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BackgroundZilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer.Patients and methodsEligible patients had locally advanced, unresectable, or metastatic HER2- breast cancer with Eastern Cooperative Group performance status of 0-2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV.ResultsStudy patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response.ConclusionThe combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted.Trial registrationNCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.

Background: HER2-positivity is an essential marker for therapeutic decisions, while HER2 expression is heterogenous. In recent years, there has been increasing recognition of a subgroup of breast cancer patients who have low levels of HER2 expression, also known as HER2-low because trastuzumab deruxtecan offers clinical benefit for patients with HER2-low metastatic breast cancer. Despite the growing interest in HER2-low breast cancer, there is limited research on how multigene assays can help differentiate between HER2-low and HER2-negative breast cancer. Among HR + HER2- breast cancer, we compared genomic characteristics between HER2-low and HER2-zero using the 21-gene assay. Methods: A retrospective review of clinical records was performed in 2,295 patients who underwent Oncotype DX® test in two hospitals between 2013 and 2020. Patients were classified into two groups as the HER2-zero and HER2-low based on HER2 immunohistochemistry. In cases with HER2 2+, no amplification of HER2 gene was confirmed by silver in situ hybridization. High genomic risk was defined as cases with 21-gene recurrence score (RS) > 25. Multivariable binary logistic-regression analysis was performed. Results: Of these, 944 (41.1%) patients were assigned to the HER2-zero group, while 1351 (58.9%) patients were assigned to the HER2-low group. The average Recurrence Score (RS) was found to be 17.802 in the HER2-zero breast cancer group and 18.503 in the HER2-low group, respectively (p-value < 0.005). When comparing the proportion of high RS between the two groups, the HER2-zero group had a high RS rate of 12.4% (117 out of 944), while the HER2-low group had a high RS rate of 17.0% (230 out of 1351) (p = 0.002). The HER2 score identified by qRT-PCR was 8.912 in the HER2-zero group and 9.337 in the HER2-low group (p < 0.005). In multivariable analysis, HER2-low status was found to be an independent factor for high RS, with an odds ratio of 1.517 (1.172–1.964), independent of ER, PR, and Ki67. Within the subgroup of patients with invasive ductal carcinoma, the high RS rates were 19% in the HER2-low group and 14% in the HER2-zero group. However, when considering all patients, there were no significant differences observed in recurrence-free survival and overall survival between the HER2-low and HER2-zero groups. Conclusion: Within HR + HER2- breast cancer, HER2-low tumors are associated with high RS, especially for histologically invasive ductal carcinoma. A prognostic influence of HER2-low expression among HR + HER2- breast cancer remains as an area that requires further study. [ABSTRACT FROM AUTHOR]

Background: Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC. Methods: We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice. Results: Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway. Conclusion: The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis. [ABSTRACT FROM AUTHOR]

