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Breast cancer is the most prevalent cancer in women. Anthracyclines are commonly used as the first line of treatment, often combined with other agents, including trastuzumab. Despite their efficacy, both drugs pose a risk of cardiotoxicity, which may impair patients’ quality of life (QoL) and hinder treatment persistence. Anthracycline-induced cardiotoxicity is dose-dependent and generally irreversible, whereas trastuzumab is associated with potentially reversible cardiac dysfunction. This review discusses the risk factors and biological mechanisms underlying chemotherapy-induced cardiotoxicity in breast cancer and explores effective strategies for prevention and treatment. It has been demonstrated that several cardioprotective strategies, such as treatments with angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), beta-blockers, and dexrazoxane, can help lessen cardiotoxic effects. A better understanding of cardioprotective strategies may help optimize cancer treatment without compromising cardiovascular function. Full article

Soy has a long history of consumption in Asia and was traditionally prepared by rinsing, cooking, and simmering, methods which remove estrogenic isoflavones (Isofls). Population studies have indicated that soy and/or Isofls may be associated with a decreased risk of breast cancer (BC), while in vitro and experimental data indicate dose-related proliferative effects of Isofls on breast cells. This review attempts to decipher the role of soy and Isofls in the risk of BC in women, since previous studies have suggested a lack of association with BC. Several dozen population studies conducted in Asian and Western countries were analyzed, as were data collected during in vitro animal and clinical trials of relevant doses of soy and Isofls. Although soy intake has been estimated well in Asian countries and could be related to preventive effects on BC risk, this has not been the case in the West, where the consumption of hidden soy is often omitted. However, in both cultures, the Isofl intake is misestimated, and the groups are misclassified. Indeed, in Asia, the origin of soy foods, i.e., homemade or industrial, has never been reported, and in the West, the amount of Isofls consumed in hidden soy has not been determined. Moreover, in most cohort studies, only a few subjects were exposed to active doses of Isofls on breast cells. Similarly, clinical interventions showed estrogenic effects of Isofls at relevant doses. Finally, population studies have not shown any convincing link between soy or Isofl intake and BC risk, likely because they have opposite effects on this pathology. Thus, based on in vitro, experimental, and clinical data, a deleterious effect of Isofls cannot be excluded when active doses are ingested, even if the soy food matrix can be protective. 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

Background/Objectives: Triple negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer, accounting for approximately 10–15% of all cases. While reproductive and metabolic factors contribute to breast cancer development, growing concerns about environmental exposures, alongside biological and socio-cultural influences, underscore the need for targeted prevention strategies across diverse populations. Despite increasing evidence linking biological, socioeconomic, and environmental factors to TNBC outcomes, the molecular mechanisms underlying these relationships remain poorly understood. Micro-RNAs (miRNAs), which regulate gene expression and play critical roles in cancer development, have emerged as potential mediators between environmental exposures and TNBC progression. The goal of this research is to identify environmental risk factors that directly relate to TNBC stages and enhance understanding of the mechanisms underlying how miRNAs link environmental exposures to TNBC stages. Methods: In this study, we analyzed 434 Formalin-Fixed, Paraffin-Embedded (FFPE) tumor samples from 434 women diagnosed with TNBC between 2009 and 2019, encompassing diverse cancer stages (184 cases from early stage and 250 cases from advanced stage), racial backgrounds, and socioeconomic statuses. The sequencing data were linked with the Louisiana Tumor Registry data and the Environmental Justice index. Results: A total of 348 unique miRNAs were identified as differentially expressed across environmental risk factors statistically associated with TNBC stage, adjusting for plate effects. An UpSet plot revealed 44 miRNAs commonly differentially expressed across TNBC stages and multiple environmental exposures. At least one differentially expressed (DE) miRNA was shared between the TNBC stage and each environmental factor, with many associated with receptor-negative and aggressive breast cancer subtypes. Conclusions: These findings highlight potential biological pathways through which exposures may drive the TNBC progression and contribute to disparities in 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

Dose-dense chemotherapy shortens the interval between chemotherapy cycles and has shown improved outcomes in high-risk breast cancer patients. We retrospectively evaluated the efficacy and safety of dose-dense chemotherapy in 80 breast cancer patients treated at our hospital from 2020 to 2024. The regimen included epirubicin and cyclophosphamide followed by paclitaxel or docetaxel, with pegfilgrastim support. The overall treatment completion rate was 82.5%. Of the 80 patients, 55 underwent neoadjuvant chemotherapy, and the pathological complete response rate was significantly higher in triple-negative breast cancer (59.1%) compared to that in luminal-type cancer (9.1%). Common adverse events included anemia, liver dysfunction, myalgia, and peripheral neuropathy. Febrile neutropenia occurred in 8.8% of patients, with some cases linked to pegfilgrastim body pod use, particularly in individuals with low subcutaneous fat. Notably, two patients developed pneumocystis pneumonia, potentially associated with steroid administration. Despite these toxicities, most were manageable and resolved after treatment. Our findings support the efficacy of dose-dense chemotherapy, particularly in triple-negative breast cancer, while highlighting the importance of individualized supportive care and vigilance regarding hematologic and infectious complications. Full article

