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This paper presents a prototype of a portable and modular electrical impedance tomography (EIT) system for breast tumor detection. The proposed system uses MATLAB to generate three-dimensional representations of breast tissue. The modular architecture of the system allows for flexible customization and scalability. It consists of several interconnected modules. Each module can be easily replaced or upgraded, facilitating system maintenance and future enhancements. Testing of the prototype has shown promising results in preliminary screening based on experimental studies. Agar models were used for the experimental stage of this project. The 3D representations provide clinicians with valuable information for accurate diagnosis and treatment planning. Further research and refinement of the system is warranted to validate its performance in future clinical trials. [ABSTRACT FROM AUTHOR]

Breast carcinoma is the most common cancer in women. Nineteen different subtypes of breast carcinomas are recognized in the current WHO classification of breast tumors. Except for these subtypes, there are a number of carcinomas with special morphologic and immunohistochemical features that are not included in the 5th WHO classification, while others are considered special morphologic patterns of invasive breast carcinoma of no special type. In this manuscript, we systematically review the literature on four different subtypes of invasive breast carcinoma, namely lymphoepithelioma-like breast carcinoma, breast carcinoma with osteoclast-like giant cells, signet-ring breast carcinoma, and metaplastic breast carcinoma with melanocytic differentiation. We describe their clinicopathological characteristics, focusing on the differential diagnosis, treatment, and prognosis. [ABSTRACT FROM AUTHOR]

We have developed an imaging biomarker for quantitatively monitoring the response to clinical treatment in cancer patients. Similar to other diffusion-weighted imaging DWI techniques, our method allows for the monitoring of breast cancer progression based on the diffusion coefficient values in the affected area. Our technique has the advantage of using images from mammograms and mesoscopic multiparticle collision MPC simulation, making it more affordable and easier to implement compared to other DWI techniques, such as diffusion-weighted MRI. To create our simulation, we start with the region of interest from a mammogram where the lesion is located and build a flat simulation box with impenetrable cylindrical obstacles of varying diameters to represent the tissue's heterogeneity. The volume of each obstacle is based on the intensity of the mammogram pixels, and the diffusion coefficient is calculated by simulating the behavior of a point particle fluid inside the box using MPC. We tested our technique on two mammograms of a male patient with a moderately differentiated breast ductal carcinoma lesion, taken before and after the first cycle of four chemotherapy sessions. As seen in other DWI studies, our technique demonstrated significant changes in the fluid concentration map of the tumor lesion, and the relative values of the diffusion coefficient showed a clear difference before and after chemotherapy. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis for TNBC patients. We performed a genome-wide analysis of DNA methylation at CpG islands on a collection of one hundred ten breast carcinoma samples and six normal breast tissue samples using reduced representation bisulfite sequencing with the XmaI restriction enzyme (XmaI-RRBS) and identified a subset of TNBC samples with significant hypomethylation at the LTB4R/LTB4R2 genes' CpG islands, including CpG dinucleotides covered with cg12853742 and cg21886367 HumanMethylation 450K microarray probes. Abnormal DNA hypomethylation of this region in TNBC compared to normal samples was confirmed by bisulfite Sanger sequencing. Gene expression generally anticorrelates with promoter methylation, and thus, the promoter hypomethylation detected and confirmed in our study might be revealed as an indirect marker of high LTB4R/LTB4R2 expression using a simple methylation-sensitive PCR test. Analysis of RNA-seq expression and DNA methylation data from the TCGA dataset demonstrates that the expression of the LTB4R and LTB4R2 genes significantly negatively correlates with DNA methylation at both CpG sites cg12853742 (R = −0.4, p = 2.6 × 10−6; R = −0.21, p = 0.015) and cg21886367 (R = −0.45, p = 7.3 × 10−8; R = −0.24, p = 0.005), suggesting the upregulation of these genes in tumors with abnormal hypomethylation of their CpG island. Kaplan–Meier analysis using the TCGA-BRCA gene expression and clinical data revealed poorer overall survival for TNBC patients with an upregulated LTB4R. To this day, only the leukotriene inhibitor LY255283 has been tested on an MCF-7/DOX cell line, which is a luminal A breast cancer molecular subtype. Other studies compare the effects of Montelukast and Zafirlukast (inhibitors of the cysteinyl leukotriene receptor, which is different from LTB4R/LTB4R2) on the MDA-MB-231 (TNBC) cell line, with high methylation and low expression levels of LTB4R. In our study, we assess the therapeutic effects of various drugs (including leukotriene receptor inhibitors) with the DepMap gene effect and drug sensitivity data for TNBC cell lines with hypomethylated and upregulated LTB4R/LTB4R2 genes. LY255283, Minocycline, Silibinin, Piceatannol, Mitiglinide, 1-Azakenpaullone, Carbetocin, and Pim-1-inhibitor-2 can be considered as candidates for the additional treatment of TNBC patients with tumors demonstrating LTB4R/LTB4R2 hypomethylation/upregulation. Finally, our results suggest that the epigenetic status of leukotriene B4 receptors is a novel, potential, predictive, and prognostic biomarker for TNBC. These findings might improve individualized therapy for TNBC patients by introducing new therapeutic adjuncts as anticancer agents. [ABSTRACT FROM AUTHOR]

HER2-low tumors have shown promise in response to antibody-drug conjugates (ADCs) in recent clinical trials, underscoring the need to characterize this group's clinical phenotype. In this study, we aimed to explore the clinicopathological features, survival rates, and HER2 amplicon mRNA expression of women affected with HER2-low breast cancer, compared with HER2-negative and HER2-positive groups. We included 516 breast cancer patients from Colombia, for whom we compared clinicopathological features, mRNA expression of three HER2 amplicon genes ( ERBB2, GRB7 and MIEN1 ), survival and risk of mortality between HER2-low cases (1+ or 2+ with negative in situ hybridization (ISH) result) with HER2-positive (3+ or 2+ with positive ISH test) and HER2-negative (0+) cases. A higher proportion of patients with better-differentiated tumors and a lower proliferation index were observed for HER2-low tumors compared to the HER2-positive group. Additionally, HER2-low tumors showed higher mRNA expression of the ERBB2 gene and longer overall survival rates compared to HER2-negative cases. Nonetheless, a Cox-adjusted model by ER status and clinical stage showed no statistically significant differences between these groups. Our results show differences in important clinicopathological features between HER2-low and both HER2-positive and negative tumors. Given this unique phenotype, it is crucial to evaluate the potential advantages of ADC therapies for this emerging subtype of breast cancer.

Breast cancer is the most common type of cancer in women, and early detection is important to significantly reduce its mortality rate. This study introduces a detection and diagnosis system that automatically detects and classifies breast tumors in CT scan images. First, the contours of the chest wall are extracted from computed chest tomography images, and two-dimensional image characteristics and three-dimensional image features, together with the application of active contours without edge and geodesic active contours methods, are used to detect, locate, and circle the tumor. Then, the computer-assisted diagnostic system extracts features, quantifying and classifying benign and malignant breast tumors using a greedy algorithm and a support vector machine. The study used 174 breast tumors for experiment and training and performed cross-validation 10 times (k-fold cross-validation) to evaluate performance of the system. The accuracy, sensitivity, specificity, and positive and negative predictive values of the system were 99.43%, 98.82%, 100%, 100%, and 98.89% respectively. This system supports the rapid extraction and classification of breast tumors as either benign or malignant, helping physicians to improve clinical diagnosis. [ABSTRACT FROM AUTHOR]

Radio-frequency (RF) ablation is a reliable technique for the treatment of deep-seated malignant tumors, including breast carcinoma, using high ablative temperatures. The paper aims at a comparative analysis of the specific absorption rate and temperature distribution during RF ablation with regard to different female breast tumors. In the study, four tumor models equivalent to an irregular tumor were considered, i.e., an equivalent sphere and ellipsoid with the same surfaces and volumes as the irregular tumor and an equivalent sphere and ellipsoid inscribed in the irregular tumor. An RF applicator with a specific voltage, operating at 100 kHz inserted into the anatomically correct female breast, was applied as a source of electromagnetically induced heat. A conjugated Laplace equation with the modified Pennes equation was used to obtain the appropriate temperature gradient in the treated area. The levels of power dissipation in terms of the specific absorption rate (SAR) inside the naturalistically shaped tumor, together with the temperature profiles of the four simplified tumor models equivalent to the irregular one, were determined. It was suggested that the equivalent tumor models might successfully replace a real, irregularly shaped tumor, and the presented numeric methodology may play an important role in the complex therapeutic RF ablation process of irregularly shaped female breast tumors. [ABSTRACT FROM AUTHOR]

