The use of the residual cancer burden (RCB) for assessing breast cancer after neoadjuvant therapy (NAT) is increasingly common, but the prognostic difference between RCB 0 and RCB I is unclear.

We systematically reviewed literature from PubMed, Embase, Web of Science, and oncology conferences until September 24, 2023. We used fixed- and random-effects models to calculate hazard ratio (HR) with 95% confidence interval (CI) for event-free survival (EFS), overall survival (OS), and distant disease-free survival (DDFS).

Our meta-analysis, encompassing 19 studies with 5894 patients, revealed that in the general population, RCB I had worse EFS (HR = 2.13; 95% CI: 1.75-2.58), OS (HR = 2.08; 95% CI: 1.48-2.93), and DDFS (HR = 2.10; 95% CI: 1.65-2.67) than RCB 0. Consistent with results from the general population, RCB I exhibited poorer EFS, OS, and DDFS in human epidermal growth factor 2-positive (HER2+) subtype and triple-negative breast cancer (TNBC) compared to RCB 0. Conversely, luminal subtype with RCB 0 and RCB I showed similar EFS (HR = 1.04; 95% CI: 0.62-1.72).

RCB I experienced a poorer prognosis compared to RCB 0 in the general population, a pattern also observed in the HER2+ subtype and TNBC. However, no significant prognostic disparity was noted between RCB 0 and RCB I in the luminal subtype.

Triple-negative breast cancer (TNBC) is a highly aggressive disease with limited approved therapeutic options. The rapid growth and genomic instability of TNBC cells makes mitosis a compelling target, and a current mainstay of treatment is paclitaxel (Ptx), a taxane that stabilizes microtubules during mitosis. While initially effective, acquired resistance to Ptx is common, and other antimitotic therapies can be similarly rendered ineffective due to the development of resistance or systemic toxicity underscoring the need for new therapeutic approaches. Interrogating CRISPR essentiality screens in TNBC cell lines, we identified PAFAH1B1 (LIS1) as a potential vulnerability in this disease. PAFAH1B1 regulates mitotic spindle orientation, proliferation, and cell migration during neurodevelopment, yet little is known regarding its function in breast cancer. We found that suppressing PAFAH1B1 expression in TNBC cells reduces cell number, while non-malignant cells remain unaffected. PAFAH1B1 suppression alters cell cycle dynamics, increasing mitotic duration and accumulation of cells in the G2/M phase. The suppression of PAFAH1B1 expression also increases DNA double-strand breaks, indicating a requirement for sustained PAFAH1B1 expression to maintain the genomic integrity of TNBC cells. Lastly, PAFAH1B1 silencing substantially enhances these defects in cells that are taxane-resistant and sensitizes both parental and Ptx-resistant TNBC cells to Ptx. These results indicate that LIS1/PAFAH1B1 may be a novel target for the development of new anti-mitotic agents for treating TNBC, particularly in the context of paclitaxel resistance.

Breast cancer (BC) is among the most common neoplasms globally and is the leading cause of cancer-related mortality in women. Despite significant advancements in prevention, early diagnosis, and treatment strategies made over the past two decades, breast cancer continues to pose a significant global health challenge. One of the major obstacles in the clinical management of breast cancer patients is the high intertumoral and intratumoral heterogeneity that influences disease progression and therapeutic outcomes. The inability of preclinical experimental models to replicate this diversity has hindered the comprehensive understanding of BC pathogenesis and the development of new therapeutic strategies. An ideal experimental model must recapitulate every aspect of human BC to maintain the highest predictive validity. Therefore, a thorough understanding of each model's inherent characteristics and limitations is essential to bridging the gap between basic research and translational medicine. In this context, omics technologies serve as powerful tools for establishing comparisons between experimental models and human tumors, which may help address BC heterogeneity and vulnerabilities. This review examines the BC models currently used in preclinical research, including cell lines, patient-derived organoids (PDOs), organ-on-chip technologies, carcinogen-induced mouse models, genetically engineered mouse models (GEMMs), and xenograft mouse models. We emphasize the advantages and disadvantages of each model and outline the most important applications of omics techniques to aid researchers in selecting the most relevant model to address their specific research questions.

Neoadjuvant chemotherapy (NACT) improves surgical outcomes for breast cancer patients, with pathologic complete response (pCR) correlated with enhanced survival. The role of radiomics, particularly from peritumoral tissue, in predicting pCR remains under investigation.

This retrospective study analyzed radiomic features from pretreatment dynamic contrast-enhanced breast MRI scans of 150 patients undergoing NACT. A proportional approach was used to define peritumoral zones, assessed both with a 10% and 30% extension, allowing more standardized assessments relative to the tumor size. Radiomic features were evaluated alongside clinical and biological data to predict pCR. The association of clinical/biological and radiomic features with pCR to NACT was evaluated using univariate and multivariate analysis, logistic regression, and a random forest model. A clinical/biological model, a radiomic model, and a combined clinical/biological and 4 radiomic models for predicting the response to NACT were constructed. Area under the curve (AUC) and 95% confidence intervals (CIs) were used to assess the performance of the models.

