled incidence of immune- related adverse events of 22.7%.

A modest response to pembrolizumab monotherapy was detected in the mTNBC patients. Furthermore, a better outcome from pembrolizumab treatment may be predicted by PD-L1-- positive status, non-liver/lung metastases, combination therapy, and first-line immunotherapy. Pembrolizumab, in combination with chemotherapy, may be more beneficial for patients whose tumors are PD-L1 positive.

Breast cancer, which exhibits an increasing incidence and high mortality rate among cancers, is predominantly attributed to metastatic malignancies. Brain metastasis, in particular, significantly contributes to the elevated mortality in breast cancer patients. Extracellular vesicles (EVs) are small lipid bilayer vesicles secreted by various cells that contain biomolecules such as nucleic acids and proteins. They deliver these bioactive molecules to recipient cells, thereby regulating signal transduction and protein expression levels. The relationship between breast cancer metastasis and EVs has been extensively investigated. In this review, we focus on the molecular mechanisms by which EVs promote brain metastasis in breast cancer. Additionally, we discuss the potential of EV-associated molecules as therapeutic targets and their relevance as early diagnostic markers for breast cancer brain metastasis.

Cancer-associated adipocytes (CAAs), one of the primary stromal components, exhibit intimate crosstalk and release multiple cell factors mediating local and systemic biological effects. However, the role of CAAs in the regulation of systemic immune responses and their potential value in the clinical treatment of triple-negative breast cancer (TNBC) are not well described. Transcriptome sequencing was performed on CAA and normal adipocyte (NA) tissues isolated from surgically resected samples from TNBC patients and healthy controls. Cytokines, including C-X-C motif chemokine ligand 8 (CXCL8, also known as IL-8), secreted from NAs and CAAs were compared by transcriptome sequencing and enzyme-linked immunosorbent assay (ELISA). Proliferation, migration and invasion assays were employed to analyze the role of CAAs and CAA-derived CXCL8 (macrophage inflammatory protein-2 (MIP2) as a functional surrogate in mice). TNBC syngraft models were established to evaluate the curative effect of targeting CXCL8 in combination with anti-PD-1 therapies. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), polymerase chain reaction (PCR) array, flow cytometry, immunohistochemistry (IHC), and immunofluorescence (IF) were applied to analyze immune cell infiltration and epithelial-mesenchymal transition (EMT) markers. Specifically, we demonstrated that CAAs and CAA-derived CXCL8 played important roles in tumor growth, EMT, metastasis and tumor immunity suppression. CAA-derived CXCL8 remodeled the tumor immune microenvironment not only by suppressing CD4+ T and CD8+ T immune cell infiltration but also by upregulating CD274 expression in TNBC. The combination of targeting the CXCL8 pathway and blocking the PD-1 pathway synergistically increased the tumor immune response and inhibited tumor progression. Thus, our results highlight the molecular mechanisms and translational significance of CAAs in tumor progression and immune ecosystem regulatory effects and provide a better understanding of the potential clinical benefit of targeting CAA-derived CXCL8 in antitumor immunity and as a new therapeutic moiety in TNBC.

Triple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer (TNBC) is largely limited by the complicated tumor microenvironment (TME) and its immunosuppressive state. Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy. Therefore, we designed and synthesized a tellurium (Te)-driven maple leaf manganese carbonate nanotherapeutics (MnCO3@Te) by gas diffusion method, but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer radioimmunotherapy. As expected, with the help of H2O2 in TEM, MnCO3@Te heterostructure with reversible Mn3+/Mn2+ transition could catalyze the intracellular ROS overproduction to amplify radiotherapy. In addition, by virtue of the ability to scavenge H+ in TME by carbonate group, MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes (STING) pathway activation, resulting in remodeling immuno-microenvironment. As a result, MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in vivo. Collectively, these findings indicate that MnCO3@Te as an agonist, successfully overcome radioresistance and awaken immune systems, showing promising potential for solid tumor radioimmunotherapy.

Breast cancer has become the most common malignant tumor worldwide. Triple-negative breast cancer (TNBC) is a type of breast cancer that is negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Compared with other molecular subtypes of breast cancer, TNBC is the most aggressive and highly heterogeneous. TNBC is insensitive to endocrine and anti-HER2 therapy, and chemotherapy is currently the main systemic treatment. With the continuous development of detection techniques and deepening research on TNBC molecular subtypes, drugs targeting immune checkpoints and different targets have emerged, such as atezolizumab, pembrolizumab, poly (ADP-ribose) polymerase (PARP) inhibitors, trophoblast cell-surface antigen 2 (TROP-2), and antibody-drug conjugates. These therapies provide new hope for TNBC treatment. Based on the analysis and classification of TNBC, this article summarizes the immunotherapy, targeted therapy, and new treatment combinations, providing references for the precise treatment of TNBC in the future.