The high dimensionality and sparsity of the microarray gene expression data make it challenging to analyze and screen the optimal subset of genes as predictors of breast cancer (BC). The authors in the present study propose a novel hybrid Feature Selection (FS) sequential framework involving minimum Redundancy-Maximum Relevance (mRMR), a two-tailed unpaired t-test, and meta-heuristics to screen the most optimal set of gene biomarkers as predictors for BC. The proposed framework identified a set of three most optimal gene biomarkers, namely, MAPK 1, APOBEC3B, and ENAH. In addition, the state-of-the-art supervised Machine Learning (ML) algorithms, namely Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Neural Net (NN), Naïve Bayes (NB), Decision Tree (DT), eXtreme Gradient Boosting (XGBoost), and Logistic Regression (LR) were used to test the predictive capability of the selected gene biomarkers and select the most effective breast cancer diagnostic model with higher values of performance matrices. Our study found that the XGBoost-based model was the superior performer with an accuracy of 0.976 ± 0.027, an F1-Score of 0.974 ± 0.030, and an AUC value of 0.961 ± 0.035 when tested on an independent test dataset. The screened gene biomarkers-based classification system efficiently detects primary breast tumors from normal breast samples. [ABSTRACT FROM AUTHOR]

The concept of BRCAness was developed because of similarities between sporadic and hereditary breast cancer. BRCAness defines the pathogenesis and treatment sensitivity of many types of cancer, as well as the presence of a defect in the homologous recombination repair of tumor cells simulating the loss of BRCA1 or BRCA2, as in the presence of germline mutations. The question of treatment effectiveness for BRCA-like tumors is controversial and open. Thus, the aim of this work was to study the effectiveness of neoadjuvant chemotherapy (NAC) in BRCA-deficient breast cancer patients without germline mutations. The study involved 130 patients with breast cancer in stages IIA–IIIB. The treatment regimen included neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy. The materials used were tumor samples from before and after chemotherapy. DNA and RNA were isolated from the tumor material. RNA was used to assess the expression level of BRCA1, while DNA was used for methyl-sensitive PCR. A microarray analysis was performed on high-density DNA chips from an Affymetrix CytoScanTM HD Array to assess DNA copy number aberration (CNA status) and loss of heterozygosity. A statistical analysis was performed using the Statistica 8.0 application package. It was noted that the existence of copy number aberrations in genes was statistically significantly associated with tumor treatment response and disease prognosis. Patients with partial regression had a statistically significantly higher amount of deletion than patients without an objective response (5/25 patients; 16%), as shown in the general sample of patients (52.9% versus 27.1%, respectively) at p = 0.0001 and in patients treated with anthracycline-containing regimen (p = 0.0001). In addition, it was shown that patients with BRCA1 deletion had higher rates of metastatic-free survival (log rank test, p = 0.009). BRCAness patients had a higher rate of 5-year metastatic survival, but not of treatment efficacy. The prospective study showed the positive effect of assessing the BRCAness phenotype of a tumor before treatment and of prescribing personalized NAC regimens. The objective response rate was statistically significantly more often observed in the group of patients with personalized chemotherapy (85.0% (34/40 patients) versus 62.3% (56/90 patients); p = 0.007). Despite the controversial effectiveness of BRCA-like tumor treatment, our data showed high predictive and prognostic significance of the BRCAness phenotype for the personalization of platinum and taxane regimens. [ABSTRACT FROM AUTHOR]

The incidence of breast and colorectal cancers is well established in studies, but the synchronous occurrence of the two types of tumors is a rarity. In general, they are discovered during screening investigations following the diagnosis of an initial tumor. Objective: Our aim is to describe the main diagnostic and therapeutic challenges for synchronous breast and colorectal tumors. Materials and methods: We performed a systematic review of the literature for cases or case series, using established keywords (synchronous breast and colon tumor and synonyms) for the period of 1970–2023. Five reviewers independently screened the literature, extracted data, and assessed the quality of the included studies. The results were processed according to the PRISMA 2020 guidelines. Results: A total of 15 cases were included in the study, including 2 males (age 50 and 57) and 13 females (median age 60, with range from 40 to 79). In a vast majority of the cases, the diagnosis of synchronous tumor was prompted by the first tumor's workup. The first diagnosed tumor was colorectal in nine cases and a breast tumor in six cases. The most common histopathological type of breast tumor was invasive ductal carcinoma, and the colon tumors were exclusively adenocarcinomas. All cases had a surgical indication for both breast and colorectal tumor, except one case, in which the breast tumor had multiple metastasis. In four cases, the surgery was performed concomitantly (colectomy and mastectomy). In three cases, surgery was initially carried out for the breast tumor, followed by colon surgery. Oncological treatment was indicated depending on the tumor stage. Conclusions: For the treatment of synchronous tumors, the Tumor Board (T.B) decision is mandatory and must be personalized for each patient. Developing new methods of treatment and investigation may play an important role in the future for understanding synchronous tumor development, incidence, and outcome. [ABSTRACT FROM AUTHOR]

Breast cancer risk factors include lifestyle, genetic–hormonal influences, and viral infections. Human papillomavirus (HPV), known primarily as the etiological agent of cervical cancer, also appears active in breast carcinogenesis, as evidenced in our study of 56 patients from northeastern Brazil. We assessed the clinical and sociodemographic characteristics, correlating them with various breast cancer tumor types. HPV detection involved amplifying the L1 region, with viral load measured using the E2/E6 ratio and viral activity indicated by E5 oncogene expression. Predominantly, patients over 56 years of age with healthy lifestyles showed a high incidence of invasive ductal carcinoma and triple-negative breast cancer. HPV was detected in 35.7% of cases, mostly HPV16, which is associated with high viral loads (80 copies per cell) and significant E5 expression. These results hint at a possible link between HPV and breast carcinogenesis, necessitating further studies to explore this association and the underlying viral mechanisms. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) represents the most aggressive breast tumor, showing a high intrinsic variability in terms of both histopathological features and response to therapies. Blocking the Akt signaling pathway is a well-studied approach in the treatment of aggressive breast tumors. The high homology among the Akt isoforms and their distinct, and possibly opposite, oncogenic functions made it difficult to develop effective drugs. Here we investigated the role of Vav1 as a potential down-regulator of individual Akt isozymes. We revealed that the over-expression of Vav1 in triple negative MDA-MB-231 cells reduced only the Akt2 isoform, acting at the post-transcriptional level through the up-modulation of miR-29b. The Vav1/miR-29b dependent decrease in Akt2 was correlated with a reduced lung colonization of circulating MDA-MB-231 cells. In cell lines established from PDX, the Vav1 induced down-modulation of Akt2 is strongly dependent on miR-29b and occurs only in some TNBC tumors. These findings may contribute to better classify breast tumors having the triple negative phenotype, and suggest that the activation of the Vav1/miR-29b axis, precisely regulating the amount of an Akt isozyme crucial for tumor dissemination, could have great potential for driving more accurate therapies to TNBCs, often not eligible or resistant to treatments. [ABSTRACT FROM AUTHOR]

Digital breast tomosynthesis (DBT) is a 3D breast cancer screening technique that can overcome the limitations of standard 2D digital mammography. However, DBT images often suffer from artifacts stemming from acquisition conditions, a limited angular range, and low radiation doses. These artifacts have the potential to degrade the performance of automated breast tumor classification tools. Notably, most existing automated breast tumor classification methods do not consider the effect of DBT image quality when designing the classification models. In contrast, this paper introduces a novel deep learning-based framework for classifying breast tumors in DBT images. This framework combines global image quality-aware features with tumor texture descriptors. The proposed approach employs a two-branch model: in the top branch, a deep convolutional neural network (CNN) model is trained to extract robust features from the region of interest that includes the tumor. In the bottom branch, a deep learning model named TomoQA is trained to extract global image quality-aware features from input DBT images. The quality-aware features and the tumor descriptors are then combined and fed into a fully-connected layer to classify breast tumors as benign or malignant. The unique advantage of this model is the combination of DBT image quality-aware features with tumor texture descriptors, which helps accurately classify breast tumors as benign or malignant. Experimental results on a publicly available DBT image dataset demonstrate that the proposed framework achieves superior breast tumor classification results, outperforming all existing deep learning-based methods. [ABSTRACT FROM AUTHOR]

High-risk benign breast tumors are known to develop breast cancer at high rates. However, it is still controversial whether they should be removed during diagnosis or followed up until cancer development becomes evident. Therefore, this study sought to identify circulating microRNAs (miRNAs) that could serve as detection markers of cancers arising from high-risk benign tumors. Small RNA-seq was performed using plasma samples collected from patients with early-stage breast cancer (CA) and high-risk (HB), moderate-risk (MB), and no-risk (Be) benign breast tumors. Proteomic profiling of CA and HB plasma was performed to investigate the underlying functions of the identified miRNAs. Our findings revealed that four miRNAs, hsa-mir-128-3p, hsa-mir-421, hsa-mir-130b-5p, and hsa-mir-28-5p, were differentially expressed in CA vs. HB and had diagnostic power to discriminate CA from HB with AUC scores greater than 0.7. Enriched pathways based on the target genes of these miRNAs indicated their association with IGF-1. Furthermore, the Ingenuity Pathway Analysis performed on the proteomic data revealed that the IGF-1 signaling pathway was significantly enriched in CA vs. HB. In conclusion, these findings suggest that these miRNAs could potentially serve as biomarkers for detecting early-stage breast cancer from high-risk benign tumors by monitoring IGF signaling-induced malignant transformation. [ABSTRACT FROM AUTHOR]

