Search Results (615)

PR/SET domain 2 (PRDM2)/RIZ is a member of the histone/protein methyltransferases (PRDMs) superfamily. Discovered to have the ability to bind retinoblastoma in the mid-1990s, PRDM2 was assumed to play a role in neuronal development. Like other family members characterized by a conserved N-terminal PR structural domain and a classical C2H2 zinc-finger array at the C-terminus, PRDM2 encodes two major protein types, the RIZ1 and RIZ2 isoforms. The two subtypes differ in the presence or absence of the PR domain: the RIZ1 subtype has the PR domain, whereas the RIZ2 subtype lacks it. The PR domain exhibits varying conservation levels across species and shares structural and functional similarities with the catalytic SET domain, defining histone methyltransferases. Functioning as an SET domain, the PR domain possesses protein-binding interfaces and acts as a lysine methyltransferase. The variable number of classic C2H2 zinc fingers at the C-terminus may mediate protein–protein, protein–RNA, or protein–DNA interactions. An imbalance in the RIZ1/RIZ2 mechanism may be an essential cause of malignant tumors, where PR-positive isoforms are usually lost or downregulated. Conversely, PR-negative isoforms are always present at higher levels in cancer cells. RIZ1 isoforms are also important targets for estradiol interaction with hormone receptors. PRDM2 can regulate gene transcription and expression combined with transcription factors and plays a role in the development of several systemic diseases through mRNA expression deletion, code-shift mutation, chromosomal deletion, and missense mutation occurrence. Thus, PRDM2 is a key indicator for disease diagnosis, but it lacks systematic summaries to serve as a reference for study. Therefore, this paper describes the structure and biological function of PRDM2 from the perspective of its role in various systemic diseases. It also organizes and categorizes its latest research progress to provide a systematic theoretical basis for a more in-depth investigation of the molecular mechanism of PRDM2’s involvement in disease progression and clinical practice. Full article

Background and Objectives: The effect of AR expression on prognosis in hormone receptor-positive her2-negative breast cancer is controversial. There are studies showing that AR is a treatment target, a mechanism of resistance to endocrine treatments, and a prognostic indicator in these patients whose standard treatment is a CDK 4/6 inhibitor added to endocrine treatment. We aimed to investigate the effect of AR, the AR/ER ratio, and the AR/PR ratio on CDK4/6 inhibitor treatment response in breast cancer, as well as their effects on PFS, and to validate the hypothesis that AR is a target for research. Materials and Methods: Patients who were diagnosed with metastatic hormone receptor-positive her2-negative breast cancer and received cdk4/6 inhibitor + aromatase inhibitor in first-line therapy were included in this study conducted at Balıkesir Atatürk City Hospital. The tru-cut biopsy samples of the patients were evaluated immunohistochemically for AR, ER, and PR. Kaplan–Meier analysis was used to calculate the estimated median survival in PFS analyses, and the variables were compared with the Log-Rank test. Receiver Operating Characteristic (ROC) analysis was applied to determine the ideal cut-off. Cox regression analysis was used in univariate survival models, and the multivariate model was established with the “Forward: Likelihood Ratio (LR)” method. Hazard ratios (HRs) were also calculated as 95% confidence intervals (95% CIs). A p value below 0.05 was accepted for statistical significance. Results: In total, 41 patients were included in the study, and 73% (n = 30) of the patients were AR-positive. Increased AR (HR 1.014; 95% CI: 1.002–1.026; p = 0.023) was an unfavorable prognostic indicator. In our study, being ≥55 years old, being postmenopausal, not having visceral metastasis, having a non-IDC histology, having a low AR level (<50%), having an AR/ER ratio < 0.74, and having an AR/PR ratio < 1.00 were found to be associated with longer PFS. All factors were evaluated with univariate Cox regression analysis. Increasing AR (HR 1.014; 95% CI: 1.002–1.026; p = 0.023) was an unfavorable prognostic marker. Having an AR/ER ratio ≥ 0.74 (HR: 2.522; 95% CI: 1.004–6.336; p = 0.049) and having AR/PR ≥ 1 (HR: 2.659; 95% CI: 1.029–6.869; p = 0.043) were negative prognostic indicators. Conclusions: Our results were consistent with the literature and demonstrated the value of the androgen receptor as a therapeutic target, a mechanism explaining resistance to endocrine therapy, and an adverse prognostic indicator for creating resistance to endocrine therapy in breast cancer. Full article

