Search Results (703)

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

Breast cancer is the leading cause of cancer-related mortality among women world-wide, and early screening is critical for improving patient survival. Medical imaging plays a central role in breast cancer screening, diagnosis, and treatment monitoring. However, conventional imaging modalities—including mammography, ultrasound, and magnetic resonance imaging—face limitations such as low diagnostic specificity, relatively slow imaging speed, ionizing radiation exposure, and dependence on exogenous contrast agents. Photoacoustic imaging (PAI), a novel hybrid imaging technique that combines optical contrast with ultrasonic spatial resolution, has shown great promise in addressing these challenges. By revealing anatomical, functional, and molecular features of the breast tumor microenvironment, PAI offers high spatial resolution, rapid imaging, and minimal operator dependence. This review outlines the fundamental principles of PAI and systematically examines recent advances in its application to breast cancer screening, diagnosis, and therapeutic evaluation. Furthermore, we discuss the translational potential of PAI as an emerging breast imaging modality, complementing existing clinical techniques. 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 (BC) is highly heterogeneous, with varying molecular characteristics, such as reliance on autophagy. Autophagy is a critical cellular degradation process that helps cells survive under stress, but its regulation can be influenced by altered microRNA (miRNA) expression. Studying miRNA changes during starvation-induced autophagy in both mammary epithelial cells and BC cells could reveal potential molecular therapy targets. Methods: Rat mammary gland healthy epithelial and cancer cells were subjected to starvation, and differences in proliferation, migration, invasion, autophagy, and expression of autophagy-associated miRNAs were determined. Afterward, we assessed the effects of miR-218-5p modulation on the aforementioned processes. Results: Starvation-induced autophagy reduced the proliferation of all cells and increased the invasive and migratory capacity of cancer cells (p ≤ 0.05). We identified a miRNA signature related to starvation, comprising twenty-seven miRNAs. One miRNA had a significantly elevated baseline expression, while another six, including miR-218-5p, had a significantly lower basal expression in cancer cells compared to healthy cells (p ≤ 0.05). However, starvation caused significant miRNA expression changes, with miR-218-5p being upregulated specifically in cancer cells (p = 0.20–0.01). Functional studies on the role of miR-218-5p show that its inhibition decreases migration and leads to autophagosome accumulation. The study of miR-218-5p molecular targets has shown that its inhibition of sorting nexin 18 (SNX18) may act as an important regulator of the starvation-induced response in cancer cells. Conclusions: The baseline expression of miRNA related to starvation and autophagy differs between rat mammary gland cancer and healthy cells. The response to starvation also varies between cancer cells and normal cells. Starvation induces BC-specific miRNA dysregulation, affecting particularly miR-218-5p, which acts via SNX18, promoting the cancer cells’ survival. 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

Breast cancer is a leading cause of central nervous system (CNS) metastases in women, often associated with poor prognosis and limited therapeutic options. However, molecular differences between primary tumors and CNS metastases remain underexplored. We aimed to characterize transcriptomic differences between primary breast tumors and matched CNS metastases and identify immune-related biomarkers associated with metastatic progression and patient outcomes. Transcriptomic profiling was based on 11 matched FFPE sample pairs (primary tumor and CNS metastasis). Paired formalin-fixed paraffin-embedded (FFPE) samples from primary tumors (T1) and CNS metastases (T2) were analyzed using the NanoString nCounter^® platform and the PanCancer IO 360™ Gene Expression Panel. Differential gene expression, Z-score transformation, and heatmap visualization were performed in R. In silico survival analyses for overall survival (OS) and recurrence-free survival (RFS) were conducted using publicly available TCGA and GEO datasets. Forty-five genes were significantly differentially expressed between the T1 and T2 samples. Immune-related genes such as CXCL9, IL7R, CD79A, and CTSW showed consistent downregulation in CNS metastases. High expression of CXCL9 and CD79A was associated with improved OS and RFS, whereas high IL7R and CTSW expression correlated with worse outcomes. These findings indicate immune suppression as a hallmark of CNS colonization. Comparative transcriptomic analysis further underscored the distinct molecular landscapes between primary and metastatic tumors. This study highlights transcriptional signatures associated with breast cancer CNS metastases, emphasizing the role of immune modulation in metastatic progression. The identified genes have potential as prognostic biomarkers and therapeutic targets, supporting the need for site-specific molecular profiling in metastatic breast cancer management. Full article