Purpose: To effectively reduce cancer burden, genetic testing programs should identify high-risk individuals prior to cancer development, when risk-reduction strategies can be implemented. We evaluated trends in BRCA1/BRCA2 testing use after implementation of a publicly funded testing program. Methods: We conducted a retrospective, near population-based study of women who underwent BRCA1/BRCA2 testing in Ontario, Canada, (2007–2016) (n = 15,986). Temporal trends were evaluated using linear and Poisson regression. Results: Although annual utilization of testing increased over time (p < 0.001), mean age at testing increased from 49.9 years (SD 13.8) in 2007 to 53.8 years (SD 13.7) in 2016 (p < 0.001). The proportion of women with a cancer history at testing also increased from 53.5% in 2007 to 66.3% in 2015 (p < 0.001); the proportion of women free from breast cancer did not change significantly (49.2% in 2007 versus 45.1% in 2015, p = 0.90). As a proportion of all tested, those with breast cancer tested within 3 months of diagnosis increased over time (0.39% of tests in 2007 versus 13.6% of tests in 2015; p < 0.001). Conclusions: While the institution of a publicly funded genetic testing program was associated with rising utilization, increasing age at testing and decreasing testing of unaffected women suggest limitations in identifying high-risk individuals eligible for risk-reduction. 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: Breast and hematological cancer treatments, especially with anthracyclines, have been shown to be associated with an increased risk of cardiotoxicity (CTX). An accurate prediction of cardiotoxicity risk and early detection of myocardial injury may allow for effective cardioprotection to be instituted and tailored to reverse cardiac dysfunction and prevent the discontinuation of essential cancer treatments. Objectives: The PRoactive Evaluation of Function to Evade Cardio Toxicity (PREFECT) study sought to evaluate the ability of fast-strain-encoded (F-SENC) cardiac magnetic resonance imaging (CMR) and 2D echocardiography (2D Echo) to stratify patients at risk of CTX prior to initiating cancer treatment, detect early signs of cardiac dysfunction, including subclinical CTX (sub-CTX) and CTX, and monitor for recovery (REC) during cardioprotective therapy. Methods: Fifty-nine patients with breast cancer or lymphoma were prospectively monitored for CTX with F-SENC CMR and 2D Echo over at least 1 year for evidence of cardiac dysfunction during anthracycline based chemotherapy. F-SENC CMR also monitored myocardial deformation in 37 left ventricular (LV) segments to obtain a MyoHealth risk score based on both longitudinal and circumferential strain. Sub-CTX and CTX were classified based on pre-specified cardiotoxicity definitions. Results: CTX was observed in 9/59 (15%) and sub-CTX in 24/59 (41%) patients undergoing chemotherapy. F-SENC CMR parameters at baseline predicted CTX with a lower LVEF (57 ± 5% vs. 61 ± 5% for all, p = 0.05), as well as a lower MyoHealth (70 ± 9 vs. 79 ± 11 for all, p = 0.004) and a worse global circumferential strain (GCS) (−18 ± 1 vs. −20 ± 1 for all, p < 0.001). Pre-chemotherapy MyoHealth had a higher accuracy in predicting the development of CTX compared to CMR LVEF and 2D Echo LVEF (AUC = 0.85, 0.69, and 0.57, respectively). The 2D Echo parameters on baseline imaging did not stratify CTX risk. F-SENC CMR obtained good or excellent images in 320/322 (99.4%) scans. During cancer treatment, MyoHealth had a high accuracy of detecting sub-CTX or CTX (AUC = 0.950), and the highest log likelihood ratio (indicating a higher probability of detecting CTX) followed by F-SENC GLS and F-SENC GCS. CMR LVEF and CMR LV stroke volume index (LVSVI) also significantly worsened in patients developing CTX during cancer treatment. Conclusions: F-SENC CMR provided a reliable and accurate assessment of myocardial function during anthracycline-based chemotherapy, and demonstrated accurate early detection of CTX. In addition, MyoHealth allows for the robust identification of patients at risk for CTX prior to treatment with higher accuracy than LVEF. Full article

