Search Results (168)

Triple-negative breast cancer (TNBC) is a clinically and molecularly heterogeneous subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. In this study, tumor specimens from 104 TNBC patients were analyzed to characterize molecular and clinicopathological features and to assess the expression and therapeutic potential of four key surface markers: epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), tissue factor (TF), and trophoblast cell surface antigen (TROP2). Multiplex immunofluorescence (mIF) demonstrated elevated EGFR and TROP2 expression in the majority of samples. Significant positive correlations were observed between EGFR and TF, as well as between TROP2 and both TF and EpCAM. Expression analyses revealed increased EGFR and TF levels with advancing tumor stage, whereas EpCAM expression declined in advanced-stage tumors. TROP2 and TF expression were significantly elevated in higher-grade tumors. Additionally, EGFR and EpCAM levels were significantly higher in patients with elevated Ki-67 indices. Binding specificity assays using single-chain variable fragment (scFv-SNAP) fusion proteins confirmed robust targeting efficacy, particularly for EGFR and TROP2. These findings underscore the therapeutic relevance of EGFR and TROP2 as potential biomarkers and targets in TNBC. Full article

Background: Male breast cancer (MBC) is extremely rare, representing less than 1% of breast cancer (BC). Owing to the rarity, there is a substantial knowledge gap regarding the survival trends of MBC compared with female breast cancer (FBC). Methods: We queried the National Cancer Database for BC patients diagnosed during 2004–2018 and utilized an inverse propensity weighted cox regression model assessed the association between sex and overall survival (OS) and survival trends over time by sex. Results: We identified 24,055 MBC and 2,532,470 FBC patients. Patients with MBC were older (mean age: 65.6 vs. 61.4 years), and more likely to have stage IV at diagnosis (7% vs. 4.7%), larger tumors (cT4: 6% vs. 3.7%), and node-positive disease (18.5% vs. 15.5%) (p < 0.001) compared with FBC. MBC were more likely to be estrogen (ER) (88.5% vs. 78.5%) and progesterone receptor (PR) (79.6% vs. 68%) positive and less likely to be HER2 receptor positive (7.9% vs. 9.3%) or triple negative (2.8% vs. 7.6%) compared with FBC (all p < 0.001). The OS rates were lower in MBC compared with FBC (5-year: 73% vs. 83%; 10-year: 54% vs. 70%, p < 0.001). In the propensity weighted cox-regression model, males had higher mortality than females with BC (HR 2.8, 95% CI 2.88–2.9, p < 0.001). The 5-year OS rates increased steadily for FBC from 2004–2015; however, the survival rates did not improve for MBC over the last decade. Conclusions: Our study shows that MBC patients continue to have poor OS compared with patients with FBC and no significant improvement in survival of MBC patients over the past decade. These results underscore the need to investigate personalized treatment interventions for patients with MBC to improve outcomes. Full article

HSD3B1 encodes an enzyme that catalyzes the conversion of adrenal precursors into potent sex steroids. A common germline variant (c.1100C) enhances this effect and is linked to breast cancer (BC) progression. As the HSD3B1 genotypes contribute to differences in local and adrenal steroid production, their transcriptional and phenotypic effects on cancers influenced by hormonal signaling such as BC and endometrial cancer (EC)—particularly in relation to menopausal status—remain unclear. We analyzed BC and EC sequenced from patients that received diagnostic tests in oncology clinics, and we determined the germline HSD3B1 c.1100 genotype (AA, AC, CC) from tumor DNA sequencing by using variant allele frequency, with inferred menopausal status assumed by age at molecular profiling. Whole-transcriptome RNA sequencing and gene set enrichment analysis showed that adrenal-permissive homozygous (CC) tumors in premenopausal ER + BC were enriched for hormone-related pathways, including Estrogen Response Early (NES ≈ +1.8). In premenopausal triple-negative BC, adrenal-restrictive homozygous (AA) tumors exhibited the elevated expression of immune and epithelial genes and the increased prevalence of MED12 alterations (AA 0.25% vs. CC 8%, p < 0.01). In endometrioid EC, CC tumors demonstrated the suppression of immune and proliferative pathways. Postmenopausal cases had higher progesterone receptor IHC positivity (AA 75% vs. CC 83%, p < 0.05) and numerically more frequent ESR1 copy number gains (AA 2.0% vs. CC 4.0%). Results highlight context-specific associations between germline HSD3B1 genotypes and tumor biology in BC and EC. Full article