Digital breast tomosynthesis (DBT) stands out as a highly robust screening technique capable of enhancing the rate at which breast cancer is detected. It also addresses certain limitations that are inherent to mammography. Nonetheless, the process of manually examining numerous DBT slices per case is notably time-intensive. To address this, computer-aided detection (CAD) systems based on deep learning have emerged, aiming to automatically identify breast tumors within DBT images. However, the current CAD systems are hindered by a variety of challenges. These challenges encompass the diversity observed in breast density, as well as the varied shapes, sizes, and locations of breast lesions. To counteract these limitations, we propose a novel method for detecting breast tumors within DBT images. This method relies on a potent dynamic ensemble technique, along with robust individual breast tumor detectors (IBTDs). The proposed dynamic ensemble technique utilizes a deep neural network to select the optimal IBTD for detecting breast tumors, based on the characteristics of the input DBT image. The developed individual breast tumor detectors hinge on resilient deep-learning architectures and inventive data augmentation methods. This study introduces two data augmentation strategies, namely channel replication and channel concatenation. These data augmentation methods are employed to surmount the scarcity of available data and to replicate diverse scenarios encompassing variations in breast density, as well as the shapes, sizes, and locations of breast lesions. This enhances the detection capabilities of each IBTD. The effectiveness of the proposed method is evaluated against two state-of-the-art ensemble techniques, namely non-maximum suppression (NMS) and weighted boxes fusion (WBF), finding that the proposed ensemble method achieves the best results with an F1-score of 84.96% when tested on a publicly accessible DBT dataset. When evaluated across different modalities such as breast mammography, the proposed method consistently attains superior tumor detection outcomes. [ABSTRACT FROM AUTHOR]

Genetic variants located in non-coding regions can affect processes that regulate protein expression, functionally contributing to human disease. Germline heterozygous mutations in the non-coding region of the PTEN gene have been previously identified in patients with PTEN hamartoma tumor syndrome (PHTS) diagnosed with breast, thyroid, and/or endometrial cancer. In this study, we report a PTEN promoter variant (rs34149102 A allele) that was identified by direct sequencing in an Italian family with a history of gastroesophageal junction (GEJ) adenocarcinoma and breast cancer. In order to investigate the putative functional role of the rs34149102 A allele variant, we evaluated the status of PTEN alterations at the somatic level. We found that PTEN protein expression was absent in the GEJ adenocarcinoma tissue of the index case. Moreover, we detected the occurrence of copy number loss involving the PTEN rs34149102 major C allele in tumor tissue, revealing that the second allele was somatically inactivated. This variant is located within an active regulatory region of the PTEN core promoter, and in silico analysis suggests that it may affect the binding of the nuclear transcription factor MAZ and hence PTEN expression. Overall, these results reveal the functional role of the PTEN promoter rs34149102 A allele variant in the modulation of PTEN protein expression and highlight its contribution to hereditary cancer risk. [ABSTRACT FROM AUTHOR]

Simple Summary: Sacituzumab govitecan is a promising treatment option for patients with triple-negative breast cancer, a type of cancer that is difficult to treat due to the absence of hormone receptors, specifically human epidermal growth factor receptor 2. This study is designed to evaluate the efficacy and safety of sacituzumab govitecan, which targets the trophoblast cell surface antigen 2 found on tumor cells, compared to standard chemotherapy. Based on a systematic review of clinical trials, the results indicate that sacituzumab govitecan significantly improves clinical outcomes, providing greater therapeutic benefit with fewer side effects compared to conventional treatments. These findings may influence future treatment guidelines for this aggressive cancer and provide a new approach to its management. Background/Objectives: Triple-negative breast cancer is difficult to treat due to the absence of hormone receptors and Her2neu. Sacituzumab govitecan is a new therapeutic approach that uses an antibody directed against the Trop-2 antigen present in solid epithelial tumors, linked to the active metabolite SN-38, similar to irinotecan, to specifically target cancer cells while minimizing damage to healthy cells. The objective of the present review was to evaluate the efficacy and safety of sacituzumab govitecan as a single treatment in patients with triple-negative breast cancer and to compare its results with the standard conventional chemotherapy regimen currently used in this disease. Methods: A systematic review of randomized clinical trials of sacituzumab govitecan was performed. The search was performed in Medline (PubMed), Web of Science, and Cochrane from September 2022 to January 2024. Results: Thirty-eight articles are included and evaluated according to inclusion and exclusion criteria corresponding to the two most relevant clinical trials, including specific analyses of cohorts and subgroup study arms within these trials. Data from more recent clinical trials are also reviewed. Conclusions: The efficacy results showed a significantly greater clinical benefit with sacituzumab govitecan compared to standard chemotherapy in patients with triple-negative breast cancer. This drug will become a treatment of substantial impact in future treatment guidelines for this type of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores the effectiveness and safety of a common breast cancer treatment in elderly patients, a group often overlooked in clinical trials. Specifically, it focuses on using CDK4/6 inhibitors with hormone therapy for treating metastatic HR+/HER2- breast cancer in patients aged 70 and older. This research aims to understand how well this treatment works and how tolerable it is for this vulnerable population, which faces unique challenges due to age and other health conditions. The results of this study may provide valuable insights for clinicians, enabling more informed treatment decisions which optimize therapeutic outcomes and enhance the quality of life for elderly patients with breast cancer. Background: Metastatic HR+/HER2- breast cancer is commonly treated with CDK4/6 inhibitors in combination with endocrine therapy. However, the efficacy and safety of this approach in elderly patients (≥70 years) remain unclear, particularly in the context of real-world clinical practice. This study aims to evaluate the clinical outcomes and tolerability of CDK4/6 inhibitor treatments in this fragile population, which is often under-represented in randomized clinical trials. Patients and methods: This retrospective multicenter study included elderly patients with metastatic HR+/HER2-negative breast cancer receiving first-line CDK4/6 inhibitors. The primary endpoint was progression-free survival (PFS). The secondary endpoints focused on the overall survival (OS), safety, and tolerability, considering variables such as tumor subtype, age, comorbidities, and treatment specifics. Results: The median PFS and OS were slightly lower than those reported in clinical trials, reflecting the inclusion of a more fragile population. The luminal B subtype was linked to a poorer PFS, while other factors like age, BMI, and ECOG status did not significantly affect the outcomes. A safety analysis indicated a higher incidence of grade 3 or higher toxicities, especially in frail patients, leading to dose reductions. Despite these challenges, CDK4/6 inhibitors were generally well-tolerated, allowing most patients to continue therapy. Conclusions: CDK4/6 inhibitors with endocrine therapy are effective in elderly patients with metastatic HR+/HER2- breast cancer, though careful management is crucial to balance efficacy and minimize adverse events. [ABSTRACT FROM AUTHOR]

Background/Objectives: Trefoil factor 1 (TFF1) plays a role in the mucus barrier. Methods: To evaluate the prevalence of TFF1 expression in cancer, a tissue microarray containing 18,878 samples from 149 tumor types and 608 samples of 76 normal tissue types was analyzed through immunohistochemistry (IHC). Results: TFF1 staining was detectable in 65 of 149 tumor categories. The highest rates of TFF1 positivity were found in mucinous ovarian carcinomas (76.2%), colorectal adenomas and adenocarcinomas (47.1–75%), breast neoplasms (up to 72.9%), bilio-pancreatic adenocarcinomas (42.1–62.5%), gastro-esophageal adenocarcinomas (40.4–50.0%), neuroendocrine neoplasms (up to 45.5%), cervical adenocarcinomas (39.1%), and urothelial neoplasms (up to 24.3%). High TFF1 expression was related to a low grade of malignancy in non-invasive urothelial carcinomas of the bladder (p = 0.0225), low grade of malignancy (p = 0.0003), estrogen and progesterone receptor expression (p < 0.0001), non-triple negativity (p = 0.0005) in invasive breast cancer of no special type, and right-sided tumor location (p = 0.0021) in colorectal adenocarcinomas. Conclusions: TFF1 IHC has only limited utility for the discrimination of different tumor entities given its expression in many tumor entities. The link between TFF1 expression and parameters of malignancy argues for a relevant biological role of TFF1 in cancer. TFF1 may represent a suitable therapeutic target due to its expression in only a few normal cell types. [ABSTRACT FROM AUTHOR]