A preliminary study investigating immunotherapy strategies for aggressive triple negative breast cancer (TNBC) revealed an overexpression of genes involved in the release of extracellular vesicles (EVs). Proteins expressed by EVs play a role in reprogramming the tumor microenvironment and impeding effective responses to immunotherapy. Galectin 3 (Gal3), found in the extracellular space of breast cancer cells, downregulates T-cell receptor expression. Gal3 binds to several receptors, including CD45, which is required for T-cell receptor activation. Previously, we reported a novel tumor escape mechanism, whereby TNBC cells suppress immune cells through CD45 intracellular signals. The objective of this study was to determine the potential association of Gal3 with TNBC-secreted EVs induction of immunosuppression via the CD45 signaling pathway. EVs were isolated from MDA-MB-231 cells and the plasma of patients with TNBC. Mass spectrometry revealed the presence of Gal3 binding protein (Gal3BP) in the isolated small EVs, which interacted with TNBC secreted Gal3. Gal3BP and Gal3 form a complex that induces a significant increase in T-regulatory cells in peripheral blood mononuclear cells (PBMCs). This increase correlates with a significant increase in suppressive interleukins 10 and 35. Blocking the CD45 receptor in PBMCs cultured with tumor-derived EVs impeded the immunosuppression exerted by the Gal3BP/Gal3 complex. This led to an increase in IFN-γ and the activation of CD4, CD8 and CD56 effector cells. This study suggests a tumor escape mechanism that may contribute to the development of a different immunotherapy strategy that complements current therapies used for TNBC.

Triple-negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer (BC) for its high aggressiveness, heterogeneity, and hypoxic nature. Based on biological and clinical observations the TNBC related mortality is very high worldwide. Emerging studies have clearly demonstrated that hypoxia regulates the critical metabolic, developmental, and survival pathways in TNBC, which include glycolysis and angiogenesis. Alterations to these pathways accelerate the cancer stem cells (CSCs) enrichment and immune escape, which further lead to tumor invasion, migration, and metastasis. Beside this, hypoxia also manipulates the epigenetic plasticity and DNA damage response (DDR) to syndicate TNBC survival and its progression. Hypoxia fundamentally creates the low oxygen condition responsible for the alteration in Hypoxia-Inducible Factor-1alpha (HIF-1α) signaling within the tumor microenvironment, allowing tumors to survive and making them resistant to various therapies. Therefore, there is an urgent need for society to establish target-based therapies that overcome the resistance and limitations of the current treatment plan for TNBC. In this review article, we have thoroughly discussed the plausible significance of HIF-1α as a target in various therapeutic regimens such as chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapy, adjuvant therapy photodynamic therapy, adoptive cell therapy, combination therapies, antibody drug conjugates and cancer vaccines. Further, we also reviewed here the intrinsic mechanism and existing issues in targeting HIF-1α while improvising the current therapeutic strategies. This review highlights and discusses the future perspectives and the major alternatives to overcome TNBC resistance by targeting hypoxia-induced signaling.

Immune checkpoint inhibitors (ICI) improve clinical outcomes in triple-negative breast cancer (TNBC) patients. However, a subset of patients does not respond to treatment. Biomarkers that show ICI predictive potential in other solid tumors, such as levels of PD-L1 and the tumor mutational burden, among others, show a modest predictive performance in patients with TNBC.

We built machine learning models based on pre-ICI treatment gene expression profiles to construct gene expression classifiers to identify primary TNBC ICI-responder patients. This study involved 188 ICI-naïve and 721 specimens treated with ICI plus chemotherapy, including TNBC tumors, HR+/HER2- breast tumors, and other solid non-breast tumors.