Pleomorphic invasive lobular carcinoma (PILC or PLC) is a malignant breast tumor considered a rare variant of invasive lobular carcinoma in women, characterized morphologically by marked nuclear pleomorphism, with cells resembling plasmacytoid, histiocytoid, or apocrine cells. One of its defining features is the loss of E-cadherin expression. Considering the biological similarities between species and the limited data available for female dogs, this study aimed to characterize PLC in canines, with an emphasis on its histopathological and immunophenotypic features and its potential applicability as a comparative model. Histopathological analysis of PLC was performed alongside immunohistochemical evaluation using HER2, estrogen receptors (ER), progesterone receptors (PR), E-cadherin, and Ki-67 (cell proliferation indexing) markers. All canine PLCs tested positive for PR, with the majority being negative for ER, and all were negative for HER2 and E-cadherin. In contrast, in women, all cases were positive for ER, most were positive for PR, and all were negative for HER2. The Luminal B molecular subtype was the most frequent in dogs, whereas Luminal A and Luminal B subtypes showed equal prevalence in women. These findings reveal shared and distinct immunophenotypic features between species. The similarities and differences observed emphasize the relevance of the canine model for comparative oncology. Furthermore, the use of spontaneous tumors in immunocompetent dogs in this study strengthens the translational potential of the findings, thereby reinforcing the use of the canine model in breast cancer research and supporting its role within the One Medicine concept. Full article

Background: As per recent scenarios, drug resistance is a significant challenge in treating breast cancer for several reasons, such as genetic mutations, altered signaling pathways, and tumor microenvironment. Endocrine resistance is one of the biggest significant barriers to treatment, particularly in hormone receptor-positive (HR+) breast cancers, which depends on estrogen or progesterone signaling for growth. While therapies such as tamoxifen, aromatase inhibitors, and selective estrogen receptor degraders (SERDs) have effectively targeted these pathways, many patients develop resistance, rendering them less effective over time, which is driving a need for innovative therapeutics to treat breast cancer and overcome drug resistance and better treatment outcomes. Recent studies suggest that combining the different therapies, including immunotherapy, targeted therapy, chemotherapy, etc., with endocrine therapy, may bypass the endocrine resistance. Methodology: We conducted a comprehensive systematic review and meta-analysis examining the molecular mechanisms of endocrine resistance and evaluating randomized clinical trial outcomes, overall survival and progression-free survival in endocrine-resistant breast cancer patients treated with endocrine therapy, targeted therapy, immunotherapy, or chemotherapy. Results: We have analyzed 35 randomized clinical trial studies for different therapies along with combination therapy, and our results demonstrated that supplementary or additional therapies in endocrine resistance breast cancer patients have better progression-free and overall survival. Conclusions: The current study has demonstrated that combination therapies may have good survival results and patient outcomes in endocrine resistance. Also, This review sheds light on current challenges in drug resistance and the future direction of cancer treatment through a comprehensive analysis of these emerging treatment approaches to improve patient outcomes. Full article

