The discovery of antibody-drug conjugates (ADCs) has revolutionized the therapeutic landscape of oncology patients, especially those suffering from breast cancer. Following the approval of the first ADC for solid tumors in breast cancer, numerous additional ADCs have also been launched in the therapeutic landscape of breast cancer and have become the new standard of care for all diverse subtypes. Sacituzumab tirumotecan (sac-TMT) (MK-2870/SKB264) is an innovative ADC targeting TROP2 and delivering a belotecan-derived topoisomerase I inhibitor payload. Several clinical trials of sac-TMT have demonstrated promising results including improved overall response and disease control rates as well as progression-free survival. The safety profile of sac-TMT seems easily manageable; adverse events include mainly grade 1/2 nausea and alopecia, while grade 3/4 neutropenia and leukopenia and grade 3/4 stomatitis have been also reported. However, no treatment-related deaths have been reported so far. Since sac-TMT offers an encouraging new option for diverse breast cancer populations with manageable toxicity profiles, this review aims to summarize the recent published data regarding its use in breast cancer.

Background: Uterine serous carcinoma (USC) represents a rare but aggressive subtype of endometrial cancer, accounting for a disproportionate number of disease-related deaths. Although molecular classification has improved risk stratification, prognostic heterogeneity highlights the need for new prognostic markers. Methods: We retrospectively analyzed 83 patients with USC treated at our institution between 1 January 2015 and 31 December 2023. Clinicopathological characteristics, treatment strategies, molecular biomarkers accessed by immunohistology (TP53, ER, PR, HER2, and MMR status), and survival outcomes were collected. Patients were first staged by FIGO 2009 and retrospectively reclassified by FIGO 2023. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) were assessed using Kaplan-Meier and Cox regression analyses. Results: The majority of patients were presented with advanced disease (FIGO stage IIIC-IV). TP53 mutations were found in 88% of cases, HER2 amplification in 18%, and ER expression in 57.8%. ER-positive patients showed significantly improved DFS in the adjuvant setting compared with ER-negative patients, whereas no significant associations were observed for first-line PFS or OS in multivariable analyses. HER2 amplification was not associated with inferior survival in our cohort. The advanced stage remained an independent predictor of worse OS. Conclusions: USC is a biologically heterogeneous disease, and its treatment should be guided by its molecular profile. ER expression identifies a subset of patients with improved DFS, suggesting potential prognostic relevance in this high-risk histology.

Background/Objectives: Autologous fat grafting (AFT) has become a widely used technique in breast reconstruction, offering natural aesthetics, tissue integration, and patient satisfaction. However, its clinical outcomes require comparison with implant-based reconstruction (IBR), the most common method in clinical practice. While AFT provides a more natural appearance and avoids foreign body-related complications, issues such as fat resorption, procedural variability, and oncological concerns necessitate further investigation. Additionally, artificial intelligence (AI) has been increasingly integrated into breast imaging and reconstructive planning, improving diagnostic accuracy, procedural optimization, and complication prevention. This study aims to compare AFT and IBR while exploring AI’s role in enhancing breast reconstruction outcomes. Methods: A comprehensive review of clinical studies was conducted to evaluate the advantages, limitations, and oncological implications of AFT versus IBR. AI-driven applications in breast imaging and reconstructive planning were examined for their potential in predicting fat graft retention and optimizing implant selection. Data from systematic reviews and meta-analyses were incorporated to refine reconstruction strategies. Results: AFT offers superior aesthetic outcomes with better tissue integration but presents variability in fat resorption. IBR remains the preferred approach due to its predictability but carries risks of implant-related complications. AI technologies contribute to improved reconstruction planning, enhancing surgical precision and long-term patient outcomes. Conclusions: Optimized patient selection and long-term follow-up are essential for improving breast reconstruction techniques. AI-driven approaches provide valuable tools for enhancing procedural predictability and personalized treatment strategies. Future research should focus on refining AI algorithms and establishing standardized protocols for reconstructive decision-making.

