Behaviour, barriers and facilitators of shared decision making in breast cancer surgical treatment: A qualitative systematic review using a 'Best Fit' framework approach.

BACKGROUND: Due to the diversity and high sensitivity of the treatment, there were difficulties and uncertainties in the breast cancer surgical decision-making process. We aimed to describe the patient's decision-making behaviour and shared decision-making (SDM)-related barriers and facilitators in breast cancer surgical treatment. METHODS: We searched eight databases for qualitative studies and mixed-method studies about breast cancer patients' surgical decision-making process from inception to March 2021. The quality of the studies was critically appraised by two researchers independently. We used a 'best fit framework approach' to analyze and synthesize the evidence. RESULTS: Twenty-eight qualitative studies and three mixed-method studies were included in this study. Four themes and 10 subthemes were extracted: (a) struggling with various considerations, (b) actual decision-making behaviours, (c) SDM not routinely implemented and (d) multiple facilitators and barriers to SDM. CONCLUSIONS: Patients had various considerations of breast surgery and SDM was not routinely implemented. There was a discrepancy between information exchange behaviours, value clarification, decision support utilization and SDM due to cognitive and behavioural biases. When individuals made surgical decisions, their behaviours were affected by individual-level and system-level factors. Therefore, healthcare providers and other stakeholders should constantly improve communication skills and collaboration, and emphasize the importance of decision support, so as to embed SDM into routine practice. PATIENT AND PUBLIC CONTRIBUTION: This systematic review was conducted as part of a wider research entitled: Breast cancer patients' actual participation roles in surgical decision making: a mixed method research. The results of this project helped us to better analyze and generalize patients' views.

Quality of Life Outcomes and Determining Factors in Breast Cancer Patients Reporting to a Tertiary Care Centre in the Sub-Himalayan Region of India.

PURPOSE: Breast cancer is the most common malignancy among women worldwide. This study was conducted to determine the quality of life (QOL) outcomes among breast cancer patients in the sub-Himalayan region and, secondly, to identify factors affecting them. METHOD: The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and BR-45 questionnaires in English and Hindi translations were used. The BR-45 Hindi translation was obtained using the forward-backward translation method. To check internal consistency and validity, Cronbach's alpha was employed. EORTC scoring manuals were used to score the questionnaires. The analysis of variance test was used to determine the impact of different treatment and sociodemographic factors on QOL domains. RESULTS: The English and Hindi translations had Cronbach's alpha values of 0.949 and 0.950, respectively, suggesting that the data gathered were reliable. The mean score for global health status was 64.4 ± 29.7, the functional scale (FS) of QLQ_C30 was 76.9 ± 21.5, the FS of BR45 was 64.6 ± 24.1, the symptom scale (SS) of QLQ_C30 was 20.3 ± 19.2, and the SS of BR45 was 22.5 ± 19.1. Factors adversely affecting global health status included younger age, pre/perimenopausal status, and ongoing chemotherapy. Functional scales were significantly affected by marital status and earlier stages of the disease. Symptom scales were adversely affected by ongoing chemotherapy, an earlier stage of the disease, and a duration of treatment of less than six months. CONCLUSION: Tailoring treatment to reduce radiotherapy, surgery, and systemic therapy-related side effects may improve QOL. Counselling and social support groups may help patients cope with the burden of family and societal roles.

The Role of Human Epidermal Growth Factor Receptor 2 (HER2)-Targeted Therapies in Early-Stage Breast Cancer: Current Practices, Treatment De-escalation, and Future Prospects.

Human epidermal growth factor receptor 2 (HER2)-targeted therapy has transformed the treatment paradigm for early-stage HER2-positive breast cancer, providing personalized and effective interventions. This comprehensive review delves into the current state of HER2-targeted therapies, emphasizing pivotal clinical trials that have demonstrated their substantial impact on long-term outcomes. Combination therapies that integrate HER2-targeted agents with chemotherapy exhibit enhanced tumor responses, particularly in neoadjuvant settings. Neoadjuvant chemotherapy (NACT) is explored for its role in tumor downsizing, facilitating breast-conserving surgery (BCS), and incorporating oncoplastic solutions to address both oncologic efficacy and aesthetic outcomes. Innovative axillary management post-NACT, such as targeted axillary dissection (TAD), is discussed for minimizing morbidity. The review further explores the delicate balance between maximal therapy and de-escalation, reflecting recent trends in treatment approaches. The therapeutic landscape of HER2-low breast cancer is examined, highlighting considerations in HER2-positive breast cancer with BReast CAncer gene (BRCA) mutations. Emerging immunotherapeutic strategies, encompassing immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy, are discussed in the context of their potential integration into treatment paradigms. In conclusion, the evolving landscape of HER2-positive early-stage breast cancer treatment, characterized by targeted therapies and multidisciplinary approaches, underscores the need for ongoing research and collaborative efforts. The aim is to refine treatment strategies and enhance patient outcomes in this dynamic and rapidly evolving field.