Ninety-five patients (average age 47 years) were finally included. HER2 + , basal-like molecular subtypes, and a high level of Ki67 (≥ 20%) were associated with a higher likelihood of pCR to NACT. The combined clinical-biological-radiomic model, especially with a 10% peritumoral extension, showed improved predictive accuracy (AUC 0.76, CI 0.65-0.85) compared to models using clinical-biological data alone (AUC 0.73, CI 0.63-0.83).

Integrating peritumoral radiomic features with clinical and biological data enhances the prediction of pCR to NACT, underscoring the potential of a multifaceted approach in treatment personalization.

Cancer cells are characterized by their altered energy metabolism. A hallmark of cancer metabolism is aerobic glycolysis, also called the Warburg effect. Hexokinase 2 (HK2), a crucial glycolytic enzyme converting glucose to glucose-6-phosphate, has been identified as a central player in the Warburg effect. Deletion of HK2 decreases cancer cell proliferation in animal models without explicit side effects, suggesting that targeting HK2 is a promising strategy for cancer therapy. In this study, we discovered a correlation between HK2 and the tumor immune response in triple-negative breast cancer. Inhibition of HK2 led to a reduction in G-CSF expression in 4T1 cells and a decrease in the development of myeloid-derived suppressor cells which, in turn, enhanced T cell immunity and prolonged the survival of 4T1 tumor-bearing mice. Furthermore, the HK2 inhibitor 3-BrPA improved the therapeutic efficacy of anti-PD-L1 therapy in 4T1 tumor-bearing mouse models. This study highlights the potential of glycolysis-targeting interventions as a novel treatment strategy, which can be combined with immunotherapy for the treatment of triple-negative breast cancer.

Purpose: Triple-negative breast cancer (TNBC) is a biologically and clinically heterogeneous disease, associated with poorer outcomes when compared with other subtypes of breast cancer. Neoadjuvant chemotherapy (NAC) is often given before surgery, and achieving a pathological complete response (pCR) has been associated with patient outcomes. There is thus strong clinical interest in the ability to accurately predict pCR status using baseline data. Materials and Methods: A cohort of 57 TNBC patients who underwent FDG-PET/CT before NAC was analyzed to develop a machine learning (ML) algorithm predictive of pCR. A total of 241 predictors were collected for each patient: 11 clinical features, 11 histopathological features, 13 genomic features, and 206 PET features, including 195 radiomic features. The optimization criterion was the area under the ROC curve (AUC). Event-free survival (EFS) was estimated using the Kaplan-Meier method. Results: The best ML algorithm reached an AUC of 0.82. The features with the highest weight in the algorithm were a mix of PET (including radiomics), histopathological, genomic, and clinical features, highlighting the importance of truly multimodal analysis. Patients with predicted pCR tended to have a longer EFS than patients with predicted non-pCR, even though this difference was not significant, probably due to the small sample size and few events observed (p = 0.09). Conclusions: This study suggests that ML applied to baseline multimodal data can help predict pCR status after NAC for TNBC patients and may identify correlations with long-term outcomes. Patients predicted as non-pCR may benefit from concomitant treatment with immunotherapy or dose intensification.

To construct a radiomics nomogram derived from multiparametric ultrasound (US) imaging using the SHapley Additive exPlanations (SHAP) method for the accurate identification of residual axillary lymph node metastases post-neoadjuvant chemotherapy (NAC) among patients with triple-negative breast cancer (TNBC).

A total of 405 consecutive patients with pathologically confirmed TNBC between 2016 and 2023 were recruited in the study and were divided into training (n = 284) and validation cohorts (n = 121). Radiomics features capturing detailed tumor characteristics were extracted from pre-NAC gray-scale US images at the locations of US-guided clip placement. The least absolute shrinkage and selection operator and the maximum relevance minimum redundancy algorithm were employed to identify key features and formulate the radiomics signature (RS). A nomogram based on US radiomics was then constructed using multivariable logistic regression analysis. The predictive efficacy of this model was evaluated through receiver operating characteristic curve analysis, calibration assessment, and decision curve analysis. SHAP summary plots were used to visualize the distribution of SHAP values across all features.

The nomogram integrates clinical and US characteristics with RS, yielded optimal AUC of 0.922 (95% CI, 0.890-0.954) in the training cohort, 0.904 (95% CI, 0.853-0.955) in the validation cohort. The calibration and decision curves confirmed favorable calibration and clinical value of the nomogram. SHAP provided further insight into the contributions of each feature to the model's outcomes.

The combined multiparametric US based radiomics nomogram plays a potential role in predicting residual axillary lymph node metastases after NAC in TNBCs.

Molecular subtyping of breast carcinoma and Ki-67 index has gained prominence in the recent past, as conventional factors such as surgical margins, tumor size, grade and lymph node involvement, are not sufficient to assess prognosis and make better therapeutic decisions. These subtypes include Luminal A, Luminal B, Triple Negative breast cancer (TNBC), and HER2-enriched subtypes. This study aimed to analyze the molecular subtypes and Ki-67 index in prognosis of breast carcinoma.