Approximately 70–80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective estrogen receptor modulator (SERM); fulvestrant, a selective estrogen receptor degrader (SERD); and aromatase inhibitors (AIs), which block estrogen synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination of ET with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) has been shown to significantly increase progression-free survival (PFS) and, in some cases, overall survival (OS). CDK4/6is works by arresting the cell cycle in the G1 phase, preventing DNA synthesis, and enhancing the efficacy of ET. This review highlights the key mechanisms of resistance to ET, whether used alone or in combination with biological agents, as well as emerging therapeutic strategies aimed at overcoming resistance. Addressing ET resistance remains a work in progress, and in the near future, better patient selection for different therapeutic approaches is expected through the identification of more precise biological and genetic markers. In particular, liquid biopsy may provide a real-time portrait of the disease, offering insights into mechanisms driving ET resistance and cancer progression. Full article

Breast cancer is the most common malignancy among women globally, with incidence rates continuing to rise. A comprehensive understanding of its risk factors and the underlying biological mechanisms that drive tumor initiation is essential for developing effective prevention strategies. This review examines key non-modifiable risk factors, such as genetic predisposition, demographic characteristics, family history, mammographic density, and reproductive milestones, as well as modifiable risk factors like exogenous hormone exposure, obesity, diet, and physical inactivity. Importantly, reproductive history plays a dual role, providing long-term protection while temporarily increasing breast cancer risk shortly after pregnancy. Current chemoprevention strategies primarily depend on selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, which have demonstrated efficacy in reducing the incidence of estrogen receptor-positive breast cancer but remain underutilized due to adverse effects. Emerging approaches such as aromatase inhibitors, RANKL inhibitors, progesterone antagonists, PI3K inhibitors, and immunoprevention strategies show promise for expanding preventive options. Understanding the interactions between risk factors, hormonal influences, and tumorigenesis is critical for optimizing breast cancer prevention and advancing safer, more targeted chemopreventive interventions Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. While TNBC is relatively less common, accounting for only 10–15% of initial breast cancer diagnosis, due to its aggressive nature, it carries a worse prognosis in comparison to its hormone receptor-positive counterparts. Despite significant advancements in the screening, diagnosis, and treatment of breast cancer, TNBC remains an important public health burden. Following treatment with chemotherapy, surgery, and radiation, over 40% of TNBC patients experience relapse within 3 years and achieve the least benefit from post-mastectomy radiation. The tumor microenvironment environment (TME) is pivotal in TNBC initiation, progression, immune evasion, treatment resistance, and tumor prognosis. TME is a complex network that consists of immune cells, non-immune cells, and soluble factors located in the region adjacent to the tumor that modulates the therapeutic response differentially between hormone receptor-positive breast cancer and TNBC. While the mechanisms underlying the radiation resistance of TNBC remain unclear, the immunosuppressive TME of TNBC has been implicated in chemotherapeutic resistance. Radiation therapy (RT) is known to alter the TME; however, immune changes elicited by radiation are poorly characterized to date, and whether these immune changes contribute to radiation resistance remains unknown. This review delves into the distinct characteristics of the TNBC TME, explores how RT influences TME dynamics, and examines mechanisms underlying tumor radiosensitization, radioresistance, and immune responses. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) is characterized by the absence of the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. As there are no specific targeted therapies, TNBC patients often face an aggressive clinical course. The expression of the androgen receptor (AR) has been found in up to 30% of TNBC cases, but the association between the AR status and survival rates in TNBC remains controversial. The aim of this study was to explore the association of AR expression with the disease outcome in patients with early TNBC within a 5-year follow-up. Methods: AR expression was determined by immunohistochemistry in a cohort of 124 early-TNBC patients treated at the Institute for Oncology and Radiology of Serbia. The cut-off value used for the positive AR status was >10% tumor cells. The association of the AR status with clinicopathological factors (age, stage, tumor diameter, lymph node invasion, metastatic spread, Ki-67 score, EGFR score, and cytokeratin 5/6 score) and the disease outcome (disease-free survival—DFS—and overall survival—OS) was investigated. Results: Our analysis showed that the AR-positive status was associated with a significantly lower Ki-67 score compared to the AR-negative samples. A univariate analysis indicated that the age, tumor size, nodal status, and EGFR score significantly influenced both 5-year DFS and OS. Multivariate Cox analysis suggested that a smaller tumor size, lower nodal status, and AR expression were independent predictors of longer survival rates in TNBC patients. Conclusions: The results of this study suggest that the positive AR status may be a favorable prognostic factor in TNBC patients within the first five years after surgery. Full article