Bioinformatics analysis and validation of genes related to paclitaxel's anti-breast cancer effect through immunogenic cell death.

Research indicated that Paclitaxel (PTX) can induce immunogenic cell death (ICD) through immunogenic modulation. However, the combination of PTX and ICD has not been extensively studied in breast cancer (BRCA). The TCGA-BRCA and GSE20685 datasets were enrolled in this study. Samples from the TCGA-BRCA dataset were consistently clustered based on selected immunogenic cell death-related genes (ICD-RGs). Next, candidate genes were obtained by overlapping differentially expressed genes (DEGs) between BRCA and normal groups, intersecting genes common to DEGs between cluster1 and cluster2 and hub module genes, and target genes of PTX from five databases. The univariate Cox algorithm and the least absolute shrinkage and selection operator (LASSO) were performed to obtain biomarkers and build a risk model. Following observing the immune microenvironment in differential risk subgroups, single-gene gene set enrichment analysis (GSEA) was carried out in all biomarkers. Finally, the expression of biomarkers was analyzed. Enrichment analysis showed that 626 intersecting genes were linked with inflammatory response. Further five biomarkers (CHI3L1, IL18, PAPLN, SH2D2A, and UBE2L6) were identified and a risk model was built. The model's performance was validated using GSE20685 dataset. Furthermore, the biomarkers were enriched with adaptive immune response. Lastly, the experimental results indicated that the alterations in IL18, SH2D2A, and CHI3L1 expression after treatment matched those in the public database. In this study, Five PTX-ICD-related biomarkers (CHI3L1, IL18, PAPLN, SH2D2A, and UBE2L6) were identified to aid in predicting BRCA treatment outcomes.

Datopotamab deruxtecan: A novel antibody drug conjugate for triple-negative breast cancer.

Triple negative breast cancer (TNBC) represents the breast cancer subtype with least favorable outcome because of the lack of effective treatment options and its molecular features. Recently, ADCs have dramatically changed the breast cancer treatment landscape; the anti-TROP2 ADC Sacituzumab Govitecan has been approved for treatment of previously treated, metastatic TNBC patients. The novel ADC Datopotecan-deruxtecan (Dato-DXd) has recently shown encouraging results for TNBC. In the current paper, we summarize and discuss available data regarding this TROP-2 directed agent mechanism of action and pharmacologic activity, we describe first results on efficacy and safety of the drug and report characteristics, inclusion criteria and endpoints of the main ongoing clinical trials.

Identification and verification of AK4 as a protective immune-related biomarker in adipose-derived stem cells and breast cancer.

Background: Breast cancer (BC) remains the most common cancer among women, and novel post-surgical reconstruction techniques, including autologous fat transplantation, have emerged. While Adipose-derived stem cells (ADSCs) are known to impact the viability of fat grafts, their influence on breast cancer progression remains unclear. This study aims to elucidate the genetic interplay between ADSCs and breast cancer, focusing on potential therapeutic targets. Methods: Using the GEO and TCGA databases, we pinpointed differentially expressed (DE) mRNAs, miRNAs, lncRNAs, and pseudogenes of ADSCs and BC. We performed functional enrichment analysis and constructed protein-protein interaction (PPI), RNA binding protein (RBP)-pseudogene-mRNA, and lncRNA-miRNA-transcription factor (TF)-gene networks. Our study delved into the correlation of AK4 expression with 33 different malignancies and examined its impact on prognostic outcomes across a pan-cancer cohort. Additionally, we scrutinized immune infiltration, microsatellite instability, and tumor mutational burden, and conducted single-cell analysis to further understand the implications of AK4 expression. We identified novel sample subtypes based on hub genes using the ConsensusClusterPlus package and examined their association with immune infiltration. The random forest algorithm was used to screen DE mRNAs between subtypes to validate the powerful prognostic prediction ability of the artificial neural network. Results: Our analysis identified 395 DE mRNAs, 3 DE miRNAs, 84 DE lncRNAs, and 26 DE pseudogenes associated with ADSCs and BC. Of these, 173 mRNAs were commonly regulated in both ADSCs and breast cancer, and 222 exhibited differential regulation. The PPI, RBP-pseudogene-mRNA, and lncRNA-miRNA-TF-gene networks suggested AK4 as a key regulator. Our findings support AK4 as a promising immune-related therapeutic target for a wide range of malignancies. We identified 14 characteristic genes based on the AK4-related cluster using the random forest algorithm. Our artificial neural network yielded excellent diagnostic performance in the testing cohort with AUC values of 0.994, 0.973, and 0.995, indicating its ability to distinguish between breast cancer and non-breast cancer cases. Conclusions: Our research sheds light on the dual role of ADSCs in BC at the genetic level and identifies AK4 as a key protective mRNA in breast cancer. We found that AK4 significantly predicts cancer prognosis and immunotherapy, indicating its potential as a therapeutic target.