Simple Summary: Improved outcomes have been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative breast cancer, regardless of age. In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. A higher discontinuation rate for abemaciclib was reported in patients ≥65 years and it can be assumed that discontinuation rates may increase with more older patients. If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population. Background: Despite early diagnosis, approximately 20% of patients with ER-positive and HER2-negative breast cancer (BC) will experience disease recurrence. Improved survival has been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative BC, regardless of age. Older patients have higher rates of ER-positive/HER2-negative BC than younger patients. Methods: In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. Results: Eligibility rates in patients ≤40 years and >80 years who underwent mastectomy were 27.8% and 24.7% for abemaciclib, respectively, and 56.6% and 65.2% for ribociclib, respectively. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. Conclusions: If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population. [ABSTRACT FROM AUTHOR]

The hypermethylation status of the promoter region of the breast cancer 1 (BRCA1), a well-known tumor suppressor gene, has been extensively investigated in the last two decades as a potential biomarker for breast cancer. In this retrospective study, we investigated the prevalence of BRCA1 promoter methylation in 84 human breast tissues, and we correlated this epigenetic silencing with the clinical and histopathological parameters of breast cancer. We used methylation-specific PCR (MSP) to analyze BRCA1 promoter hypermethylation in 48 malignant breast tumors (MBTs), 15 normal adjacent tissues (NATs), and 21 benign breast lesions (BBLs). The results showed that BRCA1 promoter hypermethylation was higher in MBTs (20/48; 41.67%) and NATs (7/15; 46.67%) compared to BBLs (4/21; 19.05%). The high percentage of BRCA1 hypermethylation in the histologically normal adjacent tissues to the tumors (NATs) suggests the involvement of this epigenetic silencing as a potential biomarker of the early genomic instability in NATs surrounding the tumors. The detection of BRCA1 promoter hypermethylation in BBLs reinforces this suggestion, knowing that a non-negligible rate of benign breast lesions was reported to evolve into cancer. Moreover, our results indicated that the BRCA1 promoter hypermethylated group of MBTs exhibited higher rates of aggressive features, as indicated by the SBR III grade (14/19; 73.68%), elevated Ki67 levels (13/16; 81.25%), and Her2 receptor overexpression (5/20; 25%). Finally, we observed a concordance (60%) in BRCA1 promoter hypermethylation status between malignant breast tumors and their paired histologically normal adjacent tissues. This study highlights the role of BRCA1 promoter hypermethylation as a potential useful biomarker of aggressiveness in MBTs and as an early marker of genomic instability in both histological NATs and BBLs. [ABSTRACT FROM AUTHOR]

Comparative studies of immune-active hot and immune-deserted cold tumors are critical for identifying therapeutic targets and strategies to improve immunotherapy outcomes in cancer patients. Tumors with high tumor-infiltrating lymphocytes (TILs) are likely to respond to immunotherapy. We used the human breast cancer RNA-seq data from the cancer genome atlas (TCGA) and classified them into hot and cold tumors based on their lymphocyte infiltration scores. We compared the immune profiles of hot and cold tumors, their corresponding normal tissue adjacent to the tumor (NAT), and normal breast tissues from healthy individuals from the Genotype-Tissue Expression (GTEx) database. Cold tumors showed a significantly lower effector T cells, lower levels of antigen presentation, higher pro-tumorigenic M2 macrophages, and higher expression of extracellular matrix (ECM) stiffness-associated genes. Hot/cold dichotomy was further tested using TIL maps and H&E whole-slide pathology images from the cancer imaging archive (TCIA). Analysis of both datasets revealed that infiltrating ductal carcinoma and estrogen receptor ER-positive tumors were significantly associated with cold features. However, only TIL map analysis indicated lobular carcinomas as cold tumors and triple-negative breast cancers (TNBC) as hot tumors. Thus, RNA-seq data may be clinically relevant to tumor immune signatures when the results are supported by pathological evidence. [ABSTRACT FROM AUTHOR]

Background: Compared to conventional 2D mammography, digital breast tomosynthesis (DBT) offers greater breast lesion detection rates. Ring-like hypodense artifacts surrounding dense lesions are a common byproduct of DBT. This study's purpose was to assess whether minuscule changes spanning this halo-termed the "broken halo sign"-could improve lesion classification., Methods: This retrospective study was approved by the local ethics review board. After screening 288 consecutive patients, DBT studies of 191 female participants referred for routine mammography with a subsequent histologically verified finding of the breast were assessed. Examined variables included patient age, histological diagnosis, architectural distortion, maximum size, maximum halo depth, conspicuous margins, irregular shape and broken halo sign., Results: While a higher halo strength was indicative of malignancy in general ( p = 0.031), the broken halo sign was strongly associated with malignancy ( p < 0.0001, odds ratio (OR) 6.33), alongside architectural distortion ( p = 0.012, OR 3.49) and a diffuse margin ( p = 0.006, OR 5.49). This was especially true for denser breasts (ACR C/D), where the broken halo sign was the only factor predicting malignancy ( p = 0.03, 5.22 OR)., Conclusion: DBT-associated halo artifacts warrant thorough investigation in newly found breast lesions as they are associated with malignant tumors. The "broken halo sign"-the presence of small lines of variable diameter spanning the peritumoral areas of hypodensity-is a strong indicator of malignancy, especially in dense breasts, where architectural distortion may be obfuscated due to the surrounding tissue.

Background/Objectives: Heterodimer peptides targeting more than one receptor can be advantageous, as tumors can simultaneously express more than one receptor type. For human breast cancer, a promising biological target is tumor angiogenesis through αvβ3 integrin expression. Another promising target is Neuropeptide Y receptors, considering Y1R is overexpressed in 90% of human breast tumors. This article details the development and preclinical evaluation, both in vitro and in vivo, of a novel heterodimer peptide dual-receptor-targeting probe, [99mTc]HYNIC-cRGDfk-NPY, designed for imaging breast tumors. Methods: Female BALB/c healthy mice were used to perform biodistrubution studies and female SCID mice were subcutaneously injected with MCF-7 and MDA-MB-231 tumor cells. [99mTc]HYNIC-cRGDfk-NPY was intravenously administered to the mice, followed by ex vivo biodistribution studies and small-animal SPECT/CT imaging. Nonspecific tracer uptake in both models was determined by coinjecting an excess of unlabeled HYNIC-cRGDfk-NPY (100 µg) along with the radiolabeled tracer. Results: Imaging and biodistribution data demonstrate good uptake to estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) tumor models. The in vivo tumor uptakes of radiolabeled conjugate were 9.30 ± 3.25% and 4.93 ± 1.01% for MCF-7 and MDA-MB231, respectively. The tumor/muscle ratios were 5.65 ± 0.94 for the MCF-7 model and 7.78 ± 3.20 for MDA-MB231. Conclusions: [99mTc]HYNIC-cRGDfk-NPY demonstrated rapid blood clearance, renal excretion, and in vivo tumor uptake, highlighting its potential as a tumor imaging agent. [ABSTRACT FROM AUTHOR]