Background: The discovery of novel antibody–drug conjugates for low-expression human epidermal growth factor receptor 2 (HER2-low) breast cancer highlights the inadequacy of the conventional binary classification of HER2 status as either negative or positive. Identification of HER2-low breast cancer is crucial for selecting patients who may benefit from targeted therapies. This study aims to determine whether qualitative and quantitative magnetic resonance imaging (MRI) features can effectively reflect low-HER2-expression breast cancer. Methods: Pre-treatment breast MRI images from 232 patients with pathologically confirmed breast cancer were retrospectively analyzed. Both clinicopathologic and MRI features were recorded. Qualitative MRI features included Breast Imaging Reporting and Data System (BI-RADS) descriptors from dynamic contrast-enhanced MRI (DCE-MRI), as well as intratumoral T2 hyperintensity and peritumoral edema observed in T2-weighted imaging (T2WI). Quantitative features were derived from diffusion kurtosis imaging (DKI) using multiple b-values and included statistics such as mean, median, 5th and 95th percentiles, skewness, kurtosis, and entropy from apparent diffusion coefficient (ADC), D_app, and K_app histograms. Differences in clinicopathologic, qualitative, and quantitative MRI features were compared across groups, with multivariable logistic regression used to identify significant independent predictors of HER2-low breast cancer. The discriminative power of MRI features was assessed using receiver operating characteristic (ROC) curves. Results: HER2 status was categorized as HER2-zero (n = 60), HER2-low (n = 91), and HER2-overexpressed (n = 81). Clinically, estrogen receptor (ER), progesterone receptor (PR), hormone receptor (HR), and Ki-67 levels significantly differed between the HER2-low group and others (all p < 0.001). In MRI analyses, intratumoral T2 hyperintensity was more prevalent in HER2-low cases (p = 0.009, p = 0.008). Mass lesions were more common in the HER2-zero group than in the HER2-low group (p = 0.038), and mass shape (p < 0.001) and margin (p < 0.001) significantly varied between the HER2 groups, with mass shape emerging as an independent predictive factor (HER2-low vs. HER2-zero: p = 0.010, HER2-low vs. HER2-over: p = 0.012). Qualitative MRI features demonstrated an area under the curve (AUC) of 0.763 (95% confidence interval [CI]: 0.667–0.859) for distinguishing HER2-low from HER2-zero status. Quantitative features showed distinct differences between HER2-low and HER2-overexpression groups, particularly in non-mass enhancement (NME) lesions. Combined variables achieved the highest predictive accuracy for HER2-low status, with an AUC of 0.802 (95% CI: 0.701–0.903). Conclusions: Qualitative and quantitative MRI features offer valuable insights into low-HER2-expression breast cancer. While qualitative features are more effective for mass lesions, quantitative features are more suitable for NME lesions. These findings provide a more accessible and cost-effective approach to noninvasively identifying patients who may benefit from targeted therapy. Full article

Breast cancer poses a significant global health challenge and includes various subtypes, such as endocrine-positive, HER2-positive, and triple-negative. Endocrine-positive breast cancer, characterized by estrogen and progesterone receptors, is commonly treated with aromatase inhibitors. However, resistance to these inhibitors can hinder patient outcomes due to genetic and epigenetic alterations, mutations in the estrogen receptor 1 gene, and changes in signaling pathways. Radiogenomics combines imaging techniques like MRI and CT scans with genomic profiling methods to identify radiographic biomarkers associated with resistance. This approach enhances our understanding of resistance mechanisms and metastasis patterns, linking them to specific genomic profiles and common metastasis sites like the bone and brain. By integrating radiogenomic data, personalized treatment strategies can be developed, improving predictive and prognostic capabilities. Advancements in imaging and genomic technologies offer promising avenues for enhancing radiogenomic research. A thorough understanding of resistance mechanisms is crucial for developing effective treatment strategies, making radiogenomics a valuable integrative approach in personalized medicine that aims to improve clinical outcomes for patients with metastatic endocrine-positive breast cancer. Full article