The 37-gene TNBC ICI predictive (TNBC-ICI) classifier performs well in predicting pathological complete response (pCR) to ICI plus chemotherapy on an independent TNBC validation cohort (AUC = 0.86). The TNBC-ICI classifier shows better performance than other molecular signatures, including PD-1 (PDCD1) and PD-L1 (CD274) gene expression (AUC = 0.67). Integrating TNBC-ICI with molecular signatures does not improve the efficiency of the classifier (AUC = 0.75). TNBC-ICI displays a modest accuracy in predicting ICI response in two different cohorts of patients with HR + /HER2- breast cancer (AUC = 0.72 to pembrolizumab and AUC = 0.75 to durvalumab). Evaluation of six cohorts of patients with non-breast solid tumors treated with ICI plus chemotherapy shows overall poor performance (median AUC = 0.67).

TNBC-ICI predicts pCR to ICI plus chemotherapy in patients with primary TNBC. The study provides a guide to implementing the TNBC-ICI classifier in clinical studies. Further validations will consolidate a novel predictive panel to improve the treatment decision-making for patients with TNBC.

Breast cancer is now the most common cancer worldwide, and it is also the main cause of cancer-related death in women. Survival rates for female breast cancer have significantly improved due to early diagnosis and better treatment. Nevertheless, for patients with advanced or metastatic breast cancer, the survival rate is still low, reflecting a need for the development of new therapies. Mechanistic insights into metastatic breast cancer have provided excellent opportunities for developing novel therapeutic strategies. Although high-throughput approaches have identified several therapeutic targets in metastatic disease, some subtypes such as triple-negative breast cancer do not yet have an apparent tumor-specific receptor or pathway to target. Therefore, exploring new druggable targets in metastatic disease is a high clinical priority. In this review, we summarize the emerging intrinsic therapeutic targets for metastatic breast cancer, including cyclin D-dependent kinases CDK4 and CDK6, the PI3K/AKT/mTOR pathway, the insulin/IGF1R pathway, the EGFR/HER family, the JAK/STAT pathway, poly(ADP-ribose) polymerases (PARP), TROP-2, Src kinases, histone modification enzymes, activated growth factor receptors, androgen receptors, breast cancer stem cells, matrix metalloproteinases, and immune checkpoint proteins. We also review the latest development in breast cancer immunotherapy. Drugs that target these molecules/pathways are either already FDA-approved or currently being tested in clinical trials.

Triple negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype, historically managed with chemotherapy regimens predominantly involving anthracyclines and taxanes, yielding unfavorable prognoses. This review endeavors to offer a thorough examination of the present state of treatment strategies for early stage triple negative breast cancer (eTNBC), with a particular emphasis on immunotherapy modalities, combination therapies, predictive biomarkers, and ongoing clinical trials. The principal aim of this review is to meticulously assess the available literature, ascertain significant discoveries, and engage in discussions regarding their potential implications for future research endeavors, clinical applications, and policy formulation.

This review was conducted using PubMed and Google Scholar databases, with the latest update performed in March 2023. The search strategy was designed to ensure a comprehensive analysis of the literature, with a focus on recent advancements.

We critically assess the current eTNBC treatment landscape, covering efficacy and limitations of monotherapy, combination therapies, and predictive biomarkers. We highlight promising results from recent trials, address controversies surrounding chemotherapy, and explore optimal approaches for adjuvant and neoadjuvant therapy (NAT). Insights into personalized treatment strategies, ongoing trials, and future perspectives are provided, advancing our understanding of therapeutic options for eTNBC.

Through a comprehensive analysis of the literature, this review highlights the potential of immunotherapy, particularly in combination with chemotherapy, as a promising approach for treating eTNBC. However, further research is warranted to optimize treatment strategies, refine patient selection criteria, and identify reliable biomarkers for predicting response to immune checkpoint inhibitors (ICIs). The findings of this review hold significant implications for future research, clinical practice, and policy-making, offering valuable insights into the current challenges and advancements in eTNBC treatment. Ultimately, this knowledge can contribute to improved patient outcomes, enhanced quality of life, and the development of more effective therapeutic approaches for eTNBC.