Background: Compared to conventional 2D mammography, digital breast tomosynthesis (DBT) offers greater breast lesion detection rates. Ring-like hypodense artifacts surrounding dense lesions are a common byproduct of DBT. This study's purpose was to assess whether minuscule changes spanning this halo—termed the "broken halo sign"—could improve lesion classification. Methods: This retrospective study was approved by the local ethics review board. After screening 288 consecutive patients, DBT studies of 191 female participants referred for routine mammography with a subsequent histologically verified finding of the breast were assessed. Examined variables included patient age, histological diagnosis, architectural distortion, maximum size, maximum halo depth, conspicuous margins, irregular shape and broken halo sign. Results: While a higher halo strength was indicative of malignancy in general (p = 0.031), the broken halo sign was strongly associated with malignancy (p < 0.0001, odds ratio (OR) 6.33), alongside architectural distortion (p = 0.012, OR 3.49) and a diffuse margin (p = 0.006, OR 5.49). This was especially true for denser breasts (ACR C/D), where the broken halo sign was the only factor predicting malignancy (p = 0.03, 5.22 OR). Conclusion: DBT-associated halo artifacts warrant thorough investigation in newly found breast lesions as they are associated with malignant tumors. The "broken halo sign"—the presence of small lines of variable diameter spanning the peritumoral areas of hypodensity—is a strong indicator of malignancy, especially in dense breasts, where architectural distortion may be obfuscated due to the surrounding tissue. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer remains a major health issue in the United States and around the world. While progress has been made in curing most types of breast cancer, there are currently no effective cures for a subtype called 'triple-negative' breast cancer. We have identified a gene named BORG that, based on experiments in cultured human cells and mice, plays an important role in triple-negative breast cancer. Here, we study the function of this gene in a large group of human triple-negative breast cancers and show that when the level of expression of this gene is high, tumors become more invasive and develop 'triple-negative'-like properties. Even in non-triple-negative tumors, high levels of expression of this gene are associated with more aggressive tumor behavior and poor response to therapy. Based on these validation studies in human tumors, we hope to leverage mechanistic vulnerabilities in BORG action to one day advance novel therapeutic strategies to alleviate hard-to-cure triple-negative breast tumors. Background/Objectives: Long noncoding RNAs (lncRNAs) are known to play key roles in breast cancers; however, detailed mechanistic studies of lncRNA function have not been conducted in large cohorts of breast cancer tumors, nor has inter-donor and inter-subtype variability been taken into consideration for these analyses. Here we provide the first identification and annotation of the human BORG lncRNA gene. Methods/Results: Using multiple tumor cohorts of human breast cancers, we show that while BORG expression is strongly induced in breast tumors as compared to normal breast tissues, the extent of BORG induction varies widely between breast cancer subtypes and even between different tumors within the same subtype. Elevated levels of BORG in breast tumors are associated with the acquisition of core cancer aggression pathways, including those associated with basal tumor and pluripotency phenotypes and with epithelial–mesenchymal transition (EMT) programs. While a subset of BORG-associated pathways was present in high BORG-expressing tumors across all breast cancer subtypes, many were specific to tumors categorized as triple-negative breast cancers. Finally, we show that genes induced by heterologous expression of BORG in murine models of TNBC both in vitro and in vivo strongly overlap with those associated with high BORG expression levels in human TNBC tumors. Conclusion: Our findings implicate human BORG as a novel driver of the highly aggressive basal TNBC tumor phenotype. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer and the leading cause of cancer-related deaths among women globally, with over 2.26 million new cases in women in 2020. Male breast cancer, while rare (less than 1% of cases), is treated similarly to female breast cancer despite some clinical differences. Advances in treatment, such as using genomic and immunohistochemical markers, have significantly improved survival rates for women. Men with breast cancer are often older at diagnosis, and their prognosis may differ due to age and other factors. The survival analysis conducted on 2162 patients (19 males and 2143 females) suggests that male breast cancer may have a poorer prognosis compared to female breast cancer. Breast cancer is one of the most common cancers and the leading cause of cancer death in women. Less than 1% of breast cancer cases are male breast cancers. Although there has been significant progress made in the management of breast cancer, due to its rarity among men, the question of whether men and women with breast cancer have the same treatment response and survival rate still needs to be answered. The primary goal of this study is to compare survival outcomes between male and female breast cancer patients. Material and Method: This cohort study represents a retrospective and anonymized data analysis of 2162 breast cancer cases (19 males and 2143 females), registered over a period of 12 years, from 1 January 2010 to 31 December 2021, in the Clinic of Obstetrics and Gynecology, Diakoneo Diak Klinikum Schwäbisch Hall, Germany. Results: According to the Kaplan–Meier survival analysis, the estimated overall 3-year survival rate was 91.1% for women and 88.9% for men. The log-rank test of equality of survival distributions indicated a statistically significant difference in survival times between the two groups (p = 0.009). In the subsequent age-matched Kaplan–Meier analysis, the p-value was below the significance threshold (p = 0.068). Conclusions: Male breast cancer is a rare disease that may show some particularities in terms of survival compared to female breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast-conserving therapy to resect only the tumor in breast cancer is a standard procedure. To replace loss of volume in the breast and to avoid dislocation of the nipple/areola, local flaps are useful. One technique that has only rarely been used is the local, pedicled rhombus-shaped flap, according to Limberg. The flap is easy and safe, and the donor site is always closed primarily. On the breast, the rhombus-shaped flap can be used as an all-layer flap to cover defects, or it can be deepithelialized to be used as a buried flap. The flap can be harvested from the breast itself or the chest wall. Especially in the lateral breast, the flap is very useful. In the axilla, it can be used to cover full-thickness defects after resection when skin is involved, avoiding a contracture in the axilla. Primarily, breast-conserving therapy is an oncological intervention, but eventually it is judged by its cosmetic result. Remaining cavities from tumor resection can promote seromas, delay healing and cause lasting discomfort. Additionally, volume loss, dislocation of nipple/areola and fat necrosis lead to (cosmetically) unfavorable results, aggravated by radiotherapy. Oncoplastic surgery can reduce these sequelae. A local flap that has rarely been used in breast cancer surgery is the Limberg rhombic flap. The tumor defect is planned as a rhombus. The sides of the rhombus are of equal length and ideally have an angle of 60° and 120°. The flap that closes the defect is planned as an extension of equal length of the short diagonal. The second incision of the flap is placed according to the defect angle of 60°, running parallel to the defect at the same length. This creates a second rhombus. The flap is transposed into the defect, and the donor area is primarily closed. It is axially perfused and safe with a 1:1 length-to-width ratio. Compared to local perforator flaps, defect closure is easily managed without microsurgical skills. In the breast, the flap can be used in volume replacement and volume displacement techniques as an all-layer flap to cover defects, or it can be deepithelialized and buried. In the axilla, it can cover full-thickness defects when skin is involved. The advantages of the rhombic flap are its safety and simplicity to add volume and close defects, thus reducing the complexity of oncoplastic surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2-positive breast cancer occurs in 15–30% of cases and has a poor prognosis. Digital image analysis of HER2 is promising, but its implementation in real clinical practice remains unclear. This systematic review evaluates the effectiveness of digital image analysis algorithms for HER2 in breast cancer and their performance, with a focus on testing them in real-world clinical settings. The authors aim to assess the applicability of these algorithms in practical clinical scenarios. By analyzing 25 papers from the period 2013–2024 and emphasizing mostly deep learning approaches, the review underscores the importance of standardized evaluation criteria, study designs tailored for clinical applications, and clinical validation. While direct evidence of clinical application was not found, the findings aim to guide future research and the implementation of digital image analysis in breast cancer diagnosis within clinical settings, potentially impacting the research community by advancing algorithmic applications in real clinical practice. This systematic review aims to address the research gap in the performance of computational algorithms for the digital image analysis of HER2 images in clinical settings. While numerous studies have explored various aspects of these algorithms, there is a lack of comprehensive evaluation regarding their effectiveness in real-world clinical applications. We conducted a search of the Web of Science and PubMed databases for studies published from 31 December 2013 to 30 June 2024, focusing on performance effectiveness and components such as dataset size, diversity and source, ground truth, annotation, and validation methods. The study was registered with PROSPERO (CRD42024525404). Key questions guiding this review include the following: How effective are current computational algorithms at detecting HER2 status in digital images? What are the common validation methods and dataset characteristics used in these studies? Is there standardization of algorithm evaluations of clinical applications that can improve the clinical utility and reliability of computational tools for HER2 detection in digital image analysis? We identified 6833 publications, with 25 meeting the inclusion criteria. The accuracy rate with clinical datasets varied from 84.19% to 97.9%. The highest accuracy was achieved on the publicly available Warwick dataset at 98.8% in synthesized datasets. Only 12% of studies used separate datasets for external validation; 64% of studies used a combination of accuracy, precision, recall, and F1 as a set of performance measures. Despite the high accuracy rates reported in these studies, there is a notable absence of direct evidence supporting their clinical application. To facilitate the integration of these technologies into clinical practice, there is an urgent need to address real-world challenges and overreliance on internal validation. Standardizing study designs on real clinical datasets can enhance the reliability and clinical applicability of computational algorithms in improving the detection of HER2 cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The indications for neoadjuvant chemotherapy (NAT) have expanded in recent years both for locally advanced and early-stage breast cancer, with different pathological complete response (pCR) rates among different molecular subtypes. This retrospective two-center study aims to evaluate the diagnostic performance of Contrast-Enhanced Mammography (CEM) in assessing the response to NAT in breast cancer patients. The CEM sensitivity and specificity were 66.2% and 75.2%, with the highest specificity (80.9%) in HR+/HER2− and the highest sensitivity (70%) in triple-negative breast cancer. CEM is a valid tool to assess the pCR with different performances among the molecular subtypes and may be reliable in the decisional process of de-escalating surgical management. Neoadjuvant chemotherapy (NAT) plays a crucial role in breast cancer (BC) treatment, both in advanced BC and in early-stage BC, with different rates of pathological complete response (pCR) among the different BC molecular subtypes. Imaging monitoring is mandatory to evaluate the NAT efficacy. This study evaluates the diagnostic performance of Contrast-Enhanced Mammography (CEM) in BC patients undergoing NAT. This retrospective two-center study included 174 patients. The breast lesions were classified based on the molecular subtypes in hormone receptor (HR+)/HER2−, HER2+, and triple-negative breast cancer (TNBC). The histopathological analysis performed following surgery was used as a reference standard for the pCR. Sensitivity, specificity, PPV, and NPV were measured overall and for the different subtypes. We enrolled 174 patients, 79/174 (46%) HR+/HER2−, 59/174 (33.9%) HER2+, and 35/174 (20.1%) TNBC; the pCR was found in 64/174 (36.8%), of which 57.1% were TNBCs. In the total population, the CEM sensitivity and specificity were 66.2% and 75.2%, with a PPV of 61.4% and an NPV of 78.8%. The highest specificity (80.9%) and NPV (91.7%) were found in HR+/HER2−, while the highest sensitivity (70%) and PPV appeared (73.7%) in TNBC. The results indicate that CEM is a valid tool to assess the pCR, with different performances among the subtypes of BC. [ABSTRACT FROM AUTHOR]