Objectives: Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options due to the absence of estrogen, progesterone receptors, and HER2 expression. This study examined the impact of DNA methylation and demethylation markers in tumor tissues on TNBC patients’ response to neoadjuvant chemotherapy (NACT) and analyzed the correlation between 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) and clinicopathological characteristics, offering new insights into the predictive value of these epigenetic markers. Methods: The study included 53 TNBC female patients, 19 of whom received neoadjuvant chemotherapy (NACT) before surgery. Global DNA methylation and demethylation levels were quantified using an ELISA-based method to measure 5-mC and 5-hmC content in DNA isolated from pre-treatment biopsy samples (in patients undergoing NACT) and postoperative tissues (in patients without NACT). Results: In patients who received NACT, those with disease progression had significantly higher pretreatment levels of 5-hmC (p = 0.028) and a trend toward higher 5-mC levels (p = 0.054) compared to those with pathological complete response, partial response, or stable disease. Higher 5-mC and 5-hmC levels were significantly associated with higher tumor grade (p = 0.039 and p = 0.017, respectively). Additionally, a positive correlation was observed between the Ki-67 proliferation marker and both 5-mC (r_S = 0.340, p = 0.049) and 5-hmC (r_S = 0.341, p = 0.048) levels in postoperative tissues. Conclusions: Our study highlights the potential of global DNA methylation and demethylation markers as predictors of tumor aggressiveness and chemotherapy response in TNBC. Further research in larger cohorts is necessary to validate these markers’ prognostic and predictive value. Full article

Background. CXCR4 is a chemokine receptor that is frequently overexpressed in invasive breast cancer and plays a major role in tumor proliferation, aggressiveness and metastasis. The aim of this prospective study was to establish the value of CXCR4-directed PET imaging in patients with breast cancer using the novel CXCR4-targeted PET probe ⁶⁸Ga-Pentixafor by comparing it with ¹⁸F-FDG PET/CT (n = 40). Materials and methods. In this prospective cross-sectional study, fifty-one patients with breast cancer aged 36–81 (median (Q1-Q3) 51 (42.5–63)), n = 47 (92%) with initially diagnosed and n = 4 (8%) patients with recurrent breast cancer, underwent CXCR4-targeted PET imaging using ⁶⁸Ga-Pentixafor. Maximum standardized uptake values (SUVmax), total lesion glycolysis (TLG) or total lesion uptake (TLU), metabolic tumor volume (MTV) and tumor-to-background ratios (TBR) of tumor lesions were measured and correlated with pathological prognostic factors, molecular subtypes and CXCR4 immunohistochemistry (IHC) staining. ¹⁸F-FDG PET/CT images were available in 40 of 51 cases (82%) and were compared semi-quantitatively. The patients were followed up for a median of 11 months (range 4–80 months) to determine whether CXCR4 expression correlated with survival. Results. ⁶⁸Ga-Pentixafor-PET/CT was visually positive in 49/51 (96%) of the cases; in addition, [¹⁸F]FDG demonstrated a higher SUVmax compared to ⁶⁸Ga-Pentixafor. The mean SUVmax was 7.26 ± 2.84 and 18.8 ± 9.1 for ⁶⁸Ga-Pentixafor and [¹⁸F]FDG, respectively. Thirty-seven percent (18/51) of patients had triple-negative breast cancer and 25/51 (49%) had estrogen receptor (ER+) disease. There was a statistically significant correlation between tumor grade, proliferative index (Ki-67) and SUVmax obtained from ⁶⁸Ga-Pentixafor PET p = 0.002. There was no correlation between the SUVmax obtained from ⁶⁸Ga-Pentixafor and PET molecular subtypes, estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2) status; however, triple-negative breast cancers had more avid ⁶⁸Ga-Pentixafor accumulation compared to luminals A and B. The median (Q1–Q3) ⁶⁸Ga-Pentixafor TLU was significantly higher in HIV-positive (376 (219–881)) compared to HIV-negative (174 (105–557)) breast cancer patients. Conclusions. In conclusion, ⁶⁸Ga-Pentixafor had a sensitivity of 96% and a specificity of 100% for detecting primary breast cancer; in addition, ⁶⁸Ga-Pentixafor exhibited significantly higher uptake in patients with higher tumor grade, high proliferative index and triple-negative breast cancer (TNBC), as well as HIV-infected breast cancer patients, highlighting the potential clinical utility and prognostic role of CXCR4-targeted PET imaging in aggressive breast cancer. Notably, ⁶⁸Ga-Pentixafor complements ¹⁸F-FDG by detecting more metastasis in the brain and the skull where FDG has limitations, while ¹⁸F-FDG remains superior for detecting skeletal metastasis. Future research should further explore the potential of CXCR4-targeted PET imaging in selecting patients with triple-negative breast cancer and high-grade breast cancer who may benefit from CXCR4-targeted therapies, particularly in the context of HIV co-infection. Full article