The Mitogen-activated protein kinase kinase (MEK) protein family has dual-specificity protein kinases with a myriad of cellular functions that include but are not limited to cell survival, cell division, immunologic response, angiogenesis, and cellular senescence. MEK is crucial in the MAPK signaling pathway, regulating different organ systems, including the CNS. Increased activation and dysregulation of the MEK pathway is reportedly observed in 30% of all malignancies. The diversity of MEK renders it a prime target for inhibition in treating cancer. MEK inhibition has been studied in the context of melanoma, non-small cell lung cancer, breast cancer, and colorectal cancer, among others. The standard treatment for glioblastoma (resection, temozolomide, and radiation) remains relatively futile, which warrants alternative treatment options. Therefore, MEK inhibition has garnered more attention in recent years as investigators have explored its role in treating the most aggressive and most common primary brain tumor, glioblastoma. MEK inhibitors have shown efficacy in pre-clinical investigations as well as some promise in clinical trials which have demonstrated improved overall and progression-free survival. This underscores the potential of MEK inhibition in glioblastoma therapy and represents an area that likely warrants further research. However, there are few comprehensive and unifying reviews discussing the current state of MEK inhibition in glioblastoma therapy. We begin this review by detailing the normal function of MEK as it pertains to the CNS. We then compiled relevant pre-clinical and clinical studies to investigate recent research discussing the role of MEK inhibition in glioblastoma therapy. Full article

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor—promoting tumor growth, cell survival, angiogenesis and metastasis—as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Full article

Background/Objectives: PEGylated liposomes are widely recognized for their biocompatibility and capacity to extend systemic circulation via “stealth” properties. However, the PEG corona often limits tumor penetration and cellular internalization. Targeting matrix metalloproteinase-2 (MMP-2), frequently upregulated in breast cancer stroma, presents an opportunity to enhance tissue-specific drug delivery. In this study, we engineered MMP-2-responsive GPLGVRG peptide-modified cleavable PEGylated liposomes for targeted paclitaxel (PTX) delivery. Methods: Molecular docking simulations employed the MMP-2 crystal structure (PDB ID: 7XJO) to assess GPLGVRG peptide binding affinity. A cleavable, enzyme-sensitive peptide-PEG conjugate (Chol-PEG_2K-GPLGVRG-PEG_5K) was synthesized via small-molecule liquid-phase synthesis and characterized by ¹H NMR and MALDI-TOF MS. Liposomes incorporating this conjugate (S-Peps-PEG_5K) were formulated to evaluate whether MMP-2-mediated peptide degradation triggers detachment of long-chain PEG moieties, thereby enhancing internalization by 4T1 breast cancer cells. Additionally, the effects of tumor microenvironmental pH (~6.5) and MMP-2 concentration on drug release dynamics were investigated. Results: Molecular docking revealed robust GPLGVRG-MMP-2 interactions, yielding a binding energy of −7.1 kcal/mol. The peptide formed hydrogen bonds with MMP-2 residues Tyr A:23 and Arg A:53 (bond lengths: 2.4–2.5 Å) and engaged in hydrophobic contacts, confirming MMP-2 as the primary recognition site. Formulations containing 5 mol% Chol-PEG_2K-GPLGVRG-PEG_5K combined with 0.15 µg/mL MMP-2 (S-Peps-PEG_5K +MMP) exhibited superior internalization efficiency and significantly reduced clonogenic survival compared to controls. Notably, acidic pH (~6.5) induced MMP-2-mediated cleavage of the GPLGVRG peptide, accelerating S-Peps-PEG_5K dissociation and facilitating drug release. Conclusions: MMP-2-responsive, cleavable PEGylated liposomes markedly improve PTX accumulation and controlled release at tumor sites by dynamically modulating their stealth properties, offering a promising strategy to enhance chemotherapy efficacy in breast cancer. Full article