Background: Preoperative breast MRI is widely used in surgical planning because of its high sensitivity. However, discrepancies with histopathology remain common and can affect tumor size assessment and treatment decisions. In addition, recent comparative studies have highlighted the growing role of contrast-enhanced mammography (CEM) and multiparametric MRI (mpMRI), both of which may improve specificity and accessibility compared to conventional MRI. Methods: A structured literature review was conducted in PubMed (2000–2025) according to PRISMA guidelines. Studies included if they evaluated preoperative breast MRI with histopathological correlation and reported sensitivity, specificity, or concordance outcomes. Data extraction focused on study design, patient and tumor characteristics, imaging methods, and clinical impact. Results: MRI demonstrates high sensitivity, particularly in detecting IDC and ILC. However, overestimation of tumor size remains a concern, particularly in ILC and high-grade DCIS, while underestimation is frequently observed after neoadjuvant therapy, especially in Luminal A tumors. Tumor size and stage significantly affect concordance, with advanced-stage tumors (T2–T3) showing better MRI-histopathology concordance than early-stage lesions (T0–T1). Specificity remains limited, particularly in DCIS and multifocal disease. Emerging evidence suggests that contrast-enhanced mammography (CEM) achieves comparable sensitivity with higher specificity, while multiparametric MRI (mpMRI) incorporating diffusion-weighted imaging (DWI) improves lesion characterization and prediction of treatment response. Conclusions: While MRI remains a valuable diagnostic tool for breast cancer, histopathological validation is essential to guide treatment decisions. Future research should focus on AI-enhanced imaging techniques, CEM and multiparametric MRI to improve concordance rates, reduce overdiagnosis and translate imaging advances into meaningful clinical outcomes.

Background/objectives: Metaplastic breast carcinoma (MpBC) is a rare, poorly differentiated breast cancer defined by the presence of ductal carcinoma along with areas of matrix-producing, spindle-cell, sarcomatous, or squamous differentiation. It does not express hormone receptors and has a poor overall prognosis. The Hippo molecular pathway was recently related to cancer progression and adjuvant therapy resistance. The objective of this study was to evaluate the expression of Hippo pathway transducers, YAP/TAZ, CCND1, and CTGF, in MpBC and their relation to the clinicopathological characteristics of the disease. Methods: Specimens from patients with MpBC treated at our department from 2003 to 2021 were analyzed utilizing immunohistochemistry and real-time PCR. Results: Forty-four female patients (62.6 ± 14.7 years old) met inclusion criteria and were included in this study. Strong nuclear YAP/TAZ expression was found in 61.4% of patients, while the expressions of CCND1 and CTGF were 3.9% and 12.5%, respectively. Patients presenting at an advanced stage had a statistically worse prognosis compared to the ones diagnosed with stage IA disease. Adjuvant chemotherapy was associated with better overall survival, while disease recurrence was significantly associated with a worse prognosis. Conclusions: Advanced stage at diagnosis and disease recurrence were significantly associated with worse prognosis in MpBC. However, adjuvant chemotherapy significantly led to better overall survival. The Hippo pathway is frequently deregulated (nuclear YAP/TAZ in 61.4% of patients), suggesting it is a compelling novel therapeutic target for this aggressive disease.

Background/Aim:Neo-lymphangiogenesis induces lymphatic invasion of cancer cells, significantly increasing the metastatic potential of breast carcinomas (BCs). Among the molecules that are implicated in lymphangiogenesis, podoplanin (PDPN, gene locus: 1p36.21) - a transmembrane receptor glycoprotein - is expressed exclusively in lymphatic vessels. The current study explored the impact of PDPN-dependent mean lymphatic micro-vessel density (mLMVD) in invasive ductal (inDBC) and invasive lobular breast adenocarcinomas (inLBC). Materials and Methods:A set of thirty (n=30) paraffin-embedded invasive BC tissue sections (22 inDBCs and 8 inLBCs, respectively) were analyzed by applying a combination of immunocytochemistry (IHC) and digital image analysis (DIA) assays. Results:High and moderate mLMVD rates (defined by the mean number of lymphatic domains with emboli in five optical fields under 400X magnification) were detected in 5/30 (16.6%) and 6/30 (20%) cases (total 11/30 (36.6%), respectively. In these cases, PDPN demonstrated strong cytoplasmic/membranous staining intensity. The remaining 19 cases (63.4%) demonstrated low levels of mLMVD. mLMVD was significantly correlated with the stage of the examined malignancies (p=0.019), whereas a marginal association with the grade of differentiation was identified (p=0.042). No significant correlation was observed with histological subtype (p=0.234) or tumor size (p=0.085). Conclusion:Neo-lymphangiogenesis in BCs is a critical histological feature in the progression of the malignancy and is correlated with an aggressive phenotype (advanced stage). PDPN expression in lymphatic micro vessels is a reliable biomarker for evaluating lymphangiogenic activity in BCs, independently of their histotype, especially when assessed with precise DIA techniques.