Background: The advent of antibody-drug conjugates (ADCs) represents a landmark advance in cancer therapy, permitting targeted delivery of a potent cytotoxic agent to tumor cells with minimal damage to surrounding cells. Although ADCs can induce sustained therapeutic responses in heavily pretreated patients, they can also cause significant toxicity and thus require careful monitoring. The prototype ADC, ado-trastuzumab emtansine (T-DM1) is comprised of a humanized, monoclonal human epidermal growth factor receptor 2 (HER2)-directed antibody, trastuzumab, linked to the cytotoxic agent, DM1, and is used for the treatment of early-stage and advanced HER2-positive breast cancer. Liver toxicities, including transaminitis and nodular regenerative hyperplasia resulting in portal hypertension have been described. We report a case series of four patients who developed hepatopulmonary syndrome (HPS) during treatment with T-DM1. HPS is characterized by hypoxemia, portal hypertension, and intrapulmonary shunting, and it can be associated with severe hypoxic respiratory failure. HPS secondary to noncirrhotic portal hypertension occurring with long-term exposure to T-DM1 has not previously been reported. Case series presentation: Four patients who received T-DM1 in our institutional cohort (n=230) developed HPS, which can be associated with severe hypoxic respiratory failure. Each patient diagnosed with HPS received >50 doses of T-DM1. Only one patient at diagnosis had resting hypoxia, while the other three patients became hypoxic with exertion only. Discontinuation of T-DM1 led to clinical improvement in hypoxia in three of the four patients. The spectrum of liver injury that occurs with long-term use of T-DM1 remains incompletely defined. Conclusions: As T-DM1 is approved for use in the management of early-stage operable and advanced breast cancer, awareness of HPS as a potential complication of long-term administration of T-DM1 is necessary. The emergence of dyspnea alone or combined with low oxygen saturation and signs of hypoxemia (clubbing or elevated hemoglobin) should raise clinical suspicion and prompt evaluation for HPS. Cancer care team members should be vigilant regarding the potential for new and serious side effects associated with novel targeted therapies, which may emerge years beyond initial regulatory approval. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, identified as the most prevalent cancer worldwide, presents considerable difficulties in advanced stages, especially when involving metastatic spread. Scalp metastasis from breast cancer represents a rare and insufficiently explored occurrence. This paper seeks to illuminate this uncommon manifestation by presenting two cases of scalp metastatic breast cancer in Chinese women. Case report: Case 1: A 45-year-old Chinese woman with a history of invasive ductal carcinoma presented with a scalp lesion indicative of recurrence. Concurrently, she was diagnosed with bone metastases and recurrence at the original site. Despite undergoing various treatments, including chemotherapy and hormonal therapy, her condition worsened, ultimately leading to her passing. Case 2: A 40-year-old Chinese woman was initially diagnosed with bilateral breast invasive mucinous carcinoma presenting with bilateral breast masses and a scalp lesion. She also had multiple bone metastases. Following chemotherapy and hormonal therapy, her disease stabilized. Conclusion: These cases of scalp metastatic breast cancer underscore the complexities involved in managing advanced stages of the disease, especially with rare metastatic manifestations. They highlight the importance of comprehensive diagnostic methods, encompassing full-body skin evaluations, and draw attention to the socioeconomic challenges faced in cancer treatment. These findings point to the necessity for more targeted research on uncommon metastatic forms in breast cancer aiming to enhance patient outcomes and refine management approaches. [ABSTRACT FROM AUTHOR]

For aromatase inhibitor treatment (AIT) in breast cancer, there is an unresolved concern about ischaemic cardiotoxicity. We investigated the association between AIT and ischaemic cardiotoxicity in a prospective cohort of female patients with early breast cancer who received contemporary treatment in Denmark. In this prospective cohort study in Denmark, we identified postmenopausal patients of any age diagnosed with breast cancer as recorded in the nationwide Danish Breast Cancer Cooperative Group (DBCG) clinical database between Jan 1, 2009, and Dec 31, 2020, and linked them to other nationwide registries. Exclusion criteria included having a history of other primary cancer, less than 2 years of residency in Denmark, and no inclusion in a treatment protocol according to the DBCG database, including for metastatic or locally advanced breast cancer. Information on demography, hospital diagnoses, filled prescriptions, laboratory testing, and socioeconomic status were recorded. We stratified the patient cohort according to history (yes vs no) of selected cardiovascular disease defined as ischaemic heart disease, ischaemic stroke, and heart failure, and defined the primary outcome as two-point major adverse cardiovascular events (MACE; acute myocardial infarction or ischaemic stroke). We estimated cause-specific hazard ratios (HRs) according to allocation to AIT versus not in an intention-to-treat analysis using a Cox proportional hazards regression model with age as the underlying time scale, adjusting for demographic characteristics, tumour characteristics, and other anti-cancer treatments. 43 440 postmenopausal patients diagnosed with breast cancer were identified, of whom 32 635 were followed up and included in analyses. Of 29 118 postmenopausal patients with no history of selected cardiovascular disease, we observed 510 two-point MACEs among 22 135 patients allocated to AIT (incidence rate 4·3/1000 person-years of follow-up) and 170 two-point MACEs among 6983 patients not allocated to AIT (4·1/1000 person-years). The adjusted HR was 0·91 (95% CI 0·73–1·14) for patients allocated to AIT versus patients not allocated to AIT. Among 3517 patients with a history of selected cardiovascular disease, we observed 158 two-point MACEs among 2661 patients allocated to AIT (incidence rate 12·4/1000 person-years) and 50 two-point MACEs (12·1/1000 person-years) among 856 patients not allocated to AIT (adjusted HR 0·81 [95% CI 0·58–1·15]). Our findings do not support a clinically relevant ischaemic cardiotoxic potential of AIT in patients with early breast cancer and do not support avoiding AIT prescription in patients with early breast cancer. Bispebjerg and Frederiksberg Hospital, Kræftens Bekæmpelse, Fonden til Lægevidenskabens Fremme, Aase og Ejnar Danielsens Fond, Helsefonden, and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat. [ABSTRACT FROM AUTHOR]