Background: Immediate direct-to-implant (DTI) breast reconstruction is associated with high patient satisfaction and faster recovery. However, concerns remain for patients requiring post-mastectomy radiation therapy (PMRT). While PMRT improves overall survival for breast cancer patients, it has been associated with increased implant-specific complications such as capsular contracture, infection, and implant loss. As the impact of PMRT on pre-pectoral DTI specifically is not well understood, the goal of this systematic review was to evaluate the impact of PMRT on outcomes in this growing patient population. Methods: PubMed, EMBASE, and Web of Science were systematically reviewed for articles published from 1 January 2000 to 23 December 2024 investigating outcomes after prepectoral DTI reconstruction with exposure to PMRT. Demographic, clinical, and post-operative variables were recorded for PMRT and non-PMRT cohorts, and primary outcomes included infection, capsular contracture, implant loss, and wound healing complications. Meta-analysis was performed for key outcomes using the Mantel-Haenszel method. Results: Of 472 initially identified records, seven studies met inclusion criteria with a combined total of 343 prepectoral DTI reconstructions exposed to PMRT and 1385 reconstructions not exposed to PMRT. PMRT significantly increased the odds of any complication (OR 2.11, p = 0.01), implant loss (OR 1.88, p = 0.02), infection (OR 2.76, p = 0.004), and capsular contracture (OR 8.88, p < 0.001). However, PMRT was not associated with significantly increased odds of wound healing complications (OR 1.5, p = 0.36). Conclusions: PMRT after pre-pectoral DTI reconstruction significantly increases odds of complications, including infection, capsular contracture, and reconstructive failure. Plastic surgeons should be mindful of the sequelae of PMRT with prepectoral DTI reconstruction to improve pre-operative counseling and shared decision-making. Full article

Background/Objectives: The tumor microenvironment (TME) plays a critical role in cancer progression by shaping immune responses and influencing patient outcomes. We hypothesized that the relative proximity of specific immune cell pairs to cancer cells within the TME could help predict their pro- or anti-tumor functions and reflect clinically relevant immune dynamics. Methods: We analyzed imaging mass cytometry (IMC) data from lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) cohorts. For each immune cell pair, we calculated a relative distance (RD) score, which quantifies the spatial difference in proximity to cancer cells. We assessed the prognostic and predictive significance of these RD-scores by comparing them with conventional features such as cell fractions, densities, and individual cell distances. To account for variations in cell abundance, we also derived normalized RD-scores (NRD-scores). Results: RD-scores were more strongly associated with overall patient survival than standard immunological metrics. Among all immune cell pairs, the RD-score comparing the proximity of B cells to that of intermediate monocytes showed the most significant association with improved survival. In TNBC, RD-scores also improved the distinction between responders and non-responders to immunochemotherapy and chemotherapy. Normalized RD-scores reinforced these findings by minimizing the influence of cell density and further highlighting the importance of immune cell spatial relationships. Conclusions: RD-scores offer a spatially informed biomarker that outperforms traditional metrics in predicting survival and treatment response. This approach provides a new perspective on immune cell behavior in the TME and has potential utility in guiding personalized cancer therapies and patient stratification. Full article