This retrospective study was conducted in the department of Pathology in a tertiary care center over a period of 3 years. All invasive breast carcinomas (IDC) which were molecularly subtyped and Ki-67 indexed were included in the study. Statistical analysis was done using SPSS software.

Out of 253 cases, 231 cases (91.3%) were IDC-NST and 22 cases (8.7%) were special types. Metaplastic and papillary tumors were associated with higher grade and high Ki-67 value. TNBC (35.2%) showing a majority of high-grade tumors, was the most prevalent subtype followed by Luminal A (32%) showing low grade, unlike other studies which showed luminal A to be most common subtype. The rare PR positive subtype was also observed in our study.

TNBC and HER 2-positive subtypes exhibited bad prognosis with higher histological grade, high Ki-67 index and higher age at presentation whereas Luminal A subtype, with lower grade and low Ki-67 index showed better prognosis. Thus, this vast array of predictive and prognostic information obtained by molecular subtyping will help clinicians in not only distinguishing between low-risk and high-risk subtypes but also in customization of the treatment and follow-up of the patients.

Tumors formed by the unchecked growth of breast cells are known as breast cancer. The second most frequent cancer in the world is breast cancer. It is the most common cancer among females. In 2022, 2,296,840 women were diagnosed with breast cancer. The therapy of breast cancer is evolving through the development of Poly (ADP-ribose) polymerase (PARP) inhibitors, which are offering people with specific genetic profiles new hope as research into the disease continues. It focuses on patients with BRCA1 and BRCA2 mutations. This review summarizes the most recent research on the mechanisms of action of PARP inhibitors and their implications for breast cancer therapy. We review how therapeutic applications are developing and highlight recent studies showing the effectiveness of these medicines whether used alone or in combination. Furthermore, the significance of customized therapy is highlighted in enhancing patient outcomes as we address the function of genetic testing in identifying candidates for PARP inhibition. Recommendations for future research areas to maximize the therapeutic potential of PARP inhibitors are also included, along with challenges and limits in their clinical usage. The objective of this review is to improve our comprehension of the complex interaction between breast cancer biology and PARP inhibition. This knowledge will help to guide screening approaches, improve clinical practice, and support preventive initiatives for people at risk.

The multicohort, open-label, phase 1b KEYNOTE-173 study was conducted to investigate pembrolizumab plus chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC). This exploratory analysis evaluated features of the tumor microenvironment that might be predictive of response.

Cell fractions from 20 paired samples collected at baseline and after one cycle of neoadjuvant pembrolizumab prior to chemotherapy initiation were analyzed by spatial localization (tumor compartment, stromal compartment, or sum of tumor and stromal compartments [total tumor]) using three six-plex immunohistochemistry panels with T-cell, myeloid cell, and natural killer cell components. Area under the receiver operating characteristic curve (AUROC) was used to assess associations between immune subsets and gene expression signatures (T-cell-inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures using RNA sequencing) and pathologic complete response (pCR).

At baseline, six immune subsets quantitated within the tumor compartment showed AUROC with 95% CIs not crossing 0.5, including CD11c+ cells (macrophage and dendritic cell [DC]: AUROC, 0.85; 95% confidence interval [CI] 0.63-1.00), CD11c+/MHCII+/CD163-/CD68- cells (DC: 0.76; 95% CI, 0.53-0.99), CD11c+/MHCII-/CD163-/CD68- cells (nonactivated/immature DC: 0.80; 95% CI 0.54-1.00), and CD11c+/CD163+ cells (M2 macrophage: 0.77; 95% CI 0.55-0.99). Other associations with pCR included baseline CD11c+/MHCII-/CD163-/CD68- (nonactivated/immature DC) within the total tumor (AUROC, 0.76; 95% CI 0.51-1.00) and the baseline CD11c/CD3 ratio within the tumor compartment (0.75; 95% CI 0.52-0.98). Changes in immune subsets following one cycle of pembrolizumab were not strongly associated with pCR. Although T-cell associations were relatively weak, specific CD8 subsets trended toward association. The AUROC for discriminating pCR based on TcellinfGEP was 0.55 (95% CI 0.25-0.85); when detrended by TcellinfGEP, AUROC varied for the non-TcellinfGEP signatures. TcellinfGEP expression trended higher in responders than in nonresponders when evaluating pCR.

Myeloid cell populations within the tumor compartment at baseline and TcellinfGEP show a promising trend toward an association with pCR in a small subgroup of patients with early-stage TNBC treated with neoadjuvant pembrolizumab plus chemotherapy.

ClinicalTrials.gov, NCT02622074; registration date, December 2, 2015.

Triple-negative breast cancer (TNBC) is known for its high malignancy, limited clinical treatment options, and poor chemotherapy outcomes. Although some advancements have been made using nanotechnology-based chemotherapy for TNBC treatment, the controlled and on-demand release of chemotherapeutic drugs at the tumor site remains a challenge.