A prognostic model for triple-negative breast cancer patients with liver metastasis: A population-based study.

However, it is still difficult for clinicians to establish prognostic stratifications and therapeutic strategies because of the lack of tools for predicting the survival of triple-negative breast cancer patients with liver metastases (TNBC-LM). Based on clinical data from large populations, a sensitive and discriminative nomogram was developed and validated to predict the prognosis of TNBC patients with LM at initial diagnosis or at the later course. Introduction/background: Liver metastasis (LM) in TNBC patients is associated with significant morbidity and mortality. The objective of this study was to construct a clinical model to predict the survival of TNBC-LM patients. Materials and methods: Clinicopathologic data were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and the Fifth Affiliated Hospital of Sun Yat-Sen University (FAFSYU). Based on patients with newly diagnosed TNBC with LM (nTNBC-LM) from the SEER database, a predictive nomogram was established and validated. Its predictive effect on TNBC patients with LM at later disease course by enrolling TNBC patients from FAFSYU who developed LM later. The prognostic effect of different treatment for nTNBC-LM was further assessed. Results: A prognostic model was developed and validated to predict the prognosis of TNBC-LM patients. For LM patients diagnosed at the initial or later treatment stage, the C-index (0.712, 0.803 and 0.699 in the training, validation and extended groups, respectively) and calibration plots showed the acceptable prognostic accuracy and clinical applicability of the nomogram. Surgical resection on the primary tumour and chemotherapy were found to be associated with significantly better overall survival (OS). Conclusion: A sensitive and discriminative model was developed to predict OS in TNBC-LM patients both at and after initial diagnosis.

PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α.

Pyruvate dehydrogenase kinase 1 (PDK1) phosphorylates the pyruvate dehydrogenase complex, which inhibits its activity. Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis, which plays an important role in tumor progression. This study aims to elucidate how PDK1 promotes breast cancer progression. We found that PDK1 was highly expressed in breast cancer tissues, and PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α (hypoxia-inducible factor 1α) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α. The HIF-1α protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1α transcriptional activity. In summary, PDK1 enhances HIF-1α protein stability by phosphorylating HIF-1α at Ser451 and promotes HIF-1α transcriptional activity by enhancing the binding of HIF-1α to P300. PDK1 and HIF-1α form a positive feedback loop to promote breast cancer progression.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases.

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival. The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect. To improve the treatment efficacy, we developed Pluronic P123 (P123)-based polymeric micelles dually decorated with alendronate (ALN) and cancer-specific phage protein DMPGTVLP (DP-8) for targeted drug delivery to breast cancer bone metastases. Doxorubicin (DOX) was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity (3.44%). The DOX-loaded polymeric micelles were spherical, 123 nm in diameter on average, and exhibited a narrow size distribution. The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release. The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells. Rapid binding of the micelles to hydroxyapatite (HA) microparticles indicated their high affinity for bone. P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model. In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity. In conclusion, our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

MTCH2 stimulates cellular proliferation and cycles via PI3K/Akt pathway in breast cancer.