Obesity is a well-established risk factor for both the incidence and poorer clinical outcomes of Breast Cancer (BC), particularly among hormone receptor-positive postmenopausal women. However, conventional weight loss interventions have yielded limited success in altering cancer prognosis. Recently, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, have emerged as effective pharmacologic agents for sustained weight loss and are under investigation in oncology. This narrative review synthesizes evidence linking obesity to poor BC prognosis and evaluates the therapeutic potential of GLP-1 RAs in this context. Mechanistically, obesity exacerbates tumor progression through hormonal imbalance, chronic inflammation, and adipokine and insulin signaling, targets that may be modifiable through weight reduction. GLP-1 RAs offer multiple benefits, such as appetite suppression, delayed gastric emptying, and enhanced insulin sensitivity. Clinical studies in BC patients have shown weight loss ranging from 2.3% to 5%, likely attenuated by concurrent endocrine therapy. Preliminary data suggest that GLP-1 RA use does not increase the risk of cancer recurrence and may reduce cardiovascular morbidity. However, prospective studies are needed to confirm long-term oncologic safety and efficacy. Disparities in access and cost remain barriers to widespread adoption. Nevertheless, GLP-1 RAs represent a promising adjunct to manage obesity among BC patients, potentially improving metabolic health and long-term cancer outcomes. Full article

Cyclin-dependent kinase (CDK)4/6 inhibitors have become a key component of adjuvant treatment for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) early breast cancer who are at high risk of recurrence. The addition of abemaciclib and ribociclib to standard endocrine therapy has demonstrated clinically meaningful improvements in invasive disease-free survival, supported by the monarchE and NATALEE trials, respectively. With expansion of patient eligibility for CDK4/6 inhibitors, multidisciplinary coordination among medical oncologists, surgeons, nurses, pharmacists, and other health care providers is critical to optimizing patient identification, monitoring, and management of adverse events. This expert guidance document provides practical recommendations for implementing adjuvant CDK4/6 inhibitor therapy in routine clinical practice, incorporating insights from multiple specialties and with patient advocacy representation. Key considerations include patient selection based on clinical trial data, treatment duration, dosing schedules, adverse event profiles, monitoring requirements, drug–drug interactions, and patient-specific factors such as tolerability, cost, and quality of life. This guidance aims to support Canadian clinicians in effectively integrating CDK4/6 inhibitors into clinical practice, ensuring optimal patient outcomes through a multidisciplinary and patient-centric approach. Full article

Background/Objectives: Breast cancer was the leading cause of malignant tumors among women in 2022. About two-thirds of breast cancer cases are hormone-receptor-positive. In these patients, aromatase inhibitors are a mainstay of treatment, but associated musculoskeletal symptoms can negatively affect patient compliance. Aromatase-inhibitor-induced carpal tunnel syndrome represents one of the main causes of aromatase inhibitor discontinuation, with a non-compliance rate of up to 67%, potentially leading to increased cancer mortality. This study investigates estrogen receptor expression in aromatase-inhibitor-induced carpal tunnel syndrome tissues, in order to better define its etiopathogenesis and derive preventive or therapeutic measures that can improve aromatase inhibitor patient compliance. To our knowledge, there is no study on this subject in the literature. Methods: Between 2023 and 2024, we recruited 14 patients at the Jewish Hospital of Rome, including seven patients with aromatase-inhibitor-induced carpal tunnel syndrome (study group) and seven with postmenopausal idiopathic carpal tunnel syndrome (control group). Each patient was evaluated based on a clinical visit, a questionnaire, instrumental exams, and serum hormone dosages and were treated with open carpal tunnel release surgery, during which transverse carpal ligament and flexor tenosynovium samples were collected. For immunohistochemical experiments, sections were treated with anti-estrogen receptor α and anti-estrogen receptor β antibodies. Results: The immunohistochemical features in the study and control groups were similar, demonstrating that tissues affected by aromatase-inhibitor-induced carpal tunnel syndrome are targets of direct estrogen action and that estrogen deprivation is correlated with disease etiogenesis. Surgery was effective in patient treatment. Conclusions: Aromatase-inhibitor-induced carpal tunnel syndrome represents a newly defined form of the disease. This syndrome represents one of the main causes of aromatase inhibitor discontinuation, due to its negative impact on the patient’s quality of life. The identification by clinicians of aromatase inhibitor use as a possible risk factor for carpal tunnel syndrome development is of essential importance, as early diagnosis and prompt management can improve patient compliance and overall breast cancer treatment outcomes. Full article