We manufactured DOX/BaTiO3@cRGD-Lip (DBRL) nanoparticles as an ultrasound (US)-controlled release platform targeting the delivery of Doxorubicin (DOX) for TNBC treatment. The nanoparticles incorporate DSPE-Se-Se-PEG-NH2 as the liposomal membrane for ROS responsiveness, cRGD peptide for TNBC cell selectivity, and polyethylene glycol for minimized phagocytic cell absorption.

The DBRL+US group achieved significant tumor inhibition (70.27% compared to control group, p < 0.001), while maintaining excellent biocompatibility with over 90% cell viability in normal cells. The selective cytotoxicity was evidenced by a 55.70% cell death rate in 4T1 cancer cells under US activation. DBRL showed enhanced tumor accumulation with peak fluorescence intensity of (1.01 ± 0.33)×109 at 12 hours post-injection.

This targeted nanocomposite material paves a new prospect for future precise piezoelectric catalytic therapy for the treatment of TNBC.

Triple-Negative Breast Cancer (TNBC) is an aggressive breast cancer subtype, in which targeting the Trophoblast cell-surface antigen-2 (Trop-2), using antibody-drug conjugates (ADC), results in significant clinical improvement. However, clinicopathological correlations with Trop-2 protein expression levels remain limited in TNBC patients.

Here we assessed by immunohistochemistry (IHC) using the mouse monoclonal anti-Trop-2 antibody (Enzo, Cat. ENZ-ABS380) cell membrane Trop-2 expression levels and classified them in 3 H-Score classes, low (< 100), moderate (100-200), and strong (> 200). We also evaluated potential associations with clinicopathological variables including basal-like and molecular apocrine phenotypes, immune infiltrate characteristics, PTEN and PIK3CA alterations in a large retrospective series of 228 nonmetastatic TNBC patients.

Trop-2 expression was evaluated as low, moderate and strong in 12.3%, 28.9%, and 58.8% of the cases respectively. Only 3 tumors showed no Trop-2 expression. Interestingly, Trop-2 expression was not associated with classical breast cancer clinicopathological variables, HER2 levels or molecular subtype, neither did we observe an association with relapse-free survival. Only a marginal association with pT1 tumors was observed, which tended to express increased levels of Trop-2 protein. In order to determine possible fluctuations of Trop-2 protein expression levels during the course of the disease, we studied a second independent cohort of 18 TNBC comprised of serial tissue samples (diagnostic biopsies, surgical resection specimens and corresponding patients-derived xenografts (PDX)). Trop-2 levels remained globally stable between cognate tumor samples with only one exception corresponding to a Trop-2-negative tumor giving rise to a Trop-2-positive PDX.

As Trop-2 expression appears nearly constant and independent of classical TNBC variables and outcome, association of anti-Trop-2 therapies with other targeted therapies can be evaluated without reducing the population in specific TNBC subgroups.

We identified an mTORC2/Rictor-directed RNAi nanomedicine that cooperates with chemotherapy to enhance in vivo tumor cell killing in PI3K-active TNBCs.

Breast cancer is a widespread type of cancer found across the world. The use of chemotherapy in breast cancer treatment may result in side effects and the emergence of drug resistance. Hence, seeking new and efficient therapies that reduce adverse reactions is imperative. Recently, combination therapy has emerged as a fresh and innovative strategy in contrast to conventional treatment methods. Photodynamic therapy (PDT) serves as a highly effective and minimally invasive technique for addressing breast cancer, providing the option to be utilized either concurrently or in conjunction with other therapeutic approaches. Resveratrol (RES) is a polyphenol found in several food sources. Research has demonstrated that RES can inhibit cell proliferation and metastasis and trigger apoptosis in tumor cells. This research aimed to assess the impact of combining RES and photodynamic therapy on MDA-MB-231 breast cancer cells.

MDA-MB-231 cells were grown in culture and subsequently exposed to different methylene blue (MB) doses while subjected to laser irradiation (PDT). Following this treatment, the cells were exposed to different RES concentrations. Cell viability was assessed utilizing the MTT assay. Light and fluorescence microscopy (AO/EB staining) were employed to observe cell morphological alterations following exposure to RES and MB-PDT. Additionally, flow cytometry was utilized to investigate cell cycle progression and apoptosis induction.

The findings indicated that the co-administration of MB-PDT and RES resulted in increased cytotoxic effects on MDA-MB-231 breast cancer cells compared to the individual application of either treatment.

The results of this study suggest that MB-PDT can reduce the dose and time of RES treatment and, therefore, can be indicated as a new approach for treating breast cancer cells.

Triple-negative breast cancer is a clinically aggressive malignancy with poorer outcomes versus other subtypes of breast cancer. Numerous reports have discussed the use of epigallocatechin-3-gallate (EGCG) against various types of cancer. However, the effectiveness of EGCG is limited by its high oxidation and instability. The Notch pathway is critical in breast cancer development and prognosis, and its inhibition is a potential treatment strategy.