The MTCH2 protein is located on the mitochondrial outer membrane and regulates mitochondria-related cell death. This study set out to investigate the role of MTCH2 in the underlying pathophysiological mechanisms of breast cancer (BC). MTCH2 expression levels in BC were analyzed using bioinformatics prior to verification by cell lines in vitro. Experiments of over-expression and siRNA-mediated knockdown of MTCH2 were conducted to assess its biological functions, including its effects on cellular proliferation and cycle progression. Xenografts were utilised for in vivo study and signaling pathway alterations were examined to identify the mechanisms driven by MTCH2 in BC proliferation and cell-cycle regulation. MTCH2 was up-regulated in BC and correlated with patients' overall survival. Over-expression of MTCH2 promoted cellular proliferation and cycle progression, while silencing MTCH2 had the opposite effect. Xenograft experiments were utilised to confirm the in vitro cellular findings and it was identified that the PI3K/Akt signaling pathway was activated by MTCH2 over-expression and suppressed by its silencing. Moreover, the activation of IGF-1R rescued cellular growth and cycle arrest induced by MTCH2-silencing. Overall, this study reveals that expression of MTCH2 in BC is upregulated and potentiates cellular proliferation and cycle progression via the PI3K/Akt pathway.

Ultrasonography is an effective tool for breast cancer screening in individuals with severe motor and intellectual disabilities.

BACKGROUND: Individuals with severe motor and intellectual disabilities have become an aging population, and high cancer morbidity and mortality are critical issues affecting their survival. Cancer screening is a crucial method of resolving this issue; however, a suitable screening method for them has not been established. METHODS: We used ultrasonography alone and performed breast cancer screening for women over 30 years old in our facility from 2016 to 2023. We observed the outcomes and calculated the recall/detection rate in this screening. RESULTS: Three cases among 379 tested positive in this screening, all of which underwent radical surgery. They are alive and well without relapse present. We detected these breast cancer cases with a low recall rate. CONCLUSION: We were able to successfully detect breast cancer cases using ultrasonography alone. Ultrasonography is an effective and feasible tool for breast cancer screening in individuals with severe motor and intellectual disabilities.

The PI3K/AKT/mTOR signaling pathway in breast cancer: Review of clinical trials and latest advances.

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer mortality in women. As the phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a wide range of physiological functions of cells including growth, proliferation, motility, and angiogenesis, any alteration in this axis could induce oncogenic features; therefore, numerous preclinical and clinical studies assessed agents able to inhibit the components of this pathway in BC patients. To the best of our knowledge, this is the first study that analyzed all the registered clinical trials investigating safety and efficacy of the PI3K/AKT/mTOR axis inhibitors in BC. Of note, we found that the trends of PI3K inhibitors in recent years were superior as compared with the inhibitors of either AKT or mTOR. However, most of the trials entering phase III and IV used mTOR inhibitors (majorly Everolimus) followed by PI3K inhibitors (majorly Alpelisib) leading to the FDA approval of these drugs in the BC context. Despite favorable efficacies, our analysis shows that the majority of trials are utilizing PI3K pathway inhibitors in combination with hormone therapy and chemotherapy; implying monotherapy cannot yield huge clinical benefits, at least partly, due to the activation of compensatory mechanisms. To emphasize the beneficial effects of these inhibitors in combined-modal strategies, we also reviewed recent studies which investigated the conjugation of nanocarriers with PI3K inhibitors to reduce harmful toxicities, increase the local concentration, and improve their efficacies in the context of BC therapy.

Epitranscriptomic orchestrations: Unveiling the regulatory paradigm of m6A, A-to-I editing, and m5C in breast cancer via long noncoding RNAs and microRNAs.

Breast cancer (BC) poses a persistent global health challenge, particularly in countries with elevated human development indices linked to factors such as increased life expectancy, education, and wealth. Despite therapeutic progress, challenges persist, and the role of epitranscriptomic RNA modifications in BC remains inadequately understood. The epitranscriptome, comprising diverse posttranscriptional modifications on RNA molecules, holds the potential to intricately modulate RNA function and regulation, implicating dysregulation in various diseases, including BC. Noncoding RNAs (ncRNAs), acting as posttranscriptional regulators, influence physiological and pathological processes, including cancer. RNA modifications in long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) add an extra layer to gene expression control. This review delves into recent insights into epitranscriptomic RNA modifications, such as N-6-methyladenosine (m6A), adenine-to-inosine (A-to-I) editing, and 5-methylcytosine (m5C), specifically in the context of lncRNA and miRNAs in BC, highlighting their potential implications in BC development and progression. Understanding this intricate regulatory landscape is vital for deciphering the molecular mechanisms underlying BC and identifying potential therapeutic targets.

The Potential of FOXP3 in Predicting Survival and Treatment Response in Breast Cancer.