Background/Objectives: This study aimed to assess real-world toxicity and efficacy data of patients with early and advanced breast cancer (BC) who received treatment with abemaciclib. Methods: This was a prospective/retrospective multi-institutional collection of clinicopathological, toxicity, and outcome data from patients with early or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC who received treatment with abemaciclib in combination with endocrine therapy in departments of oncology in Greece. Treatment combinations of abemaciclib with any endocrine therapy were accepted. The primary end point was toxicity rate in all patients of the study. Results: From June/2021 to May/2024, 245 women received abemaciclib/endocrine combination therapy; the median age was 57 years. Of these, 169 (69%) received abemaciclib as adjuvant therapy for early-stage disease, while 76 (31%) were treated for advanced BC. At the time of the data cutoff, 133 (84.7%) patients remained in the 2-year treatment period. The most common adverse event (AE) was diarrhea (51%), primarily Grade ≤ 2. Dose modifications due to AEs were required in 19.2% of cases, while treatment discontinuation occurred in 5.1%. There was no difference in dose modification/discontinuation rates between older patients (>65 years) and the remaining patients. For early-stage BC patients, the 2-year DFS and OS rates were 90.8% and 100%, respectively. In patients with advanced cancer (70, 30.8%), 1-year PFS and OS rates were 78% and 96.3%, respectively. Conclusions: This study confirms the safety and effectiveness of abemaciclib in alignment with registrational trials offering valuable insights into toxicity management and clinical outcomes in routine practice without identifying new safety concerns. Clinical Trial Registration: ClinicalTrials.gov NCT04985058. Full article

Background: Unlike most cancers, breast cancer poses a persistent risk of distant recurrence—often years after initial treatment—making long-term risk stratification uniquely challenging. Current tools fall short in predicting late metastatic events, particularly for early-stage patients. Methods: We present an interpretable machine learning (ML) pipeline to predict distant recurrence-free survival at 5, 10, and 15 years, integrating Bayesian network-based causal feature selection, deep feed-forward neural network models (DNMs), and SHAP-based interpretation. Using electronic health record (EHR)-based clinical data from over 6000 patients, we first applied the Markov blanket and interactive risk factor learner (MBIL) to identify minimally sufficient predictor subsets. These were then used to train optimized DNM classifiers, with hyperparameters tuned via grid search and benchmarked against models from 10 traditional ML methods and models trained using all predictors. Results: Our best models achieved area under the curve (AUC) scores of 0.79, 0.83, and 0.89 for 5-, 10-, and 15-year predictions, respectively—substantially outperforming baselines. MBIL reduced input dimensionality by over 80% without sacrificing accuracy. Importantly, MBIL-selected features (e.g., nodal status, hormone receptor expression, tumor size) overlapped strongly with top SHAP contributors, reinforcing interpretability. Calibration plots further demonstrated close agreement between predicted probabilities and observed recurrence rates. The percentage performance improvement due to grid search ranged from 25.3% to 60%. Conclusions: This study demonstrates that combining causal selection, deep learning, and grid search improves prediction accuracy, transparency, and calibration for long-horizon breast cancer recurrence risk. The proposed framework is well-positioned for clinical use, especially to guide long-term follow-up and therapy decisions in early-stage patients. Full article