Autologous fat transplantation to the breast, a minimal invasive technique, has significantly expanded in aesthetic and reconstructive surgery over the past two decades. Initially used for lumpectomy defects or correcting contour deformities post-breast reconstruction, it is now also performed as a stand-alone technique for primary breast augmentation or as a complementary method to implant-based augmentation. However, this surgical technique is associated with a high absorption rate. The use of fat grafts for breast augmentation remains controversial due to concerns about its safety, efficacy, and impact on breast cancer. This review examines the literature on cell-assisted lipotransfer (CAL) and PRP-assisted lipotransfer, comparing fat graft survival, complication rates, and oncological safety with conventional autologous lipotransfer. CAL and PRP-assisted lipotransfer techniques demonstrate improved fat graft retention and reduced complications compared to conventional methods. Several studies report a potential reduction in the absorption rate of fat grafts with improvements in aesthetic outcomes. While CAL and PRP-assisted lipotransfer have shown promising results in enhancing fat graft survival and reducing complications, there are still concerns about their oncological safety. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

BACKGROUND/AIM:Pregnancy-associated breast cancer (PABC) is one of the most frequently diagnosed pregnancy-related malignancies, characterized by a notably rising incidence. Data remain scarce in the literature regarding the molecular nature and pathophysiology of PABC. Proteomic analyses are known to reflect cellular functions more accurately when compared to genomic or transcriptomic studies. MATERIALS AND METHODS:In the present study, two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were employed to identify differentially expressed serum proteins among five patients with PABC, five matched (according to age, histological type and stage) non-pregnant patients diagnosed with BC, and five healthy pregnant controls. RESULTS:A panel of 53 differentially expressed (>1.5-fold) proteins with diverse biological roles and various functional interactions was identified among the three groups examined in our study. Of the 53 differentially expressed proteins, 23 proteins were identified in the PABC group, 8 proteins in the non-PABC group, and 22 proteins in healthy pregnant controls. Many of the proteins differentially expressed in patients with PABC were involved in biological processes known to be deregulated in carcinogenesis, such as metabolism (e.g., apolipoprotein-E, and apolipoprotein-A1) and immune system regulation (e.g., complement factor B, and defensin-5). CONCLUSION:Differential proteomic expression was detected in PABC-derived serum samples, implying distinct PABC molecular features that require further investigation. The identification of PABC proteomic signatures provides significant insight into PABC pathophysiology and offers novel targets for early diagnosis and optimal treatment.

Cyclin-dependent kinase 4/6 inhibitors have transformed hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC) therapeutics. Ribociclib has been associated with survival gain, yet its potential cardiovascular toxicities (CVTs) remain an area of uncertainty. Our single-center study prospectively recruited adult patients in order to assess treatment-related CVT incidence and spectrum as well as decipher proteins' differential expression in affected patients by data-independent acquisition liquid chromatography-tandem mass spectrometry (DIA LC-MS/MS). After a median follow-up of 27.2 months, five cases of CVT have occurred among the 62 enrolled participants (8.06%; mean age, 67 years). CVTs were in the form of asymptomatic QTc prolongation, transient ischemic attack, deep vein thrombosis, syncope, and pericardial effusion, which developed within 7.56 months. The in-depth proteomics quantified 144 differentially expressed proteins, of which 109 and 35 were down- and up-regulated, respectively, in these five cases (enrolled participants with CVT) compared to five sex- and age-matched controls (enrolled participants without CVT). Negative regulation of endopeptidase activity, phosphatidylcholine metabolism, and immune response were the most affected signaling pathways in the subsequent functional analysis. Large-scale external validation of our hypothesis-generating findings could potentially support individualized cardiovascular prevention in BC patients under ribociclib combinational therapy. SUMMARY: Ribociclib has unequivocally revolutionized hormone-dependent metastatic breast cancer therapeutics. Its potential cardiotoxicity, however, remain inadequately characterized, whereas the underlying pathophysiological mechanisms are poorly understood so far. Our prospective case-control study revealed that despite cardiovascular toxicity was not very common (<10%), its phenotype was not limited to QTc prolongation. Moreover, utilizing mass spectrometry-based serum proteomics, we highlighted for the very first time a number of distinct proteins, which could be of predictive value to identify patients at high risk. The prospective validation of our preliminary, proof-of-concept study's results in larger cohorts could inform optimized preventive strategies.