Simple Summary: Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is discussed. We evaluated the impact of cALND omission on survival in breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 BC, the non-SN involvement rate was 13.2%. With a median follow-up of 66.46 months, multivariate analysis showed that cALND omission was significantly associated with overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly impacted by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative patients, DFS, OS, RFS, and MFS were also significantly affected (HR: 2.358, 3.317, 2.538, 2.756). For 161 patients ≤ 50 years with ER-positive/Her2-negative BC, OS and BCSS were notably associated with cALND omission (HR: 103.47 and 50.874). These findings suggest a negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is debated due to potential under-treatment, with non-sentinel node (NSN) involvement detected in 7% to 18% of patients. This study evaluated the survival impact of cALND omission in a cohort of breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 early BC patients (391 pN1mi, 163 ITC), the NSN involvement rate was 13.2% (49/371). With a median follow-up of 66.46 months, multivariate analysis revealed significant associations between cALND omission and overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly affected by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative BC, DFS, OS, recurrence-free survival (RFS), and MFS were significantly associated with cALND omission (DFS HR: 2.358, p = 0.043; OS HR: 3.317; RFS HR: 2.538; MFS HR: 2.756). For 161 patients aged ≤50 years with ER-positive/Her2-negative cancer, OS and breast cancer-specific survival (BCSS) were notably impacted by cALND omission (OS HR: 103.47, p = 0.004; BCSS HR: 50.874, p = 0.035). These findings suggest a potential negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Further randomized trials are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Liquid-nitrogen-based cryoablation presents a minimally invasive therapeutic option for small local cancer of the breast. The aim of this study was to investigate the efficacy and safety of cryoablation according to safety and efficacy. Therefore, this study reports on the outcome of 45 patients who were treated with liquid nitrogen-based cryoablation at our clinic. This study shall retrospectively evaluate the efficacy and safety of liquid-nitrogen based CT-guided cryoablation (CA) as a minimal-invasive technique for the curative treatment of primary breast cancer. A total of 45 female patients with 56 tumors were treated by CT-guided CA in analgosedation as an outpatient procedure. We used a liquid-nitrogen based system with a single cryoprobe and performed two freeze cycles with an intermediate thawing. The mean tumor diameter was 1.6 ± 0.7 cm. Follow-up was conducted via contrast-enhanced MR images of the breast. No complications were observed in all 56 ablations. Initial complete ablation was achieved in 100% of cases. Four cases of local tumor progression were reported, resulting in a rate of 8.9%, and 6 cases of intramammary distant recurrence at a rate of 13.3%. The extramammary tumor progression was observed in 7 patients at a rate of 15.6%. The mean overall survival was 4.13 years (95% CI: 3.7–4.5). The mean overall progression-free survival was 2.5 years (95% CI: 1.8–3.2) and the mean local progression-free survival was 2.9 years (95% CI: 2.3–3.6). Cryoablation is a safe and effective treatment for primary breast cancer tumors, which can be performed in analgosedation and as an outpatient procedure. However, potential for improvement exists and further evidence is necessary. [ABSTRACT FROM AUTHOR]

Background: The molecular mechanisms underlying the de novo metastasis of luminal breast cancer (dnMBC) remain largely unknown. Materials and Methods: Newly diagnosed dnMBC patients (grade 2/3, ER+, PR+/-, HER2-), with available core needle biopsy (CNB), collected from the primary tumor, were selected from our clinical-pathological database. Tumors from dnMBC patients were 1:1 pairwise matched (n = 32) to tumors from newly diagnosed patients who had no distant metastases at baseline (eBC group). RNA was extracted from 5 × 10 µm sections of FFPE CNBs. RNA sequencing was performed using the Illumina platform. Differentially expressed genes (DEG)s were assessed using EdgeR; deconvolution was performed using CIBERSORTx to assess immune cell fractions. A paired Wilcoxon test was used to compare dnMBC and eBC groups and corrected for the false discovery rate. Results: Many regulatory DEGs were significantly downregulated in dnMBC compared to eBC. Also, immune-related and hypoxia-related signatures were significantly upregulated. Paired Wilcoxon analysis showed that the CCL17 and neutrophils fraction were significantly upregulated, whereas the memory B-cell fraction was significantly downregulated in the dnMBC group. Conclusions: Primary luminal tumors of dnMBC patients display significant transcriptomic and immunological differences compared to comparable tumors from eBC patients.

This commentary focuses on the DESTINY-Breast12 study, published in Nature Medicine on 13 September 2024, which evaluates the efficacy of Trastuzumab deruxtecan (T-DXd) in treating HER2-positive advanced breast cancer, including those with brain metastases. We emphasize the broadened clinical potential of T-DXd in treating brain metastases from tumors originally classified as HER2-null or HER2-low, extending beyond its current use for breast cancer. This expanded application of T-DXd could provide new hope to patients dealing with challenging brain metastases, addressing an urgent need for effective treatment options. [ABSTRACT FROM AUTHOR]

Mesenchymal breast tumors are a rare and diverse group of tumors that present some of the most challenging cases for multidisciplinary breast cancer teams. As a result of overlapping morphologies and a lack of large-scale studies on these tumors, practices are often heterogeneous and slow to evolve. Herein, we present a non-systematic review that focuses on progress, or lack thereof, in the field of mesenchymal breast tumors. We focus on tumors originating from fibroblastic/myofibroblastic cells and tumors originating from less common cellular origins (smooth muscle, neural tissue, adipose tissue, vascular tissue, etc.). [ABSTRACT FROM AUTHOR]

Simple Summary: Estrogen receptor-positive (ER+) breast cancer is the most prevalent breast cancer subtype, accounting for 70–85% of all cases. The combination of endocrine therapy, such as aromatase inhibitors (AIs), with target therapy is one of the most recent approaches, but its effectiveness is not optimal. Cannabidiol (CBD) has demonstrated important anti-tumor effects on ER+ breast cancer cells. Considering this, our goal was to evaluate the effects of combining CBD with the AIs currently in use in the clinical context. Our results revealed that CBD may be particularly beneficial when combined with the AI exemestane (Exe), since it potentiates the anti-tumor effects of Exe through the modulation of cell death and specific targets, including ERα and androgen receptor (AR). This reinforces the beneficial potential of cannabinoids in breast cancer and points to the possibility of improving Exe effects through an adjuvant therapy with CBD. Background: Estrogen receptor-positive (ER+) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER+ breast cancer cells by targeting aromatase and ERs. Considering this, we studied, in vitro, whether CBD when combined with AIs could improve their effectiveness. Methods: MCF-7aro cells were used and the effects on cell viability and on the modulation of specific targets were investigated. Results: CBD when combined with anastrozole (Ana) and letrozole (Let) caused no beneficial effect in comparison to the isolated AIs. In contrast, when combined with the AI exemestane (Exe), CBD potentiated its pro-cell death effects, abolished its estrogen-like effect, impaired ERα activation, and prevented its oncogenic role on the androgen receptor (AR). Moreover, this combination inhibited ERK1/2 activation, promoting apoptosis. The study of the hormonal microenvironment suggests that this combination should not be applied in early stages of ER+ breast tumors. Conclusions: Contrary to Ana and Let, this study highlights the potential benefits of combining CBD with Exe to improve breast cancer treatment and opens up the possibility of new therapeutic approaches comprising the use of cannabinoids. [ABSTRACT FROM AUTHOR]

This study introduces a sophisticated neural network structure for segmenting breast tumors. It achieves this by combining a pretrained Vision Transformer (ViT) model with a UNet framework. The UNet architecture, commonly employed for biomedical image segmentation, is further enhanced with depthwise separable convolutional blocks to decrease computational complexity and parameter count, resulting in better efficiency and less overfitting. The ViT, renowned for its robust feature extraction capabilities utilizing self-attention processes, efficiently captures the overall context within images, surpassing the performance of conventional convolutional networks. By using a pretrained ViT as the encoder in our UNet model, we take advantage of its extensive feature representations acquired from extensive datasets, resulting in a major enhancement in the model's ability to generalize and train efficiently. The suggested model has exceptional performance in segmenting breast cancers from medical images, highlighting the advantages of integrating transformer-based encoders with efficient UNet topologies. This hybrid methodology emphasizes the capabilities of transformers in the field of medical image processing and establishes a new standard for accuracy and efficiency in activities related to tumor segmentation. [ABSTRACT FROM AUTHOR]