In this study, we investigated the effects of prodelphinidin B-2,3,3''-O-gallate (named PB2,3,3''/OG or compound 2) via chemical oxidation of EGCG on cell viability and the Notch1 signaling pathway in breast cancer cells. We found that compound 2 showed significant cytotoxicity against triple-negative breast cancer cells, with the half maximal inhibitory concentration (IC50) values ranging 20-50 µM. In MDA-MB453 cells, compound 2 inhibited proliferation, clone formation, and the expression of proteins involved in the Notch1 signaling pathway. Furthermore, compound 2 induced cell cycle arrest and apoptosis. Consistent with the results of in-vitro experiments, treatment with compound 2 significantly reduced tumor growth. Mechanistically, compound 2 directly bound to Notch1 with high binding affinity (dissociation constant: KD=4.616 × 10- 6 M).

Our finding suggested that compound 2 may be a promising agent for the development of novel anti-cancer therapy options.

As a systematic review, this study addresses a gap in the literature by evaluating both the short-term and long-term outcomes of breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The purpose of the current study was to evaluate NAC's impact on breast cancer patients' surgical outcomes. We performed a comprehensive search of international databases, including PubMed, Scopus, Embase, and Science Direct, covering studies from 2000 to 2023, using carefully selected keywords. Our search strategy aimed to capture a wide variety of relevant studies. To ensure a structured and unbiased selection, we followed PRISMA guidelines throughout the process. We concentrated on identifying studies that reported on short-term outcomes, like surgical complications (e.g., operation time, blood loss), as well as long-term outcomes, including overall survival, tumor size reduction, metastasis rates, breast conservation surgery, and recurrence rates. The findings highlighted the benefits of NAC in terms of lower recurrence and metastasis rates. The results also emphasized the significance of considering tumor characteristics and nodal involvement for prognostication in this patient population. The findings of this study will contribute to a better understanding of the impact of NAC on surgical outcomes in breast cancer patients, providing valuable insights for treatment planning and optimizing patient care.

Triple-negative breast cancer (TNBC) is difficult to treat and has a low five-year survival rate. In South Africa, a large percentage of the population still relies on traditional plant-based medicine. To establish the utility of both methanol and water-soluble extracts from the leaves of Tulbaghia violacea, cytotoxicity assays were carried out to establish the IC50 values against a TNBC cell line. Cell cycle and apoptosis assays were carried out using the extracts. To identify the molecular compounds, present in water-soluble leaf extracts, NMR spectroscopy was performed. Compounds of interest were then used in computational docking studies with the anti-apoptotic protein COX-2. The IC50 values for the water- and methanol-soluble extracts were determined to be 400 and 820 µg/mL, respectively. The water-soluble extract induced apoptosis in the TNBC cell line to a greater extent than in the normal cell line. RNAseq indicated that there was an increase in the transcription of pro-apoptotic genes in the TNBC cell line. The crude extract also caused these cells to stall in the S phase. Of the 61 compounds identified in this extract, five demonstrated a high binding affinity for COX-2. Based on these findings, the compounds within the extract show significant potential for further investigation as candidates for the development of cancer therapeutics, particularly for TNBC.

Identification of biomarkers to optimize treatment strategies for early-stage triple-negative breast cancer (TNBC) is crucial. This study presents the development and validation of TNBC-DX, a novel test aimed at predicting both short- and long-term outcomes in early-stage TNBC. The objective of this study was to evaluate the association between TNBC-DX and efficacy outcomes [pathologic complete response (pCR), distant disease-free survival (DDFS) or event-free survival (EFS), and overall survival (OS)] in the validation cohorts.

Information from 1259 patients with early-stage TNBC (SCAN-B, CALGB-40603, and BrighTNess) was used to establish the TNBC-DX scores. Independent validation of TNBC-DX was carried out in three studies: (i) WSG-ADAPT-TN; (ii) MMJ-CAR-2014-01; and (iii) NeoPACT, including 527 patients with stage I-III TNBC undergoing neoadjuvant chemotherapy. In WSG-ADAPT-TN, patients were randomized to receive nab-paclitaxel plus gemcitabine or carboplatin. In MMJ-CAR-2014-01, patients received carboplatin plus docetaxel. In NeoPACT, patients received carboplatin plus docetaxel and pembrolizumab.

TNBC-DX test was created incorporating the 10-gene Core Immune Gene module, the 4-gene tumor cell proliferation signature, tumor size, and nodal staging. In the two independent validation cohorts without pembrolizumab, the TNBC-DX pCR score was significantly associated with pCR after adjustment for clinicopathological variables and treatment regimen [odds ratio per 10-unit increment 1.34, 95% confidence interval (CI) 1.20-1.52, P < 0.001]. pCR rates for the TNBC-DX pCR-high, pCR-medium, and pCR-low categories were 56.3%, 53.6%, and 22.5% respectively (odds ratio for pCR-high versus pCR-low 3.48, 95% CI 1.72-7.15, P < 0.001). In addition, the TNBC-DX risk score was significantly associated with DDFS [hazard ratio (HR) high-risk versus low-risk 0.24, 95% CI 0.15-0.41, P < 0.001] and OS (HR 0.19, 95% CI 0.11-0.35, P < 0.001). In the validation cohort with pembrolizumab, the TNBC-DX scores were significantly associated with pCR, EFS, and OS.