Background: Breast cancer (BC) continues to pose a substantial challenge to global health, necessitating an enhanced understanding of its fundamental mechanisms. Among its various pathological classifications, breast invasive carcinoma (BRCA) is the most prevalent. The role of the transcription factor forkhead box P3 (FOXP3), associated with regulatory T cells, in BRCA's diagnosis and prognosis remains insufficiently explored, despite its recognized importance. Methods: We examined the mRNA expression profile of FOXP3 in BRCA patients, assessing its correlation with disease detection, patient survival, immune checkpoint alterations, and response to anticancer drugs. Results: Our analysis revealed significantly elevated FOXP3 mRNA levels in BRCA patients, with a 95.7% accuracy for BRCA detection based on the area under the curve. High FOXP3 mRNA levels were positively correlated with overall survival and showed significant associations with CTLA4, CD274, PDCD1, TMB, and immune cell infiltration status. Furthermore, FOXP3 mRNA expression was linked to the efficacy of anticancer drugs and the tumor inflammation signature. Discussion: These findings suggest that FOXP3 serves as a promising biomarker for BRCA, offering valuable insights into its diagnosis and prognosis. The correlation between FOXP3 expression and immune checkpoint alterations, along with its predictive value for treatment response, underscores its potential in guiding therapeutic strategies. Conclusion: FOXP3 stands out as an influential factor in BRCA, highlighting its diagnostic accuracy and prognostic value. Its association with immune responses and treatment efficacy opens new avenues for research and clinical applications, positioning FOXP3 as a vital target for further investigation in BRCA management.

Joint global and local interpretation method for CIN status classification in breast cancer.

Breast cancer is among the cancer types with the highest numbers of new cases. The study of this disease from a microscopic perspective has been a prominent research topic. Previous studies have shown that microRNAs (miRNAs) are closely linked to chromosomal instability (CIN). Correctly predicting CIN status from miRNAs can help to improve the survival of breast cancer patients. In this study, a joint global and local interpretation method called GL_XGBoost is proposed for predicting CIN status in breast cancer. GL_XGBoost integrates the eXtreme Gradient Boosting (XGBoost) and SHapley Additive exPlanation (SHAP) methods. XGBoost is used to predict CIN status from miRNA data, whereas SHAP is used to select miRNA features that have strong relationships with CIN. Furthermore, SHAP's rich visualization strategies enhance the interpretability of the entire model at the global and local levels. The performance of GL_XGBoost is validated on the TCGA-BRCA dataset, and it is shown to have an accuracy of 78.57% and an area under the curve value of 0.87. Rich visual analysis is used to explain the relationships between miRNAs and CIN status from different perspectives. Our study demonstrates an intuitive way of exploring the relationship between CIN and cancer from a microscopic perspective.

Triple-negative accessory breast cancer occurring concurrently with primary invasive breast carcinoma: a case report.

Introduction: Accessory breast cancer (ABC) is an extremely rare condition, particularly the presence of triple-negative ABC with ipsilateral invasive in situ breast cancer. Binary breast tumors are controversial in terms of surgical methods and comprehensive treatment. Case presentation: We share the case of a 64-year-old postmenopausal woman who presented with an underarm mass for 3 months. Ultrasonography and computed tomography suggested possible breast cancer with axillary lymph node metastasis. The patient underwent a left modified radical mastectomy combined with axillary lymph node dissection. The postoperative pathology confirmed a binary tumor, prompting us to initiate comprehensive treatment. Conclusion: We present the treatment approach for a rare case of triple-negative para-breast cancer complicated with carcinoma in situ of the breast, hoping to contribute new therapeutic ideas for the treatment of this disease.

Preclinical Efficacy of Cabazitaxel Loaded Poly(2-alkyl cyanoacrylate) Nanoparticle Variants.