Background: Many patients harbor minimal residual disease (MRD)—small clusters of residual tumor cells that survive therapy and evade conventional detection but drive recurrence. Although advances in molecular and computational methods have improved circulating tumor DNA (ctDNA)-based MRD detection, these approaches face challenges: ctDNA shedding fluctuates widely across tumor types, disease stages, and histological features. Additionally, low levels of driver mutations originating from healthy tissues can create background noise, complicating the accurate identification of bona fide tumor-specific signals. These limitations underscore the need for refined technologies to further enhance MRD detection beyond DNA sequences in solid malignancies. Methods: Profiling circulating cell-free mRNA (cfmRNA), which is hyperactive in tumor and non-tumor microenvironments, could address these limitations to inform postoperative surveillance and treatment strategies. This study reported the development of OncoMRD BREAST, a customized, gene signature-informed cfmRNA assay for residual disease monitoring in breast cancer. OncoMRD BREAST introduces several advanced technologies that distinguish it from the existing ctDNA-MRD tests. It builds on the patient-derived gene signature for capturing tumor activities while introducing significant upgrades to its liquid biopsy transcriptomic profiling, digital scoring systems, and tracking capabilities. Results: The OncoMRD BREAST test processes inputs from multiple cutting-edge biomarkers—tumor and non-tumor microenvironment—to provide enhanced awareness of tumor activities in real time. By fusing data from these diverse intra- and inter-cellular networks, OncoMRD BREAST significantly improves the sensitivity and reliability of MRD detection and prognosis analysis, even under challenging and complex conditions. In a proof-of-concept real-world pilot trial, OncoMRD BREAST’s rapid quantification of potential tumor activity helped reduce the risk of incorrect treatment strategies, while advanced predictive analytics contributed to the overall benefits and improved outcomes of patients. Conclusions: By tailoring the assay to individual tumor profiles, we aimed to enhance early identification of residual disease and optimize therapeutic decision-making. OncoMRD BREAST is the world’s first and only gene signature-powered test for monitoring residual disease in solid tumors. 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

Artocarpus heterophyllus (jackfruit) is widely distributed in subtropical and tropical regions, and some phytochemicals isolated from this species have demonstrated anti-proliferative effects. However, its impact on triple-negative breast cancer (TNBC) and HPV-related cervical cancer models remains unclear. This study evaluated the phytochemical profile and anticancer activity of an ethanolic extract from A. heterophyllus leaves (AHEE) in the TNBC cell line MDA-MB-231 and in the HPV-16⁺ murine cancer cell line TC-1. Phytochemical screening and spectroscopic analyses (UV-Vis, IR, ¹H, and ¹³C NMR) revealed the presence of tannins, alkaloids, steroids, coumarins, and flavone-type flavonoids, with a total phenolic content of 3.34 µg GAE/mg and flavonoid content of 0.44 mg QE/g extract. In 2D cultures, AHEE reduced cell viability by 49% in TC-1 and 24% in MDA-MB-231 at 300 µg/mL, inhibited colony formation and migration in TC-1, and impaired survival but not migration in MDA-MB-231. In 3D cultures, 250 µg/mL inhibited proliferation, migration, and anchorage-independent growth in both cell lines. Furthermore, the combination of AHEE with one-fifth of the IC₅₀ of doxorubicin or cisplatin produces an effect comparable to that observed with the full IC₅₀ of these drugs. These findings suggest that AHEE possesses anticancer activity with cell-type-specific effects and highlight its potential as an adjuvant therapy. Further studies are warranted to elucidate its mechanisms of action. Full article

Introduction: An inverse association between high mammographic breast density (MBD) and pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early breast cancer (EBC) has been reported. However, the relationship of MBD to relapse-free (RFS) and breast cancer-specific survival (BCSS) is unexplored. This study aims to validate the relationship between MBD and NAC pCR in EBC and to assess correlations with RFS and BCSS. Materials & Methods: MBD was measured on contralateral mammograms in 127 women before NAC using Cumulus software. The percent dense area was correlated with patient and tumour characteristics, pCR, RFS and BCSS. Results: Mean MBD was higher in relapsing patients (p = 0.041) but did not vary by pCR or BC-deaths. As a dichotomous variable, no difference was seen between high and low MBD cohorts for pCR (17.5 vs. 25.0%, p = 0.15), BC relapse (38 vs. 30%, p = 0.15) or BC death (32 vs. 25%, p = 0.20). A planned analysis by body mass index (BMI) demonstrated high MBD associated with lower pCR (0% vs. 28.1%, p = 0.036) and trends for higher relapse (56% vs. 28%, p = 0.063) and BC deaths (56 vs. 28%, (p = 0.071)) in obese patients. No relationship was observed in non-obese patients. Conclusions: Obesity and high MBD may interact to cause chemoresistance. Further research in these patients is warranted. Full article