Breast cancer is the most clinically relevant pathology of the mammary gland and is currently the most diagnosed malignant disease among women worldwide. In breast cancer prevention, it is important to consider that the risk of developing the disease is not the same for the entire population. This pathology presents heterogeneous clinical manifestations and the most common classification is related to the following hormonal receptors: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and triple-negative (TNBC). Currently, a new class of therapy is being used for cancer treatment: anti-body-drug conjugates. A bibliographic search was performed by establishing keywords and then combining them using Boolean operators OR and AND. Thus, the search equation was formulated according to the PICO search question to be used in the PubMed database. Results: Fifteen studies that met the established inclusion criteria were analyzed, and their methodological quality was assessed using the Joanna Briggs Institute approach, demonstrating high reliability in the results obtained, the analyzed studies focus on the combination of adjuvant Pertuzumab + Trastuzumab with chemotherapy for the treatment of HER2-positive breast cancer. Scientific evidence suggests that the combination of pertuzumab and trastuzumab not only improves the survival of patients with HER2-positive breast cancer but also provides a safe and flexible treatment option. Full article

Breast cancer (BC) is the most common cancer in women, and a higher level of prolactin-induced protein (PIP) is associated with better responses to adjuvant chemotherapy. The signal transducer and activator of transcription 5 (STAT5) is a potential regulator of the PIP gene. Prolactin (PRL) and its receptor (PRLR) activate JAK2/STAT5 signaling in BC, which is modulated by inhibitors like suppressors of cytokine signaling (SOCS) proteins and protein inhibitors of activated STAT (PIAS). Using real-time PCR and immunohistochemistry, we studied the relationship between PIP and STAT5 inhibitors in BC. Our findings indicated that PIP and STAT5 levels decrease with a higher tumor grade, size, and tumor/nodes/metastasis (TNM) clinical stage, while nuclear PIAS3 levels increase with tumor progression. Both STAT inhibitors are linked to estrogen and progesterone receptor status. Notably, STAT5 correlates positively with PIP, SOCS3, and PIAS3, suggesting that it may be a favorable prognostic factor. Among the STAT inhibitors, only nuclear PIAS3 expression correlates with PIP. In vitro studies indicated that silencing PIAS3 in T47D cells does not affect PIP expression or sensitivity to doxorubicin (DOX), but T47D control cells with a higher PIP expression are more sensitive to DOX, highlighting the need for further investigation into these mechanisms. Full article