Simple Summary: It has long been known that breast tumors harbor various types of microbes. However, it was little known where these tumor-resident microbes came from and how they could contribute to breast cancer pathogenesis. Now, recent discoveries have unveiled that these tumor-resident microbes come from different parts of the body and live inside tumor cells to participate not only in tumorigenesis events, i.e., DNA damage and genomic instability, but also in tumor progression and metastasis. Such important findings have helped identify these intratumoral microbes as potential new targets for breast cancer treatment and prevention. Cumulative evidence attests to the essential roles of commensal microbes in the physiology of hosts. Although the microbiome has been a major research subject since the time of Luis Pasteur and William Russell over 140 years ago, recent findings that certain intracellular bacteria contribute to the pathophysiology of healthy vs. diseased tissues have brought the field of the microbiome to a new era of investigation. Particularly, in the field of breast cancer research, breast-tumor-resident bacteria are now deemed to be essential players in tumor initiation and progression. This is a resurrection of Russel's bacterial cause of cancer theory, which was in fact abandoned over 100 years ago. This review will introduce some of the recent findings that exemplify the roles of breast-tumor-resident microbes in breast carcinogenesis and metastasis and provide mechanistic explanations for these phenomena. Such information would be able to justify the utility of breast-tumor-resident microbes as biomarkers for disease progression and therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous research highlights the involvement of the Serum Amyloid A (SAA) protein family in inflammation and various diseases. This study explores the role of SAA1 and SAA2 (SAA1/2) in triple-negative breast cancer using a mouse model. Syngeneic breast tumors were established in wild-type and SAA1/2-deficient (SAADKO) mice, with assessments of tumor volume, survival, inflammatory profiles, and tumor characteristics. Background: Previous research has shown that the Serum Amyloid A (SAA) protein family is intricately involved in inflammatory signaling and various disease pathologies. We have previously demonstrated that SAA is associated with increased colitis disease severity and the promotion of tumorigenesis. However, the specific role of SAA proteins in breast cancer pathology remains unclear. Therefore, we investigated the role of systemic SAA1 and SAA2 (SAA1/2) in a triple-negative breast cancer mouse model. Methods: Syngeneic breast tumors were established in wild-type mice, and mice lacking the SAA1/2 (SAADKO). Subsequently, tumor volume was monitored, species survival determined, the inflammatory profiles of mice assessed with a multiplex assay, and tumor molecular biology and histology characterized with Western blotting and H&E histological staining. Results: WT tumor-bearing mice had increased levels of plasma SAA compared to wild-type control mice, while SAADKO control and tumor-bearing mice presented with lower levels of SAA in their plasma. SAADKO tumor-bearing mice also displayed significantly lower concentrations of systemic inflammatory markers. Tumors from SAADKO mice overall had lower levels of SAA compared to tumors from wild-type mice, decreased apoptosis and inflammasome signaling, and little to no tumor necrosis. Conclusions: We demonstrated that systemic SAA1/2 stimulates the activation of the NLRP3 inflammasome in breast tumors, leading to the production of pro-inflammatory cytokines. This, in turn, promoted apoptosis and tumor necrosis but did not significantly impact tumor growth or histological grading. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most prevalent forms of cancer diagnosed in women worldwide. Since the estradiol receptor (ER) is overexpressed in 75% of breast tumors, it is a reasonable target for tumor diagnosis and therapy. This study focuses on the development and preclinical evaluation of readily synthesized 18F-labeled estradiol derivatives with different lipophilicity. The least hydrophilic derivative, 18F-TA-Glyco-EE, showed the highest cellular uptake in ER-positive breast cancer cells. The in vivo PET imaging of breast tumor-bearing mice demonstrated the desired rapid clearance of the tracer from the excretory organ through the liver. The in vitro autoradiography of ER-positive tumor sections confirmed the high specific binding of 18F-TA-Glyco-EE. In conclusion, 18F-TA-Glyco-EE may be a promising candidate for imaging of ER-positive breast cancer. About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER− MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60–90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer. [ABSTRACT FROM AUTHOR]

Cancer is one of the main health problems worldwide. Only in 2020, this disease caused more than 19 million new cases and almost 10 million deaths, with breast cancer being the most diagnosed worldwide. Today, despite recent advances in breast cancer treatment, a significant percentage of patients will either not respond to therapy or will eventually experience lethal progressive disease. Recent studies highlighted the involvement of calcium in the proliferation or evasion of apoptosis in breast carcinoma cells. In this review, we provide an overview of intracellular calcium signaling and breast cancer biology. We also discuss the existing knowledge on how altered calcium homeostasis is implicated in breast cancer development, highlighting the potential utility of Ca 2+ as a predictive and prognostic biomarker, as well as its potential for the development of new pharmacological treatments to treat the disease.

Simple Summary: Breast cancer is a heterogeneous disease and treatment needs to be adapted to individual tumors. Two thirds of breast tumors may benefit from treatment with drugs targeting a specific protein, the estrogen receptor alpha, a regulator of gene expression activated by female sex hormones. However, a significant percentage of tumors will recur and progress. To help detect more accurately the expression status and activity of this protein, a gene that it upregulates, the progesterone receptor (PR), is routinely used in the clinic as an additional marker. Here, we show that PR status is an imperfect reflection of the expression and/or overall activity of estrogen receptor alpha and identify another marker that can perform this task more consistently. Overall, use of CAXII as a marker of ER+ tumors should reinforce the diagnosis of ER status and prediction of its activity and enhance the accuracy of hormonal therapy delivery. Estrogen receptor alpha (ERα) expression in ~2/3 breast tumors selects patients for hormonal therapies. Tumors negative for ERα but positive for the progesterone receptor (PR, encoded by PGR) have also been candidates for ER-targeting therapies, as PR expression may reflect undetected ER activity. Conversely, PR− status in ER+ tumors predicts a worse therapeutic response. Our analysis of breast tumor transcriptome datasets, however, revealed that in tumors with lower PGR expression, the clinical PR status does not correlate accurately with the expression of ESR1 or of ER target genes, including PGR itself. We identified carbonic anhydrase 12 (CA12) as an estrogen target gene better correlated with ESR1 than PGR, reflecting CA12 regulation by both ERα and the luminal factor and upstream ESR1 regulator GATA3. Immunostaining supported strong positive correlations at the protein level with ERα and GATA3 in a cohort of 118 tumors. Most ER+PR− tumors expressed CAXII at levels similar to those of ER+PR+ tumors, consistent with observations in tumor transcriptome datasets and with active estrogenic signaling in some ER+PR− breast cancer cell lines. The few ER−PR+ tumors did not express CAXII or the other luminal markers FOXA1 and GATA3. Overall, CAXII is a luminal marker that can help interpret ER status in single ER/PR positive tumors. [ABSTRACT FROM AUTHOR]

Determining histological subtypes, such as invasive ductal and invasive lobular carcinomas (IDCs and ILCs) and immunohistochemical markers, such as estrogen response (ER), progesterone response (PR), and the HER2 protein status is important in planning breast cancer treatment. MRI-based radiomic analysis is emerging as a non-invasive substitute for biopsy to determine these signatures. We explore the effectiveness of radiomics-based and CNN (convolutional neural network)-based classification models to this end. T1-weighted dynamic contrast-enhanced, contrast-subtracted T1, and T2-weighted MR images of 429 breast cancer tumors from 323 patients are used. Various combinations of input data and classification schemes are applied for ER+ vs. ER−, PR+ vs. PR−, HER2+ vs. HER2−, and IDC vs. ILC classification tasks. The best results were obtained for the ER+ vs. ER− and IDC vs. ILC classification tasks, with their respective AUCs reaching 0.78 and 0.73 on test data. The results with multi-contrast input data were generally better than the mono-contrast alone. The radiomics and CNN-based approaches generally exhibited comparable results. ER and IDC/ILC classification results were promising. PR and HER2 classifications need further investigation through a larger dataset. Better results by using multi-contrast data might indicate that multi-parametric quantitative MRI could be used to achieve more reliable classifiers. [ABSTRACT FROM AUTHOR]

Automatic classification of benign and malignant breast ultrasound images is an important and challenging task to improve the efficiency and accuracy of clinical diagnosis of breast tumors and reduce the rate of missed and misdiagnosis. The task often requires a large amount of data to train. However, it is difficult to obtain medical images, which contradicts the large amount of data needed to obtain good diagnostic models for training. In this paper, a novel classification model for the classification of breast tumors is proposed to improve the performance of diagnosis models trained by small datasets. The method integrates three features from medical features extracted from segmented images, features selected from the pre-trained ResNet101 output by principal component analysis (PCA), and texture features. Among the medical features that are used to train the naive Bayes (NB) classifier, and the PCA-selected features are used to train the support vector machine (SVM) classifier. Subsequently, the final results of boosting are obtained by weighting the classifiers. A five-fold cross-validation experiment yields an average accuracy of 89.17%, an average precision of 90.00%, and an average AUC value of 0.95. According to the experimental results, the proposed method has better classification accuracy compared to the accuracy obtained by other models trained on only small datasets. This approach can serve as a reliable second opinion for radiologists, and it can also provide useful advice for junior radiologists who do not have sufficient clinical experience. [ABSTRACT FROM AUTHOR]