Background: Biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) are receiving increasing attention in anti-cancer nanomedicine development not only for targeted cancer chemotherapy, but also for modulation of the tumor microenvironment. We previously reported promising results with cabazitaxel (CBZ) loaded poly(2-ethylbutyl cyanoacrylate) NPs (PEBCA-CBZ NPs) in a patient derived xenograft (PDX) model of triple-negative breast cancer, and this was associated with a decrease in M2 macrophages. The present study aims at comparing two endotoxin-free PACA NP variants (PEBCA and poly(2-ethylhexyl cyanoacrylate); PEHCA), loaded with CBZ and test whether conjugation with folate would improve their effect. Methods: Cytotoxicity assays and cellular uptake of NPs by flow cytometry were performed in different breast cancer cells. Biodistribution and efficacy studies were performed in PDX models of breast cancer. Tumor associated immune cells were analyzed by multiparametric flow cytometry. Results: In vitro studies showed similar NP-induced cytotoxicity patterns despite difference in early NP internalization. On intravenous injection, the liver cleared the majority of NPs. Efficacy studies in the HBCx39 PDX model demonstrated an enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs. Furthermore, the folate conjugated PEBCA variant did not show any enhanced effects compared with the unconjugated counterpart which might be due to unfavorable orientation of folate on the NPs. Finally, analyses of the immune cell populations in tumors revealed that treatment with drug loaded PEBCA variants affected the myeloid cells, especially macrophages, contributing to an inflammatory, immune activated tumor microenvironment. Conclusion: We report for the first time, comparative efficacy of PEBCA and PEHCA NP variants in triple negative breast cancer models and show that CBZ-loaded PEBCA NPs exhibit a combined effect on tumor cells and on the tumor associated myeloid compartment, which may boost the anti-tumor response.

Neuroendocrine breast carcinoma.

Neuroendocrine breast cancer (NEBC) is a rare and heterogeneous entity. It most commonly presents a luminal phenotype and a worse prognosis. When diagnosed in an advanced stage, metastasis from another neuroendocrine tumor should be excluded. This case features a premenopausal woman with an oligometastatic breast large cell neuroendocrine carcinoma, estrogen receptor (ER) positive, and human epidermal growth factor receptor 2 (HER2) negative. Since the patient was very symptomatic at the presentation of the disease, chemotherapy was started. Complete radiological response of the metastatic disease was achieved, and the patient was then submitted to radical breast surgery and bilateral oophorectomy. She subsequently underwent radiation therapy. Since then and to date, she has been under endocrine therapy (ET) and a CDK4/6 inhibitor (CDK4/6i), with no evidence of malignant disease. Evidence to guide the choice of treatment for these tumors is currently scarce. In cases with oligometastatic disease, radical treatment should be considered. Given that this entity is rare, its reporting should be encouraged.

HER2 Low Expression in Primary Male Breast Cancer.

Purpose: The introduction of HER2-targeting antibody drug conjugates (ADCs) offers new treatment options for female breast cancer patients (FBC) expressing low levels of HER2 (HER2 low). No evidence was found that HER2 low describes a new FBC subtype. There is a lack of studies determining the impact of HER2 low in male breast cancer (MBC). In this study, we evaluate the prevalence of HER2 low in primary MBC and correlate the results with patient characteristics. Patients and Methods: In this study, histological specimens were obtained from 120 male patients diagnosed and treated for primary invasive breast cancer from 1995 to 2022 at Breast Cancer Units in Bergisch Gladbach, Chemnitz, and Zwickau, Germany. HER2 immunostaining and in situ hybridization were performed by central pathology and evaluated based on the ASCO/CAP guidelines. The correlation of expression of HER2 low with tumor biological characteristics and patient outcomes was investigated. Results: Out of all cases, four patients (3.3%) showed HER2 positivity (3+), 39 (32.5%) patients were classified as HER2 low, 7 (5.8%) were HER2 2+ (no amplification), 32 (26.7%) were HER2 1+, and 77 (64.2%) were classified as HER2 zero. Out of 77 HER2 zero cases, 47 tumors (61.0%) showed incomplete staining, with <10% of tumor cells classified as HER2 ultralow. No statistical correlation between HER2 low and tumor biological characteristics and patients' survival was found. Conclusion: Our findings show a notable, albeit lower, prevalence of HER2 low expression in primary MBC. However, tumors expressing HER2 low do not show specific tumor biological features to define a new breast cancer subtype in MBC. Our results suggest that a significant number of MBC patients could benefit from ADCs, as shown in FBC. Further studies are required to better understand HER2 low breast cancer, both generally and in MBC.

Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance.

Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive (ER+) breast cancer. However, the efficacy of agents such as tamoxifen (Tam) is often compromised by the development of resistance. Here we report that cytokines-activated nuclear IKKα confers Tam resistance to ER+ breast cancer by inducing the expression of FAT10, and that the expression of FAT10 and nuclear IKKα in primary ER+ human breast cancer was correlated with lymphotoxin ß (LTB) expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam. IKKα activation or enforced FAT10 expression promotes Tam-resistance while loss of IKKα or FAT10 augments Tam sensitivity. The induction of FAT10 by IKKα is mediated by the transcription factor Pax5, and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKα attenuates p53-directed repression of FAT10. Thus, our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+ breast cancer.