Background: Pathological complete response (pCR) serves as a prognostic surrogate endpoint for long-term clinical outcomes in breast cancer patients receiving neoadjuvant systemic therapy (NAST). This study aims to develop and evaluate machine learning-based biomarkers for predicting pCR and recurrence-free survival (RFS). Methods: This retrospective monocentric study included 235 women (mean age 46 ± 11 years) with non-metastatic breast cancer treated with NAST. We developed various machine learning models using clinical features (age, genetic mutations, TNM stage, hormonal receptor expression, HER2 status, and histological grade), along with morphological features (size, T2 signal, and surrounding edema) and radiomics data extracted from pre-treatment MRI. Patients were divided into training and test groups with different MRI models. A customized machine learning pipeline was implemented to handle these diverse data types, consisting of feature selection and classification components. Results: The models demonstrated superior prediction ability using radiomics features, with the best model achieving an AUC of 0.72. Subgroup analysis revealed optimal performance in triple-negative breast cancer (AUC of 0.80) and HER2-positive subgroups (AUC of 0.65). Conclusion: Machine learning models incorporating clinical, qualitative, and radiomics data from pre-treatment MRI can effectively predict pCR in breast cancer patients receiving NAST, particularly among triple-negative and HER2-positive breast cancer subgroups. Full article

Oligometastasis represents a clinically relevant state of limited metastatic disease that could be amenable to selected local therapies in carefully chosen patients. Although initial trials such as SABR-COMET demonstrated a survival benefit with aggressive local treatment, breast cancer was underrepresented. Subsequent breast cancer-specific trials, including NRG-BR002, failed to show a clear survival benefit, highlighting uncertainties and the need for further refinement in patient selection and integration with systemic approaches. The definitions of oligometastasis continue to evolve, incorporating radiological, clinical, and biological features. Advances in imaging and molecular profiling suggest that oligometastatic breast cancer might represent a distinct biological subtype, with potential biomarkers including PIK3CA mutations and YAP/TAZ expression. Organ-specific strategies using stereotactic radiotherapy, surgery, and proton therapy have shown favorable local control in certain settings, though their impact on the overall survival remains under investigation. Emerging techniques, including circulating tumor DNA (ctDNA) analysis, are being explored to improve patient selection and disease monitoring. Ongoing trials may provide further insight into the role of local therapy, particularly in hormone receptor-positive or HER2-positive subtypes. Local and systemic strategies need to be carefully coordinated to optimize the outcomes. This review summarizes the current definitions of and evidence and therapeutic considerations for oligometastatic breast cancer and outlines potential future directions. Full article

Background: Transcription factor pancreatic and duodenal homeobox 1 (PDX1) plays a central role in pancreatic development and insulin regulation. However, its role in breast cancer remains largely unexplored. Objective: This study investigated the effects of PDX1 knockdown and overexpression on MCF7 breast cancer cell proliferation and responsiveness to paclitaxel and doxorubicin. Methods: PDX1 knockdown and overexpression models were established in MCF7 cells. Cell viability was assessed using the XTT assay following exposure to paclitaxel (5–100 nM) or doxorubicin (125–10 µM). Gene and protein expression levels were analyzed by qRT-PCR and western blotting. Results: PDX1 knockdown in MCF7 cells led to a significant increase in proliferation compared to the scrambled control, with approximately 3.22-fold at 72 h, whereas PDX1 overexpression markedly reduced proliferation by about 2.4-fold at 72 h when compared with the control. Upon treatment with paclitaxel or doxorubicin, knockdown cells showed higher viability, indicating reduced drug sensitivity. In contrast, PDX1-overexpressing cells exhibited a significant decrease in viability after treatment with both drugs, demonstrating enhanced sensitivity. Conclusions: PDX1 exhibits tumor-suppressive properties in MCF7 cells and modulates drug response, suggesting that it may serve as a biomarker or therapeutic target in hormone receptor-positive breast cancer. Full article