Modern cancer therapies greatly improve clinical outcomes for both early and advanced breast cancer patients. However, these advances have raised concerns about potential short- and long-term toxicities, including cardiovascular toxicities. Therefore, understanding the common risk factors and underlying pathophysiological mechanisms contributing to cardiovascular toxicity is essential to ensure best breast cancer outcomes. While cardio-oncology has emerged as a sub-speciality to address these challenges, it is essential that all cardiologists recognize and understand the cardiovascular consequences of cancer therapy. This review aims to provide a comprehensive overview of the potential adverse cardiovascular effects associated with modern breast cancer therapies. A preventive, diagnostic, and therapeutic workflow to minimize the impact of cardiovascular toxicity on patient outcomes is presented. Key aspects of this workflow include regular monitoring of cardiovascular function, early detection and management of cancer therapy-related cardiovascular toxicities, and optimization of cardiovascular risk factor control. By highlighting the gaps in knowledge in some areas, this review aims to emphasize the critical role of cardio-oncology research in ensuring the holistic well-being of patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) constitutes a significant peril to global women's health. Contemporary research progressively suggests that mitochondrial dysfunction plays a pivotal role in both the inception and advancement of BC. However, investigations delving into the correlation between mitochondrialrelated genes (MRGs) and the prognosis and metastasis of BC are still infrequent. Methods: Utilizing data from the TCGA database, we employed the "limma" R package for differential expression analysis. Subsequently, both univariate and multivariate Cox regression analyses were executed, alongside LASSO Cox regression analysis, to pinpoint prognostic MRGs and to further develop the prognostic model. External validation (GSE88770 merged GSE425680) and internal validation were further conducted. Our investigation delved into a broad spectrum of analyses that included functional enrichment, metabolic and immune characteristics, immunotherapy response prediction, intratumor heterogeneity (ITH), mutation, tumor mutational burden (TMB), microsatellite instability (MSI), cellular stemness, single-cell, and drug sensitivity analysis. We validated the protein and mRNA expressions of prognostic MRGs in tissues and cell lines through immunohistochemistry and qRT-PCR. Moreover, leveraging the GSE102484 dataset, we conducted differential gene expression analysis to identify MRGs related to metastasis, subsequently developing metastasis models via 10 distinct machine-learning algorithms and then selecting the bestperforming model. The division between training and validation cohorts was set at 70% and 30%, respectively. Results: A prognostic model was constructed by 9 prognostic MRGs, which were DCTPP1, FEZ1, KMO, NME3, CCR7, ISOC2, STAR, COMTD1, and ESR2. Patients within the high-risk group experienced more adverse outcomes than their counterparts in the low-risk group. The ROC curves and constructed nomogram showed that the model exhibited an excellent ability to predict overall survival (OS) for patients and the risk score was identified as an independent prognostic factor. The functional enrichment analysis showed a strong correlation between metabolic progression and MRGs. Additional research revealed that the discrepancies in outcomes between the two risk categories may be attributed to a variety of metabolic and immune characteristics, as well as differences in intratumor heterogeneity (ITH), tumor mutational burden (TMB), and cancer stemness indices. ITH, TIDE, and IPS analyses suggested that patients possessing a low-risk score may exhibit enhanced responsiveness to immunotherapy. Additionally, distant metastasis models were established by PDK4, NRF1, DCAF8, CHPT1, MARS2 and NAMPT. Among these, the XGBoost model showed the best predicting ability. Conclusion: In conclusion, MRGs significantly influence the prognosis and metastasis of BC. The development of dual clinical prediction models offers crucial insights for tailored and precise therapeutic strategies, and paves the way for exploring new avenues in understanding the pathogenesis of BC. [ABSTRACT FROM AUTHOR]