Introduction Genetic testing for inherited breast cancer predisposing pathogenic variants (PVs) inform treatment choices and guide clinical management strategies in breast cancer patients. Methods The study enrolled 146 patients, sourced from the Breast Unit database of the First Department of Obstetrics and Gynecology at the University of Athens, Alexandra Hospital. Blood samples were collected for genetic testing, utilizing a detailed 94-cancer gene panel. The results were then descriptively correlated with the clinicopathological data of the patients. Results In this study, 17 PVs were identified across several genes, BRCA1 (10), BRCA2 (3), CHEK2 (3) and TP53 (1), while 4 variants of unknown clinical significance (VUSs) were found in BRCA2 (1), CHEK2 (1), BRIP1 (1), MSH2 (1). This corresponds to a prevalence rate of 11.6% (17/146). Cascade testing was conducted for 7 of the 17 positive families, resulting in 11 individuals being tested, of whom 3 tested positive.  Conclusions Our study findings on the selected Greek population align with current literature. Genetic testing following National Comprehensive Cancer Network (NCCN) guidelines offers valuable insights for patients and their families. This information enhances counseling and identifying germline PVs could refine treatment strategies, potentially improving prognostic outcomes.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have unprecedentedly advanced hormone-dependent breast cancer treatment paradigm. In the metastatic setting, ribociclib has consistently demonstrated survival benefit in pre-, peri-, and postmenopausal patients, conjugating efficacy with health-related quality of life preservation. Accordingly, the emergence of cardiac and/or vascular adverse events related to this novel targeted agent is gaining significant interest. This narrative review provides an overview of the incidence and spectrum of cardiovascular toxicity, in both clinical trial framework and real-world evidence. The potential pathogenetic mechanism, along with the available diagnostic parameters including biomarkers, and proper management, are also summarized.

Background: The female genital tract is rarely involved by metastatic tumors. The most common anatomic locations for metastases to the female genital tract are the ovaries and the vagina. Among extragenital cancers metastasizing to the female genital tract, breast is the most common primary site, followed by the gastrointestinal tract, lung, kidney, and skin melanoma. Metastases to the uterus from extragenital cancer are less common, but up to 8% of breast carcinomas will metastasize to that organ. Lobular carcinoma is the most common type of breast carcinoma that metastasizes to the uterus. In our case, we present a case of concurrent metastatic breast carcinoma to the uterine cervix.

Abstract Background: We previously published 10-year results (from March 2008-March 2018) from the Dayton prospective breast cancer prevention study, which showed a 40% reduction in the incidence of invasive breast cancer in women receiving testosterone or testosterone with anastrozole implant therapy compared to the age-matched Surveillance Epidemiology and End Results (SEER) expected incidence rate. We continued to follow the study subjects on therapy through March 2023. Methods: This 10-year prospective cohort study was approved in March 2008, at which time recruitment was initiated. Recruitment was closed in March 2013. Pre- and postmenopausal women who received at least two pellet insertions were eligible for analysis (n=1267). Breast cancer incidence rates are reported as an unadjusted, unweighted value of newly diagnosed cases divided by the sum of the person-time of observation for the at-risk population. The incidence rates on testosterone therapy were compared to age-specific SEER incidence rates and expected local Montgomery County incidence rates (the location of most study patients). Results: As of March 1, 2023, a total of 16 (versus 30 expected) eligible patients were diagnosed with invasive breast cancer within 240 days of their last testosterone pellet insert equating to an incidence rate of 189/100000 p-y, which is significantly less than the national SEER expected incidence rate of 355/100000, i.e., a 47% reduction. Interestingly, local incidence rates in Montgomery County are higher than US national averages. Conclusion: The 15-year follow-up data revealed a reduced incidence of invasive breast cancer with long-term testosterone or testosterone combined with anastrozole implant therapy. Because of the increased incidence of invasive breast cancer in our area, the amount of reduction (benefit) from testosterone therapy may be underestimated using national data/statistics for comparison.

Background: Ectopic breast tissue is found in 2-6% of female patients, and undergoes the same physiological changes of the breast's mammary gland. Usual sites include the sternum, the infraclavicular area, the epigastrium, the vulva but predominantly it is located in the axilla. Ectopic breast tissue has the ability of developing breast cancer, representing 0.3% of all breast neoplasms.

Background: Breast cancer is the most common malignancy among women nowadays. It spreads to the regional axillary and internal mammary humph nodes and usually metastasizes by hematological spread to the bones, lung, liver and brain.

DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved system in bacteria, prokaryotic, and eukaryotic cells, and provides the highest protection to DNA by repairing micro-structural alterations. DNA MMR proteins are involved in the detection and repair of intra-nucleotide base-to-base errors inside the complementary DNA strand recognizing the recently synthesized strand from the parental template. During DNA replication, a spectrum of errors including base insertion, deletion, and miss-incorporation negatively affect the molecule's structure and its functional stability. A broad spectrum of genomic alterations such as promoter hyper methylation, mutation, and loss of heterozygosity (LOH) in MMR genes including predominantly hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 lead to their loss of base-to-base error repairing procedure. Microsatellite instability (MSI) refers to the DNA MMR gene alterations that are observed in a variety of malignancies of different histological origins. In the current review, we present the role of DNA MMR deficiency in breast adenocarcinoma, a leading cancer-based cause of death in females worldwide.

e15074 Background: Cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) have fundamentally transformed the therapeutic landscape of hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer, either as monotherapy (abemaciclib) or combined with classic endocrine therapy (ribociclib, abemaciclib, and palbociclib). However, evidence regarding treatment-related cardiovascular complications, beyond the context of clinical trials, remains scarce. Methods: We retrospectively explored the FDA Adverse Events Reporting System (FAERS) to gain insight into both frequency and spectrum of cardiovascular toxicities of these novel targeted agents in real-world setting. Results: For the period January 2018 - September 2022, a total of 90,999 adverse events (AEs) in patients under CDK4/6i have been reported, with 2,739 (3.01%) and 5,176 (5.69%) records being submitted as cardiac and vascular events, respectively. The incidence of these AEs was higher in the case of ribociclib, with arrhythmia representing the main cardiac complication (512 cases), followed by palpitations (120 cases), and acute coronary syndrome (115 cases). Interestingly, there was only one report of QT prolongation; of note, ribociclib has labeling guidance for QTc assessment. Hypertension/hypertensive crisis (302 cases), flushing (251 cases), and thrombotic events (226 cases) -with the exception of pulmonary embolism which was categorized as respiratory AE- comprised the foremost vascular toxicities associated with ribociclib. Conclusions: FAERS displays a public, post-market safety evaluation database with reports from healthcare professionals as well as consumers, yet it may include duplicates, inaccurate information, and fails to confirm causal relationship between the AEs and the medicinal product. In the light of CDK4/6i long-term usage, pharmacovigilance studies are warranted to elucidate their potential cardiovascular hazard. [Table: see text]

Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline pathogenic variants in the tumor protein p53 (TP53) gene and elevated risk of a broad range of early-onset malignancies. Patients with LFS are at risk of a second and third primary tumor. A 15-month-old girl consulted for clitoromegaly and pubic hair. Adrenal ultrasound detected a large left adrenal tumor. Left total adrenalectomy confirmed adrenocortical carcinoma. Family history revealed multiple highly malignant neoplasms at an early age across five generations, and a genetic dominant trait seemed probable. Whole-genome sequencing was performed. Multiple members of the family were found positive for a novel likely pathogenic variant (c. 892delGinsTTT, p. Glu298PhefsX48, NM_000546.6) in the TP53 gene, causing the loss of normal protein function through non-sense-mediated mRNA decay. According to the PSV1 supporting criteria and the Auto PVS1 online tool this frameshift variant: hg19/17-7577045-TC-TAAA:NM_000546.6 has a very strong, definitive clinical validity for LFS with autosomal dominant inheritance. Proper guidance resulted in timely diagnosis of a second tumor (primary osteosarcoma) in the index case and in the early detection of breast and cervical cancer in her young mother. Patients with cancer predisposition syndromes like LFS require close multidisciplinary cancer surveillance and appropriate referral to expert centers.

Metaplastic carcinoma of the breast (MpBC) is a very rare and aggressive type of breast cancer. Data focusing on MpBC are limited. The aim of this study was to describe the clinicopathological features of MpBC and evaluate the prognosis of patients with MpBC. Eligible articles about MpBC were identified by searching CASES SERIES gov and the MEDLINE bibliographic database for the period of 1 January 2010 to 1 June 2021 with the keywords metaplastic breast cancer, mammary gland cancer, neoplasm, tumor, and metaplastic carcinoma. In this study, we also report 46 cases of MpBC stemming from our hospital. Survival rates, clinical behavior, and pathological characteristics were analyzed. Data from 205 patients were included for analysis. The mean age at diagnosis was 55 (14.7) years. The TNM stage at diagnosis was mostly stage II (58.5%) and most tumors were triple negative. The median overall survival was 66 (12–118) months, and the median disease-free survival was 56.8 (11–102) months. Multivariate Cox regression analysis revealed that surgical treatment was associated with decreased risk of death (hazard ratio 0.11, 95% confidence interval 0.02–0.54, p = 0.01) while advanced TNM stage was associated with increased risk of death (hazard ratio 1.5, 95% confidence interval 1.04–2.28, p = 0.03). Our results revealed that surgical treatment and TNM stage were the only independent risk factors related to patients’ overall survival.