Background/Objectives: Cancer suffers from unresolved therapeutic challenges owing to the lack of targeted therapies and heightened recurrence risk. This study aimed to investigate the new series of hydroxamate by structurally modifying the pharmacophore of vorinostat. Methods: The present work involves the synthesis of 15 differently substituted 2H-1,2,3-triazole-based hydroxamide analogs by employing triazole ring as a cap with varied linker fragments. The compounds were evaluated for their anticancer effect, especially their anti-breast cancer response. Molecular docking and molecular dynamics simulations were conducted to examine binding interactions. Results: Results indicated that among all synthesized hybrids, the molecule VI(i) inhibits the growth of MCF-7 and A-549 cells (GI₅₀ < 10 μg/mL) in an antiproliferative assay. Compound VI(i) was also tested for cytotoxic activity by employing an MTT assay against A549, MCF-7, and MDA-MB-231 cell lines, and the findings indicate its potent anticancer response, especially against MCF-7 cells with IC₅₀ of 60 µg/mL. However, it experiences minimal toxicity towards the normal cell line (HEK-293). Mechanistic studies revealed a dual-pathway activation: first, apoptosis (17.18% of early and 10.22% of late apoptotic cells by annexin V/PI analysis); second, cell cycle arrest at the S and G2/M phases. It also promotes ROS generation in a concentration-dependent manner. The HDAC–inhibitory assay, extended in silico molecular docking, and MD simulation experiments further validated its significant binding affinity towards HDAC 1 and 6 isoforms. DFT and ADMET screening further support the biological proclivity of the title compounds. The notable biological contribution of VI(i) highlights it as a potential candidate, especially against breast cancer cells. Full article

Cancer metabolic reprogramming plays a critical role in tumor progression and therapeutic resistance, underscoring the need for advanced analytical strategies. Metabolomics, leveraging mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, offers a comprehensive and functional readout of tumor biochemistry. By enabling both targeted metabolite quantification and untargeted profiling, metabolomics captures the dynamic metabolic alterations associated with cancer. The integration of metabolomics with machine learning (ML) approaches further enhances the interpretation of these complex, high-dimensional datasets, providing powerful insights into cancer biology from biomarker discovery to therapeutic targeting. This review systematically examines the transformative role of ML in cancer metabolomics. We discuss how various ML methodologies—including supervised algorithms (e.g., Support Vector Machine, Random Forest), unsupervised techniques (e.g., Principal Component Analysis, t-SNE), and deep learning frameworks—are advancing cancer research. Specifically, we highlight three major applications of ML–metabolomics integration: (1) cancer subtyping, exemplified by the use of Similarity Network Fusion (SNF) and LASSO regression to classify triple-negative breast cancer into subtypes with distinct survival outcomes; (2) biomarker discovery, where Random Forest and Partial Least Squares Discriminant Analysis (PLS-DA) models have achieved >90% accuracy in detecting breast and colorectal cancers through biofluid metabolomics; and (3) prognostic modeling, demonstrated by the identification of race-specific metabolic signatures in breast cancer and the prediction of clinical outcomes in lung and ovarian cancers. Beyond these areas, we explore applications across prostate, thyroid, and pancreatic cancers, where ML-driven metabolomics is contributing to earlier detection, improved risk stratification, and personalized treatment planning. We also address critical challenges, including issues of data quality (e.g., batch effects, missing values), model interpretability, and barriers to clinical translation. Emerging solutions, such as explainable artificial intelligence (XAI) approaches and standardized multi-omics integration pipelines, are discussed as pathways to overcome these hurdles. By synthesizing recent advances, this review illustrates how ML-enhanced metabolomics bridges the gap between fundamental cancer metabolism research and clinical application, offering new avenues for precision oncology through improved diagnosis, prognosis, and tailored therapeutic strategies. Full article

Background: Breast cancer remains a major public health challenge in Latin America, where access to personalized risk assessment tools is still limited. This study aimed to evaluate the implementation of a polygenic risk score (PRS)-based stratification model combined with remote genomic counseling in Colombian women with sporadic breast cancer and healthy women. Methods: In 2023, an embedded mixed-methods observational study was conducted in Medellín involving 1997 women aged 40–75 years who underwent clinical PRS testing. The intervention integrated PRS-based risk categorization with individualized risk factor assessment and lifestyle recommendations delivered through a remote counseling platform. Results: PRS analysis classified 9.7% of women as high risk and 46% as low risk. Healthier lifestyle patterns were significantly associated with lower PRS categories (p = 0.034). Physical activity showed a protective effect (OR = 0.60, 95% CI: 0.5–0.8), while prior smoking, elevated BMI, and sedentary behavior were associated with higher risk. The counseling model achieved high delivery (93%) and satisfaction (85%) rates. Qualitative insights revealed improved understanding of genomic risk and greater engagement in preventive behaviors. Only one new case of breast cancer was detected among intermediate-risk participants, with a diagnostic lead time of 12 months. Conclusions: These findings support the feasibility, acceptability, and potential impact of integrating PRS and genomic counseling in cancer prevention strategies in middle-income settings. Full article