Objective: This study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval. Methods: We identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response's relative risk (RR) alongside objective response rate (ORR) were meta-analyzed. Results: The median development time for breast cancer drugs was 7.8 years (95% CI 6.2–10.8). 26% of treatments were considered innovative ("first-in-indication") with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA's special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417–752) at 181 centers (IQR 142–223) across 19 countries (IQR 17–20). New drugs' HR were 0.78 for OS (95% CI 0.74–0.82) and 0.59 for PFS (95% CI 0.54–0.64) with a RR for tumor response of 1.61 (95% CI 1.46–1.76). Median improvements of OS were 2.8 months (IQR 1.8–5.8) and PFS were 4.4 months (IQR 2.2–7.1). In single-arm trials, the average ORR was 31% (95% CI 10–53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a 'high-value' ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097–17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840–86,062). Conclusions: Over the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life. [ABSTRACT FROM AUTHOR]

The article discusses the advancements in the treatment of estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, focusing on combining endocrine therapy with cyclin-dependent kinase 4/6 inhibitors, phosphoinositide 3-kinase inhibitors, and selective estrogen-receptor degraders. Topics include the effectiveness of cyclin-dependent kinase 4/6 inhibitors, PI3K pathway-targeted therapy in patients with PIK3CA mutations, and clinical trial outcomes.

BACKGROUND Inavolisib is a highly potent and selective inhibitor of the alpha isoform of the pllO catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CÄ) that also promotes the degradation of mutated pllOa. Inavolisib plus palbociclib-fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials. METHODS In a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib-fulvestrant (inavolisib group) with placebo plus palbociclib-fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator. RESULTS A total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group. CONCLUSIONS In patients with PIKJCA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. [ABSTRACT FROM AUTHOR]

Aims Materials and methods Results Conclusions This study evaluates the utility of breast specific markers in identifying breast cancer subtypes within metastatic settings. The subtype alteration in metastatic disease and its consequent impact on breast‐specific marker expression is also examined.GATA‐binding protein 3 (GATA3), mammaglobin (MMG), transcriptional repressor GATA binding 1 (TRSP1) and SRY‐box transcription factor 10 (SOX10) expression were assessed in a large cohort of metastatic breast cancer (MBC) cases and correlated with the characteristics of both MBC and primary breast cancer (PBC).GATA3 was the most sensitive in MBC (83.1%), followed by TRPS1 (77.0%), MMG (58.5%) and SOX10 (7.1%). This trend was consistent in hormonal receptor (HR)+ and HR− MBC. Combining GATA3/TRPS1 yielded the highest detection rates in the overall cohort (90.1%) and HR+ MBC (97.1%), while TRSP1/MMG was most effective in HR− (76.2%) and TN (71.1%) MBC. Marker expression did not correlate with metastatic site, except SOX10 in lung metastases (P = 0.031). Subtype discordance between MBC and PBC occurred in 43 cases (24.4%), with GATA3 expression in HR− MBC significantly linked to subtype discordance (P = 0.005). Conversely, SOX10 expression was significantly associated with subtype concordance in HR− and TNBC (P ≤ 0.003). Despite a higher expression of GATA3 in all HR− cases, TRSP1 outperformed GATA3 in detecting concordant HR− cases (64.0% versus 38.5%). TRPS1 and SOX10 were expressed in more than 50% of concordant TNBC cases.The expression of breast‐specific markers is mainly determined by the PBC subtype. GATA3 retains high sensitivity in HR+ cancers, even after HR loss during metastasis. TRPS1 and SOX10 are identified as valuable markers in TNBC metastasis. [ABSTRACT FROM AUTHOR]