TNBC-DX predicts pCR to neoadjuvant taxane-carboplatin in stage I-III TNBC and helps to forecast the patient's long-term survival in the absence of neoadjuvant anthracycline-cyclophosphamide, and independent of pembrolizumab use.

Nowadays, chemotherapy and immunotherapy remain the major treatment strategies for Triple-Negative Breast Cancer (TNBC). Identifying biomarkers to pre-select and subclassify TNBC patients with distinct chemotherapy responses is essential. In the current study, we performed an unbiased Reverse Phase Protein Array (RPPA) on TNBC cells treated with chemotherapy compounds and found a leading significant increase of phosphor-AURKA/B/C, AURKA, AURKB, and PLK1, which fall into the mitotic kinase group. The increase of AURKA and AURKB protein was majorly due to a post-transcription level regulation, and Paclitaxel treatment induced Aurora Kinases protein phosphorylation on AURKA(T288)/AURKB(T232) sites and their protein stability. In our UAB TNBC cohort, the expression of AURKA and AURKB was significantly higher in TNBC tumors compared to normal adjacent tissues, and AURKB was found to be highly expressed in African American TNBC patients compared to European Americans. Moreover, Aurora Kinases overexpression in TNBC cells renders resistance to Paclitaxel treatment and attenuates the apoptosis effect triggered by chemotherapy treatment, suggesting Aurora Kinases could mediate the chemo-resistance in TNBC. Hence, a combination of Aurora kinase inhibitors or PROTAC degrader and taxane-type chemotherapy significantly enhanced the chemotherapy effect. In summary, we revealed that Aurora Kinases upregulation after treatment with chemotherapy could confer chemotherapy resistance to TNBC cells, and AURKB could serve as preselection markers for stratifying patients' response to neoadjuvant chemotherapy.

Breast cancer will overtake all other cancers in terms of diagnoses in 2024. Breast cancer counts highest among women in terms of cancer incidence and death rates. Innovative treatment approaches are desperately needed because treatment resistance brought on by current clinical drugs impedes therapeutic efficacy. The T cell-based immunotherapy known as chimeric antigen receptor (CAR) T cell treatment, which uses the patient's immune cells to fight cancer, has demonstrated remarkable efficacy in treating hematologic malignancies; nevertheless, the treatment effects in solid tumors, like breast cancer, have not lived up to expectations. We discuss in detail the role of tumor-associated antigens in breast cancer, current clinical trials, barriers to the intended therapeutic effects of CAR-T cell therapy, and potential ways to increase treatment efficacy. Finally, our review aims to stimulate readers' curiosity by summarizing the most recent advancements in CAR-T cell therapy for breast cancer.

Triple-negative breast cancer (TNBC) remains a challenging subtype due to its aggressive nature and limited treatment options. This study investigated the potential synergistic effects of Korean mistletoe lectin (Viscum album L. var. coloratum agglutinin, VCA) and cisplatin on MDA-MB-231 TNBC cells using both 2D and 3D culture models. In 2D cultures, the combination of VCA and cisplatin synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase. Also, the combination treatment significantly reduced cell migration and invasion. Gene expression analysis showed significant changes in specific genes related to apoptosis (Bax, Bcl-2), metastasis (MMP-2, MMP-9), and EMT (E-cadherin, N-cadherin). Three-dimensional spheroid models corroborated these findings, demonstrating enhanced cytotoxicity and reduced invasion with the combination treatment. Significantly, the 3D models exhibited differential drug sensitivity compared to 2D cultures, emphasizing the importance of utilizing physiologically relevant models in preclinical studies. The combination treatment also reduced the expression of angiogenesis-related factors VEGF-A and HIF-1α. This comprehensive study provides substantial evidence for the potential of VCA and cisplatin combination therapy in TNBC treatment and underscores the significance of integrating 2D and 3D models in preclinical cancer research.

Optimizations are expected in the development of immunotherapy for the treatment of Triple-negative breast cancer (TNBC). We studied the expression of galectin-9 (Gal-9) after irradiation and assessed the differential impacts of its targeting with or without radiotherapy. Tumor resections from TNBC patients who received neoadjuvant radiotherapy revealed higher levels of Gal-9 in comparison to their baseline level, only in non-responder patients. Gal-9 expression was also found to be increased in TNBC tumor biopsies and cell lines after irradiation. We investigated the therapeutic advantage of targeting Gal-9 after radiotherapy in mice. Irradiated 4T1 cells or control non-irradiated 4T1 cells were injected into BALB/c mice. Anti-Gal-9 antibody treatment decreased tumor progression only in mice injected with irradiated 4T1 cells. This proof-of-concept study demonstrates that Gal-9 could be considered as a dynamic biomarker after radiotherapy for TNBC and suggests that Gal-9 induced-overexpression could represent an opportunity to develop new therapeutic strategies for TNBC patients.

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.

Estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers have different genomic architecture and show large-scale gene expression differences consistent with different cellular origins, which is reflected in the luminal (i.e., ER+) versus basal-like (i.e., ER-) molecular class nomenclature. These two major molecular subtypes have distinct epidemiological risk factors and different clinical behaviors. Luminal cancers can be subdivided further based on proliferative activity and ER signaling. Those with a high expression of proliferation-related genes and a low expression of ER-associated genes, called luminal B, have a high risk of early recurrence (i.e., within 5 years), derive significant benefit from adjuvant chemotherapy, and may benefit from adding immunotherapy to chemotherapy. This subset of luminal cancers is identified as the genomic high-risk ER+ cancers by the MammaPrint, Oncotype DX Recurrence Score, EndoPredict, Prosigna, and several other molecular prognostic assays. Luminal A cancers are characterized by low proliferation and high ER-related gene expression. They tend to have excellent prognosis with adjuvant endocrine therapy. Adjuvant chemotherapy may not improve their outcome further. These cancers correspond to the genomic low-risk categories. However, these cancers remain at risk for distant recurrence for extended periods of time, and over 50% of distant recurrences occur after 5 years. Basal-like cancers are uniformly highly proliferative and tend to recur within 3-5 years of diagnosis. In the absence of therapy, basal-like breast cancers have the worst survival, but these also include many highly chemotherapy-sensitive cancers. Basal-like cancers are often treated with preoperative chemotherapy combined with an immune checkpoint inhibitor which results in 60-65% pathologic complete response rates that herald excellent long-term survival. Patients with residual cancer after neoadjuvant therapy can receive additional postoperative chemotherapy that improves their survival. Currently, there is no clinically actionable molecular subclassification for basal-like cancers, although cancers with high androgen receptor (AR)-related gene expression and those with high levels of immune infiltration have better prognosis, but currently their treatment is not different from basal-like cancers in general. A clinically important, minor subset of breast cancers are characterized by frequent HER2 gene amplification and high expression of a few dozen genes, many residing on the HER2 amplicon. This is an important subset because of the highly effective HER2 targeted therapies which are synergistic with endocrine therapy and chemotherapy. The clinical behavior of HER2-enriched cancers is dominated by the underlying ER subtype. ER+/HER2-enriched cancers tend to have more indolent course and lesser chemotherapy sensitivity than their ER counterparts.

It remains unknown whether the tumor stage at initial diagnosis and adjuvant treatments had any impacts on the long-term survival outcomes of patients with triple-negative breast cancer (TNBC) achieving pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT).

Clinical stage II-III patients with TNBC who achieved pCR after NACT were identified from the Surveillance, Epidemiology, and End Results (SEER) program (SEER cohort) and the National Clinical Research Center for Cancer (Tianjin) in China (TMUCIH cohort). Survival analyses were conducted based on tumor stages and the types of adjuvant treatment received by the patients. The outcomes of interest were overall survival (OS) and breast cancer-specific survival (BCSS).

The TMUCIH cohort comprised 178 patients with a median follow-up of 55.5 months. Two and 3 patients experienced BCSS and OS events, respectively. The SEER cohort included 1218 patients with a median follow-up of 65.5 months, where 53 and 78 patients experienced BCSS and OS events, respectively. Patients diagnosed with stage III disease had significantly higher hazards of death compared to stage II disease (OS: hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.84-6.07; P < .001; BCSS: HR, 2.86; 95% CI, 1.38-5.92; P < .001). Adjuvant systemic and radiation therapy did not confer additional benefits to OS and BCSS.

Tumor stage at initial diagnosis remains an independent predictor of long-term survival outcomes in patients with TNBC achieving pCR after NACT. Postoperative adjuvant chemotherapy and radiation therapy do not appear to provide additional benefit to their long-term prognosis.

In triple-negative breast cancer (TNBC) patients receiving adjuvant capecitabine, the impact of HER2 expression on survival outcomes is unclear.

 Between June 2017 and December 2023, 112 patients with TNBC who received adjuvant capecitabine due to residual masses after neoadjuvant chemotherapy (NACT) in three hospitals were identified. HER2 is analyzed through immunohistochemistry (IHC) and/or in situ hybridization in the core biopsy and/or post-surgical histopathologies. Relapse-free survival (RFS) and overall survival (OS), according to HER2 expression (0, 1 + , 2 +) status, were calculated (Kaplan-Meier method).

 Seventy-eight (69.6%) patients had HER2 zero, 20 (17.9%) patients had HER2 + 1, and 14 (12.5%) patients had HER2 + 2/ISH- BC. The 5-year OS was 62.6%, and the 5-year RFS was 55.8%. HER2 2 + expression was associated with worse OS (27.5 vs. 84.5 months; HR 4.82, 95% CI 2.15-10.80, p < 0.001) and worse RFS (11.90 months vs. not reached; HR 4.30, 95% CI 2.06-8.99, p < 0.001) compared with HER2 0/1 + expression. The 5-year OS rates were 32.7% and 72.1%, and the 5-year RFS rates were 30.6% and 64.7% in the HER2 2 + and HER2 0/1 + groups, respectively. No statistically significant differences were detected in clinicopathologic features or pathologic responses to NACT according to the HER2 expression level.