Simple Summary: This study is focused on exploring the anticancer properties of proguanil, an old antimalarial drug. Proguanil demonstrated a significant ability to induce cell death through the increased production of reactive oxygen species (ROS) and subsequent disruption in mitochondrial function in breast cancer cells. In several breast cancer cell lines and mouse tumor models, proguanil showed promising results by inhibiting tumor growth and altering key proteins associated with cancer progression. These findings suggest that proguanil could be a promising candidate for further clinical investigation as a potential treatment option for breast cancer. Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects on diverse breast cancer cell lines, including those derived from patients. Proguanil-induced apoptosis was associated with a substantial increase in reactive oxygen species (ROS) production, leading to reduced mitochondrial membrane potential, respiration, and ATP production. Proguanil treatment upregulated apoptotic markers (Bax, p-H2AX, cleaved-caspase 3, 9, cleaved PARP) and downregulated anti-apoptotic proteins (bcl-2, survivin) in breast cancer cell lines. In female Balb/c mice implanted with 4T1 breast tumors, daily oral administration of 20 mg/kg proguanil suppressed tumor enlargement by 55%. Western blot analyses of proguanil-treated tumors supported the in vitro findings, demonstrating increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 as compared to controls. Our results collectively highlight proguanil's anticancer efficacy in vitro and in vivo in breast cancer, prompting further consideration for clinical investigations. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most prevalent malignancy all over the world. Intraoperative histological imaging of frozen tissue sections is frequently used in the evaluation of surgical margins for the presence of residual transformed cells. However, this method is time consuming, prone to sampling error and subjective interpretation. The purpose of this work was to investigate a sensitivity of the 1H HR-MAS NMR (high-resolution magic angle spinning nuclear magnetic resonance) technique in the detection of cancer cells in the tissue material collected during breast-conserving surgery and to gain an insight into a metabolic reprogramming of intratumoral fibrosis. The multivariate classification models permitted discrimination of the cancerous from non-cancerous samples with an accuracy of 87%. The accumulation of several metabolites (inter alia lactate, glutamate, succinate) in the fibrotic tissue within the tumor in reference to the extratumoral fibrous connective tissue was detected. The results of our work contribute to the increased understanding of breast cancer heterogeneity. Breast tumors constitute the complex entities composed of cancer cells and stromal components. The compositional heterogeneity should be taken into account in bulk tissue metabolomics studies. The aim of this work was to find the relation between the histological content and 1H HR-MAS (high-resolution magic angle spinning nuclear magnetic resonance) metabolic profiles of the tissue samples excised from the breast tumors and the peritumoral areas in 39 patients diagnosed with invasive breast carcinoma. The total number of the histologically verified specimens was 140. The classification accuracy of the OPLS-DA (Orthogonal Partial Least Squares Discriminant Analysis) model differentiating the cancerous from non-involved samples was 87% (sensitivity of 72.2%, specificity of 92.3%). The metabolic contents of the epithelial and stromal compartments were determined from a linear regression analysis of the levels of the evaluated compounds against the cancer cell fraction in 39 samples composed mainly of cancer cells and intratumoral fibrosis. The correlation coefficients between the levels of several metabolites and a tumor purity were found to be dependent on the tumor grade (I vs II/III). The comparison of the levels of the metabolites in the intratumoral fibrosis (obtained from the extrapolation of the regression lines to 0% cancer content) to those levels in the fibrous connective tissue beyond the tumors revealed a profound metabolic reprogramming in the former tissue. The joint analysis of the metabolic profiles of the stromal and epithelial compartments in the breast tumors contributes to the increased understanding of breast cancer biology. [ABSTRACT FROM AUTHOR]

Simple Summary: We here show that CD169+ TAMs in primary breast tumors are associated with tertiary lymphoid-like structures (TLLSs), Treg and Breg signatures, and a worse prognosis for the patient. In contrast, CD169+ TAMs and TLLSs present in lymph node metastases were associated with better prognosis. We propose that the negative prognostic value related to CD169+ TAMs and TLLSs in primary breast tumors is a unique consequence of an immunosuppressive tumor environment in advanced breast cancers. This knowledge is important for understanding the immune landscape in breast cancer and for future targeted therapies. The presence of CD169+ macrophages in the draining lymph nodes of cancer patients is, for unknown reasons, associated with a beneficial prognosis. We here investigated the prognostic impact of tumor-infiltrating CD169+ macrophages in primary tumors (PTs) and their spatial relation to tumor-infiltrating B and T cells. Using two breast cancer patient cohorts, we show that CD169+ macrophages were spatially associated with the presence of B and T cell tertiary lymphoid-like structures (TLLSs) in both PTs and lymph node metastases (LNMs). While co-infiltration of CD169+/TLLS in PTs correlated with a worse prognosis, the opposite was found when present in LNMs. RNA sequencing of breast tumors further confirmed that SIGLEC1 (CD169) expression was associated with mature tertiary lymphoid structure (TLS), and Treg and Breg signatures. We propose that the negative prognostic value related to CD169+ macrophages in PTs is a consequence of an immunosuppressive tumor environment rich in TLSs, Tregs and Bregs. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer is an aggressive subtype of this frequent malignancy in women, for which new therapeutic options are urgently needed. Changes in the packaging of the chromosomes within the cell nucleus, so called "epigenetic modifications", cooperate with direct changes of the DNA sequence, called "genetic alterations", in the development and progression of human tumors. The definition of epigenetic phenomena and the identification of the underlying molecular mechanisms is an active field of research with many open questions. So far, the best-defined players in the field of epigenetics are the methylation of DNA and the covalent modification of histone proteins around which the DNA is wrapped in the nucleus of human cells. Both modifications affect the expression of genes. The principal reversibility of these epigenetic modifications of the DNA strands and the histone proteins make them an attractive target for therapeutic intervention by so-called "epidrugs", and several promising clinical trials are under way. However, many questions regarding specificity, safety, and efficiency of these drugs are still unresolved. Breast cancer, the most frequent malignancy in women worldwide, is a molecularly and clinically very heterogeneous disease. Triple-negative breast cancer is defined by the absence of hormone receptor and growth factor receptor ERBB2/HER2 expression. It is characterized by a more aggressive course of disease and a shortage of effective therapeutic approaches. Hallmarks of cancer cells are not only genetic alterations, but also epigenetic aberrations. The most studied and best understood alterations are methylation of the DNA base cytosine and the covalent modification of histone proteins. The reversibility of these covalent modifications make them attractive targets for therapeutic intervention, as documented in numerous ongoing clinical trials. Epidrugs, targeting DNA methylation and histone modifications, might offer attractive new options in treating triple-negative breast cancer. Currently, the most promising options are combination therapies in which the epidrug increases the efficiency of immuncheckpoint inhibitors. This review focusses exclusively on DNA methylation and histone modifications. In reviewing the knowledge about epigenetic therapies in breast cancer, and especially triple-negative breast cancer, the focus is on explaining concepts and raising awareness of what is not yet known and what has to be clarified in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple Negative Breast Cancer (TNBC) comprises approximately 15–20% of all breast cancer (BC) cases, is often diagnosed at an advanced stage, and is generally associated with an adverse clinical outcome. This systematic review explores differences in the tumor immune microenvironment (TIME) across various molecular subtypes of TNBC. Six studies meeting our inclusion criteria were analyzed, revealing diverse TIMEs with distinct compositions among TNBC molecular subtypes. The IM subtype shows robust immune infiltration, while LAR and MSL subtypes display more immunosuppressive milieu. The spatial distribution of immune cells and immune checkpoint expression varies across TNBC molecular subtypes. TIME heterogeneity reflects genomic diversity, along with differential signaling pathways and metabolic activation. Understanding TIME variability offers strategic opportunities for personalized therapeutic interventions in TNBC. Triple Negative Breast Cancer (TNBC) is characterized by distinct molecular subtypes with unique biological and clinical features. This systematic review aimed to identify articles examining the differences in the tumor immune microenvironment (TIME) across different TNBC molecular subtypes. Six studies meeting inclusion criteria were analyzed, utilizing gene expression profiling and bioinformatic analyses to classify TNBC samples into molecular subtypes, as well as immunohistochemistry and cell deconvolution methods to characterize the TIME. Results revealed significant heterogeneity in immune cell composition among TNBC subtypes, with the immunomodulatory (IM) subtype demonstrating robust immune infiltration, composed mainly of adaptive immune cells along with an increased density of CTLA-4+ and PD-1+ TILs, high PD-L1 tumor cell expression, and upregulation of FOXP3+ Tregs. A more immunosuppressive TIME with a predominance of innate immune cells and lower levels of tumor-infiltrating lymphocytes (TILs) was observed in luminal androgen receptor (LAR) tumors. In mesenchymal stem-like (MSL) tumors, the TIME was mainly composed of innate immune cells, with a high number of M2 tumor-associated macrophages (TAMs), while the BL and M tumors displayed poor adaptive and innate immune responses, indicating an "immune-cold" phenotype. Differential activation of signaling pathways, genomic diversity, and metabolic reprogramming were identified as contributors to TIME heterogeneity. Understanding this interplay is crucial for tailoring therapeutic strategies, especially regarding immunotherapy. [ABSTRACT FROM AUTHOR]