Background: Vasculogenic mimicry (VM) is an alternative intratumoral microcirculation system that depends on the capacity of tumor cells to reorganize and grow in three-dimensional (3D) channel architectures like the capillaries formed by endothelial cells. Both VM and angiogenesis may coordinately function to feed cancer cells, allowing tumor growth. Long noncoding RNAs (lncRNAs) regulate critical cellular functions in cancer cells, including cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. The lncRNA, known as actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1), has been described as an oncogene in diverse types of cancers. However, its role in VM and metastasis in triple-negative breast cancer (TNBC) is unknown. Methods: Reverse transcription and quantitative polymerase chain reaction (RT‒qPCR) experiments were performed to evaluate the expression of 10 selected lncRNAs from literature in metastatic and nonmetastatic biopsies from TNBC patients. The expression of AFAP1-AS1 was analyzed in Genotype-Tissue Expression Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. The AFAP1-AS1 expression was knocked in TNBC Hs578T cells by transfection of specific siRNAs. Channel-like formation assays were performed using 3D cultures over Matrigel in hypoxia-treated Hs578T cancer cells with diminished expression of AFAP1-AS1. The angiogenesis tests were conducted using human umbilical vein endothelial cells (HUVECs) and AFAP1-AS1- silenced Hs578T cells on 3D cell cultures. The presence of VM (CD31-/PAS+) in tumor tissues from TNBC patients with and without metastasis was assessed through immunohistochemistry using endothelial marker CD31 antibodies and periodic acid-Schiff (PAS) staining. Results: Compared with normal mammary tissues, AFAP1-AS1 expression was higher in breast cancer tissues. Moreover, AFAP1-AS1 expression was upregulated in the TNBC subtype compared to receptor-positive breast tumors. In addition, the expression of AFAP1-AS1 was correlated with the expression of the thirteen genes characteristic of a previously reported hypoxia signature. Interestingly, AFAP1-AS1 was upregulated in primary TNBC tumors from patients who developed metastasis compared with the nonmetastatic group. Functional analysis revealed that the knockdown of AFAP1-AS1 in Hs578T cells significantly impaired the hypoxia-induced VM, accompanied by a decrease in the development of 3D channel networks. Similarly, AFAP1-AS1 knockdown counteracts the angiogenic potential of cancer cells, as indicated by a reduction in the number of polygons, sprouting cells, and nodes in HUVEC cells. Remarkably, an increase in CD31-/PAS + staining of 3D channel networks in primary breast tumors from metastatic patients was found compared with the nonmetastatic group. Finally, we found that the number of blood vessels increased in the nonmetastatic group more than in the metastatic cohort. Conclusions: Our data suggested that AFAP1-AS1 controls both VM and angiogenesis in Hs578T breast cancer cells and that increased metastasis is associated with VM in TNBC patients. [ABSTRACT FROM AUTHOR]

Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers. [ABSTRACT FROM AUTHOR]

Most deaths in breast cancer patients are attributed to metastasis, and lung metastasis is associated with a particularly poor prognosis; therefore it is imperative to identify potential target for intervention. The transforming growth factor‐β (TGF‐β) pathway plays a vital role in breast cancer metastasis, in which Smad3 is the key mediator and performs specific functions by binding with different cofactors. However, Smad3 cofactors involved in lung metastasis have not yet been identified. This study first establishes the interactome of Smad3 in breast cancer cells and identifies ZNF8 as a novel Smad3 cofactor. Furthermore, the results reveal that ZNF8 is closely associated with breast cancer lung metastasis prognosis, and specifically facilitates TGF‐β pathway‐mediated breast cancer lung metastasis by participating in multiple processes. Mechanistically, ZNF8 binds with Smad3 to enhance the H3K4me3 modification and promote the expression of lung metastasis signature genes by recruiting SMYD3. SMYD3 inhibition by BCI121 effectively prevents ZNF8‐mediated lung metastasis. Overall, the study identifies a novel cofactor of TGF‐β/Smad3 that promotes lung metastasis in breast cancer and introduces potential therapeutic strategies for the early management of breast cancer lung metastasis. [ABSTRACT FROM AUTHOR]