Background and Objectives: The objective of this review is to evaluate the current evidence regarding hormone treatments for both premenopausal and postmenopausal women with early-stage hormone receptor (HR) positive breast cancer. Materials and Methods: An in-depth exploration of the existing literature was conducted, with landmark clinical trials such as TEXT, SOFT, ATLAS, and aTTom serving as primary references. Results: Through an extensive review of the literature, our findings indicate that for premenopausal women with HR-positive, HER2-negative BC with a low risk of recurrence, standard 5-year monotherapy with tamoxifen represents the optimal therapeutic management, given its favorable clinical outcomes and lower associated toxicity. In contrast, for premenopausal women with an intermediate to high risk of recurrence with the same tumor characteristics, the most effective approach stated in the literature is a combination of ovarian suppression therapy (chemical/surgical) and an aromatase inhibitor/selective estrogen receptor modulator (tamoxifen), with a possible extension of the standard therapeutic period. In postmenopausal patients with HR-positive, HER2-negative breast cancer with a low recurrence risk, the first line of treatment is usually a standard 5-year period of treatment with aromatase inhibitors (AIs)(letrozole, anastrozole, or exemestane). On the other hand, in postmenopausal women with an intermediate to high risk, combination therapy might be needed, as well as an extension of the standard therapeutic time. Conclusions: Treatment consensus depends on pre- vs. postmenopausal status and recurrence risk. Full article

Emerging evidence suggests a bidirectional relationship between gut microbiota, melatonin synthesis, and breast cancer (BC) development in hormone receptor-positive patients (HR+HER2+ and HR+HER2-). This study investigated alterations in gut microbiota composition, the serum serotonin–N-acetylserotonin (NAS)–melatonin axis, fecal short-chain fatty acids (SCFAs) and beta-glucuronidase (βGD) activity, and serum zonulin in HR+ BC patients compared to healthy controls. Blood and fecal samples were analyzed using mass spectrometry for serotonin, NAS, melatonin, and SCFAs; ELISA for AANAT, ASMT, 14-3-3 protein, and zonulin; fluorometric assay for βGD activity; and 16S rRNA sequencing for gut microbiota composition. HR+ BC patients exhibited gut dysbiosis with reduced Bifidobacterium longum and increased Bacteroides eggerthii, alongside elevated fecal βGD activity, SCFA levels (e.g., isovaleric acid), and serum zonulin, indicating increased intestinal permeability. Serum serotonin and N-acetylserotonin (NAS) levels were elevated, while melatonin levels were reduced, with a higher NAS/melatonin ratio in BC patients. AANAT levels were increased, and ASMT levels were decreased, suggesting disrupted melatonin synthesis. Bifidobacterium longum positively correlated with melatonin and negatively with βGD activity, while Bacteroides eggerthii showed a positive correlation with βGD activity. These findings suggested that gut microbiota alterations, disrupted melatonin synthesis, microbial metabolism, and intestinal permeability may contribute to BC pathophysiology. The NAS/melatonin ratio could represent a potential biomarker, necessitating further mechanistic studies to confirm causality and explore therapeutic interventions. Full article

The adjuvant treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) early breast cancer (EBC) is rapidly evolving, with a diverse range of therapeutic options—including endocrine therapies, bisphosphonates, ovarian function suppression, olaparib, CDK4/6 inhibitors, and emerging agents such as immunotherapy. While these advances have markedly improved patient outcomes, they also introduce challenges related to implementation, monitoring, and resource allocation. Notably, therapies like CDK4/6 inhibitors require particularly close monitoring, creating logistical and capacity challenges for medical oncologists, whose workloads are already stretched due to rising cancer incidence and treatment complexities. These challenges underscore the need for innovative care delivery solutions to ensure patients with EBC continue to receive optimal care. This paper offers a comprehensive guide—a playbook—of multidisciplinary-team-based care models designed to optimize adjuvant treatment delivery in EBC. Drawing on real-world evidence and successful applications across Canadian centers, we explore models led by nurses, nurse practitioners (NPs), general practitioners in oncology (GPO), and pharmacists. Each model leverages the unique expertise of its team to manage treatment toxicities, facilitate adherence, and enhance patient education, thereby promoting effective and sustainable care delivery. Importantly, these models are not intended to compete with one another, but rather to serve as a flexible recipe book from which breast cancer care teams can draw strategies tailored to their local resources and patient needs. By detailing implementation strategies, benefits, and challenges—in many instances supported by quantitative metrics and economic evaluations—this work aims to inspire care teams nationwide to optimize the adjuvant management of patients with HR+, HER2– EBC. Full article