 Despite the use of the adjuvant capecitabine in HER2 2 + TNBC patients, these poor results will pave the way for further investigations of anti-HER2 therapeutic agents in adjuvant treatment.

The combination of immunotherapy and chemotherapy has demonstrated an enhancement in progression-free survival (PFS) for individuals with advanced and metastatic triple-negative breast cancer (TNBC) when compared to the use of chemotherapy alone. Nevertheless, the extent to which different subgroups of metastatic TNBC patients experience this benefit remains uncertain.

Our objective was to conduct subgroup analyses to more precisely identify the factors influencing these outcomes.

The PubMed database was searched until Dec 2023 for studies that compared PD-1 checkpoint inhibitors plus chemotherapy (ICT) with chemotherapy (CT) alone. The primary outcome of interest was progression-free survival (PFS). Review Manager (RevMan) version 5.4. was used for the data analysis.

Four randomized controlled trials (RCTs) comprising 2468 advanced and metastatic TNBC were included in this systematic review and meta-analysis. PFS surge with combined therapy was observed in White (HR 0.80 [0.70, 0.91], p = 0.0007) and Asian ethnicities (HR 0.73 [0.58, 0.93], p = 0.01) but not in Blacks (HR 0.72 [0.42, 1.24], p = 0.24). Overall, patients with distant metastasis demonstrated to derive the PFS benefit from additional immunotherapy (HR 0.87 [0.77, 0.99], p = 0.03); however, metastasis to individual distant site was associated with failure to achieve any treatment difference (Bone: HR 0.79 [0.41, 1.52], p = 0.49; Lung: HR 0.85 [0.70, 1.04], p = 0.11; Liver: HR 0.80 [0.64, 1.01], p = 0.06). While number of metastases > 3 also showed to impact the PFS advantage (HR 0.89 [0.69, 1.16], p = 0.39). While patients, regardless of prior chemotherapy, experienced a notable enhancement in PFS with ICT (Overall: HR 0.79 [0.71, 0.88], p < 0.0001; Yes: HR 0.87 [0.76, 1.00], p = 0.05; No: HR 0.67 [0.56, 0.80], p < 0.00001), those previously exposed to chemotherapy exhibited a significantly smaller PFS advantage compared to those without prior chemotherapy, as evidenced by a significant subgroup difference (Test for subgroup difference: P = 0.02, I2 = 82.2%). Patients lacking PD-L1 expression also failed to achieve any additional benefit from immunotherapy (PD-L1-: HR 0.95 [0.81, 1.12]; p = 0.54; PD-L1+: HR 0.73 [0.64, 0.85], p < 0.0001). Age, ECOG status, and presentation with de novo metastasis/recurrent shown no impact on IT-associated PFS advantage.

Patient- and treatment- related factors such as ethnicity, distant metastases, number of metastases (> 3), previous exposure to chemotherapy and PD-L1 expression, seem to influence or restrict the advantage in progression-free survival associated with the addition of immunotherapy to chemotherapy, as opposed to chemotherapy alone, in patients with advanced and metastatic TNBC. Larger studies are warranted to validate these outcomes.

Paclitaxel is a widely used chemotherapeutic agent for the treatment of breast cancer (BC), including as a front-line treatment for triple-negative breast cancer (TNBC) patients. However, resistance to paclitaxel remains one of the major causes of death associated with treatment failure. Multiple studies have demonstrated that miRNAs play a role in paclitaxel resistance and are associated with both disease progression and metastasis. In the present study, we used a miRNA-encoding lentiviral library as a gain-of-function screen for paclitaxel resistance in the MDA-MB-231 TNBC cell line. We identified that miR-181b, miR-29a, miR-30c, miR-196 and miR-1295 conferred a resistant phenotype to cells. The expression of miR-29a also induced resistance to eribulin and vinorelbine, while miR-181b and miR-30c induced resistance to vinorelbine. We measured the levels of these miRNAs in breast cancer patients and observed higher levels of miR-29a in treatment-refractory patients. Taken together, we suggest that miR-29a and miR-181b may be good candidates for miRNA inhibition to overcome resistance to chemotherapy.

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy.

Triple-negative breast cancer (TNBC) is a heterogeneous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted toward tumors carrying a specific genomic, transcriptomic, or protein biomarker, it is poorly understood how these biomarkers are correlated.

To better understand the molecular features of TNBC and their correlation with one another, we performed multimodal profiling on a cohort of 95 TNBC. Our approach involved quantifying tumor-infiltrating lymphocytes through hematoxylin and eosin staining, assessing the abundance of retinoblastoma, androgen receptor, and PDL1 proteins through IHC, and carrying out transcriptomic profiling using the NanoString BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival.

Levels of RB1 mRNA and RB proteins are better correlated with markers of retinoblastoma functionality than RB1 mutational status. Luminal androgen receptor tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PDL1-positive by the presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared with HER2-zero. The majority of TNBC were classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival.

Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.