Among the different breast cancer subsets, triple-negative breast cancer (TNBC) has the worst prognosis and limited options for targeted therapies. Immunotherapies are emerging as novel treatment opportunities for TNBC. However, the surging immune response elicited by immunotherapies to eradicate cancer cells can select resistant cancer cells, which may result in immune escape and tumor evolution and progression. Alternatively, maintaining the equilibrium phase of the immune response may be advantageous for keeping a long-term immune response in the presence of a small-size residual tumor. Myeloid-derived suppressor cells (MDSCs) are activated, expanded, and recruited to the tumor microenvironment by tumor-derived signals and can shape a pro-tumorigenic micro-environment by suppressing the innate and adaptive anti-tumor immune responses. We recently proposed a model describing immune-mediated breast cancer dormancy instigated by a vaccine consisting of dormant, immunogenic breast cancer cells derived from the murine 4T1 TNBC-like cell line. Strikingly, these 4T1-derived dormant cells recruited fewer MDSCs compared to aggressive 4T1 cells. Recent experimental studies demonstrated that inactivating MDSCs has a profound impact on reconstituting immune surveillance against the tumor. Here, we developed a deterministic mathematical model for simulating MDSCs depletion from mice bearing aggressive 4T1 tumors resulting in immunomodulation. Our computational simulations indicate that a vaccination strategy with a small number of tumor cells in combination with MDSC depletion can elicit an effective immune response suppressing the growth of a subsequent challenge with aggressive tumor cells, resulting in sustained tumor dormancy. The results predict a novel therapeutic opportunity based on the induction of effective anti-tumor immunity and tumor dormancy.

Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.

An innovative strategy for cancer therapy is to combine the inhibition of cancer cell-intrinsic oncogenic signaling with cancer cell-extrinsic immunological activation of the tumor microenvironment (TME). In general, such approaches will focus on two or more distinct molecular targets in the malignant cells and in cells of the surrounding TME. In contrast, the protease Mucosa-associated lymphoid tissue protein 1 (MALT1) represents a candidate to enable such a dual approach by engaging only a single target. Originally identified and now in clinical trials as a lymphoma drug target based on its role in the survival and proliferation of malignant lymphomas addicted to chronic B cell receptor signaling, MALT1 proteolytic activity has recently gained additional attention through reports describing its tumor-promoting roles in several types of non-hematological solid cancer, such as breast cancer and glioblastoma. Besides cancer cells, regulatory T (Treg) cells in the TME are particularly dependent on MALT1 to sustain their immune-suppressive functions, and MALT1 inhibition can selectively reprogram tumor-infiltrating Treg cells into Foxp3-expressing proinflammatory antitumor effector cells. Thereby, MALT1 inhibition induces local inflammation in the TME and synergizes with anti-PD-1 checkpoint blockade to induce antitumor immunity and facilitate tumor control or rejection. This new concept of boosting tumor immunotherapy in solid cancer by MALT1 precision targeting in the TME has now entered clinical evaluation. The dual effects of MALT1 inhibitors on cancer cells and immune cells therefore offer a unique opportunity for combining precision oncology and immunotherapy to simultaneously impair cancer cell growth and neutralize immunosuppression in the TME. Further, MALT1 targeting may provide a proof of concept that modulation of Treg cell function in the TME represents a feasible strategy to augment the efficacy of cancer immunotherapy. Here, we review the role of MALT1 protease in physiological and oncogenic signaling, summarize the landscape of tumor indications for which MALT1 is emerging as a therapeutic target, and consider strategies to increase the chances for safe and successful use of MALT1 inhibitors in cancer therapy.

Inflammatory breast cancer (IBC) is highly metastatic at the onset of the disease with no IBC-specific treatments, resulting in dismal patient survival. IBC treatment is a clear unmet clinical need. This commentary highlights findings from a recent seminal approach in which pembrolizumab, a checkpoint inhibitor against programmed cell death protein 1 (PD-1), was provided to a triple-negative IBC patient as a neoadjuvant immune therapy combined with anthracycline-taxane-based chemotherapy. We highlight the findings of the case report and offer a perspective on taking a proactive approach to deploy approved immune checkpoint inhibitors. On the basis of our recently published research study, we propose in situ vaccination with direct injection of immunostimulatory agents into the tumor as an option to improve outcomes safely, effectively, and economically for IBC patients.

The programmed death ligand 1 (PD-L1) is a pivotal biomarker of immunotherapy in triple negative breast cancer (TNBC). TP53 is reported as a positive regulatory predictor of immune efficacy. The correlation of p53 expression or mutation and PD-L1 expression is explored. By immunohistochemistry, PD-L1 expression between p53 mutation (missense and nonsense) and wild type; p53 no-expression/loss vs. expression were compared. There was a significant association between p53 mutation, especially missense mutation with higher histological grade, and PD-L1 expression in immune cells (ICs). Both p53 missense mutation and PD-L1 expression may be potential targets for improving immunotherapy response in TNBC.