Purpose: Neoadjuvant endocrine therapy (NET) represents a valuable treatment option for hormone receptor-positive (HR+)/HER2-negative breast cancer, particularly in postmenopausal women. This study aimed to evaluate the clinical and histopathological efficacy of NET and to explore early and late changes in Ki-67 and progesterone receptor (PgR) expression as indicators of endocrine response. Methods: A prospective cohort of 127 postmenopausal patients with stage cT1–4N0–3M0 HR+/HER2− breast cancer was enrolled between 2019 and 2021. Patients received NET (mostly letrozole) for a mean of 7.7 months. In 80 cases, a second core biopsy was performed after four weeks. Tumor size, histological grade, and biomarkers (Ki-67, PgR) were assessed pre- and post-treatment. Results: NET led to a significant reduction in tumor size, with median shrinkage of 47.0% (from 32.0 mm to 17.0 mm, p < 0.0001). Breast-conserving surgery (BCS) was performed in 52.2% of patients and lymph node negativity (pN0) was observed in 50.4%. Median Ki-67 decreased from 20.0% at baseline to 5.0% after four weeks (p < 0.0001) and remained low in surgical specimens (median 5.0%, p < 0.0001). In 33.3% of patients, Ki-67 dropped below 2.7%, and 67.0% showed a concordant decrease in both Ki-67 and PgR. PgR expression declined significantly during treatment (p < 0.0001). HER2 status conversion was noted in 6.4% of patients during treatment. Pathological complete response (pCR) occurred in 3.5%, while minimal or moderate residual disease (RCB I–II) was identified in 71.3% of cases. Conclusions: NET effectively reduced tumor burden and histological aggressiveness, enabling higher rates of BCS. Early reduction in Ki-67 and PgR may serve as surrogate markers of endocrine responsiveness, supporting their use for treatment stratification and monitoring during NET in HR+/HER2− breast cancer. Full article

Pathological complete response (pCR) following neoadjuvant therapy for IBC has shown a strong correlation with event-free survival and overall survival. Over the past three decades, the five-year net survival rate for breast cancer has generally increased; however, several Eastern European countries exhibit lower survival rates. Data from Romania, specifically regarding Her2-positive breast cancer response to therapy, are notably limited. Background/Objectives: The aim of our study was to evaluate the response to NAT using chemotherapy and Her2-targeted therapy in a cohort of 167 patients diagnosed with invasive breast cancer in our institution. Methods: We retrospectively analyzed 167 consecutive cases diagnosed with IBC in our institution between January 2020 and September 2024 with Stages II and III Her2-positive IBC. The overall pCR rates and several factors cited in the literature as predictors of pCR were analyzed. Results: Overall, the pCR rate was 50.29%, with higher values in 3+ cases (62.28%) compared to 2+ cases/ISH amplified (24.53%). Higher pCR rates were observed in hormone-negative cases, Stage II cases, estrogen receptor-negative cases, and high Ki-67 values. Patient age, ISH group, Her2 copy number, Her2:CEP17 ratio, and clinical lymph node involvement did not seem to influence pCR rates in our study. Conclusions: The data presented in our study represent, to the best of our knowledge, the largest cohort of patients diagnosed with Her2-positive IBC from Romania. The presented results and the pCR predictive factors were comparable to those cited in other studies on Her2-positive IBC cases. Full article