Background: Obese women have a significantly higher risk of bearing breast tumors that are resistant to therapies and are associated with poorer prognoses/treatment outcomes. Breast cancer-promoting action of obesity is often attributed to elevated levels of insulin, glucose, inflammatory mediators, and misbalanced estrogen production in adipose tissue under obese conditions. Metabolic endotoxemia, characterized by chronic presence of extremely low levels of bacterial endotoxin (lipopolysaccharide [LPS]) in the circulation, is a less explored obesity-associated factor. Results: Here, utilizing in vitro and in vivo models of breast carcinoma (BC), we report that subclinical levels of LPS typical for metabolic endotoxemia enhance the malignant phenotype of breast cancer cells and accelerate breast tumor progression. Conclusions: Our study, while focusing primarily on the direct effects of metabolic endotoxemia on breast tumor progression, also suggests that metabolic endotoxemia can contribute to obesity–breast cancer link. Thus, our findings add novel mechanistic insights into how obesity-associated metabolic changes, particularly metabolic endotoxemia, modulate the biological and clinical behavior of breast carcinoma. In turn, understanding of the mechanistic aspects underlying the association between obesity and breast cancer could help inform better strategies to reduce BC risk in an increasingly obese population and to suppress the breast cancer-promoting consequences of excess adiposity. Full article

Background/Objectives: Genetic polymorphisms in the BRCA2 gene have been implicated in breast cancer susceptibility. While numerous studies have investigated this polymorphism, its precise role in breast cancer development remains unclear. Furthermore, to the best of our knowledge, no related studies have been conducted in Azerbaijan. The aim of this study was to determine the distribution of the BRCA2 Met1915Thr polymorphism (rs4987117) in the Azerbaijani population and to evaluate its potential association with breast cancer risk. Methods: A total of 144 breast cancer patients and 152 healthy controls were recruited from the Oncology Clinic of Azerbaijan Medical University between 2021 and 2024. The Met1915Thr polymorphism was genotyped using PCR-RFLP and visualized on a 2% agarose gel. Results: A statistically significant association with increased breast cancer susceptibility was observed for the heterozygous Met/Thr genotype (OR = 1.83, 95%CI = 1.08–3.11, p = 0.02), the Thr allele (OR = 1.57, 95%CI = 1.12–2.20, p = 0.008), and under the dominant inheritance model (OR = 1.83, 95%CI = 1.15–2.90, p = 0.01). Notably, this association was more evident among individuals aged over 58 years, in whom the Met/Thr genotype conferred a significantly elevated risk (OR = 2.35, 95%CI = 1.17–4.73, p = 0.02). Conclusions: The BRCA2 Met1915Thr polymorphism is associated with an increased risk of breast cancer in the Azerbaijani population. These findings suggest a potential role of this polymorphism in breast cancer susceptibility and highlight the need for further studies in larger cohorts to validate these associations. Full article

Although evidence suggests adiposity as a modifiable risk factor for postmenopausal breast cancer (BC), its association with premenopausal BC remains uncertain. This potential differential relationship for menopausal status has been insufficiently investigated in the Moroccan population due to limited data. This study aims to assess the relationship between various indicators of adiposity and the risk of BC among Moroccan women by menopausal status. A multicenter case-control study was conducted in Morocco between December 2019 and August 2023, including 1400 incident BC cases and 1400 matched controls. Detailed measures of adiposity and self-reported measures from different life stages were collected. Unconditional logistic regression analyses were conducted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between body size indicators and the risk of BC, adjusting for a range of known risk factors for BC. Higher waist circumference (WC) and hip circumference (HC) were associated with an increased risk of BC in both pre- (p-trend < 0.001 for both WC and HC) and post-menopausal women (p-trend < 0.001 for WC, 0.002 for HC). Current body mass index (BMI) ≥30 kg/m² increased the risk of postmenopausal BC (p-trend = 0.012). Among postmenopausal women, higher weight at age 20 was positively associated with BC risk (p-trend < 0.001), while, weight at age 30 was significantly associated with increased BC risk in both pre- (p-trend = 0.008) and post-menopausal women (p-trend = 0.028). Interestingly, weight gain since age 20 was inversely associated with BC risk in postmenopausal women in the adjusted model (p-trend = 0.006). Young-adult BMI observed a significant increased trend with BC risk in both pre- (p-trend = 0.008) and post-menopausal women (p-trend < 0.001). In premenopausal women, larger body shape during childhood and early adulthood was positively associated with BC risk (p-trend = 0.01 and = 0.011, respectively). In postmenopausal women, larger childhood and adolescent body silhouettes were also associated with increased BC risk (p-trend = 0.045 and 0.047, respectively). These results suggest that anthropometric factors may have different associations with pre- and post-menopausal BC among Moroccan women. This underscores the importance of conducting large prospective studies to better understand these findings and explore their links to different molecular subtypes of BC. Full article