Breast cancer is currently the most frequent malignant tumor and the leading cause of cancer death among women globally. Although the five-year survival rate for early breast cancer has risen to more than 90%, medication resistance persists in advanced breast cancer and some intractable breast cancer, resulting in a poor prognosis, a high recurrence rate, and a low survival rate. Single-cell sequencing (SCS) is the study of a single cell's gene structure and expression level differences in order to discover unusual molecular subgroups, disease development, and a variety of mechanisms. This review briefly discusses single-cell sequencing and its application, and lists the research on single-cell sequencing in the development and metastasis of breast cancer, in order to bring fresh ideas for the comprehensive treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic adaptability, including glucose metabolism, enables cells to survive multiple stressful environments. Glycogen may serve as a critical storage depot to provide a source of glucose during times of metabolic demand during the metastatic cascade; therefore, understanding glycogen metabolism is critical. Our goal was to determine mechanisms driving glycogen accumulation and its role in metastatic (MCF10CA1a) compared to nonmetastatic (MCF10A-ras) human breast cancer cells. Methodology:13C6-glucose flux analysis in combination with inhibitors of the gluconeogenic pathway via phosphoenolpyruvate carboxykinase (PCK), the anaplerotic enzyme pyruvate carboxylase (PC), and the rate-limiting enzyme of the pentose phosphate pathway (PPP) glucose 6-phosphate dehydrogenase (G6PD). To determine the requirement of glycogenolysis for migration or survival in extracellular matrix (ECM) detached conditions, siRNA inhibition of glycogenolysis (liver glycogen phosphorylase, PYGL) or glycophagy (lysosomal enzyme α-acid glucosidase, GAA) enzymes was utilized. Results: Metastatic MCF10CA1a cells had 20-fold greater glycogen levels compared to non-metastatic MCF10A-ras cells. Most glucose incorporated into glycogen of the MCF10CA1a cells was in the five13C-containing glucose (M+5) instead of the expected M+6 glycogen-derived glucose moiety, which occurs through direct glucose conversion to glycogen. Furthermore,13C6-glucose in glycogen was quickly reduced (~50%) following removal of13C-glucose. Incorporation of 13C6-glucose into the M+5 glucose in the glycogen stores was reduced by inhibition of PCK, with additional contributions from flux through the PPP. Further, inhibition of PC reduced total glycogen content. However, PCK inhibition increased total unlabeled glucose accumulation into glycogen, suggesting an alternative pathway to glycogen accumulation. Inhibition of the rate-limiting steps in glycogenolysis (PYGL) or glycophagy (GAA) demonstrated that both enzymes are necessary to support MCF10CA1a, but not MCF10A-ras, cell migration. GAA inhibition, but not PYGL, reduced viability of MCF10CA1a cells, but not MCF10A-ras, in ECM detached conditions. Conclusion: Our results indicate that increased glycogen accumulation is primarily mediated through the gluconeogenesis pathway and that glycogen utilization is required for both migration and ECM detached survival of metastatic MCF10CA1a cells. These results suggest that glycogen metabolism may play an important role in the progression of breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Contralateral axillary lymph node metastasis (CAM) is a rare clinical condition in patients with breast cancer (BC). CAM can be either a locoregional event or a distant metastasis. Molecular application for clonal evolution in BC has not been reported in CAM cases.We studied six patients with CAM with clinical, pathological and/or molecular evidence of distant metastasis; those patients had poor outcomes.Two cases with molecular analysis of paired primary and CAM established clonal evolution of the CAM with its corresponding primary with additional molecular alteration, increased tumour mutation burden, and copy number variations (CNVs) in the CAMs. Four cases containing alterations from genes potentially modulate chromatin organization, supporting chromatin and subsequent transcriptional signature changes are essential in CAM. Molecular analysis is critical to establish the connection between CAM and its primary counterpart. Distant CAM shows clonal evolution compared with its corresponding primary with additional molecular alterations, increased mutation burden and/or copy number variations.CAM should be evaluated individually and handled in a personalized fashion. Evidence of a true metastatic CAM can be supported by distant metastasis to other organs, specific morphological features and/or clonal evolution. [ABSTRACT FROM AUTHOR]

Background: The status of sentinel lymph nodes is crucial for prognosis and treatment decisions in breast cancer patients. This study aimed to evaluate the predictive value of combined methylene blue and indocyanine green for sentinel lymph node metastasis in breast cancer. Methods: This prospective cohort study enrolled 90 clinically node-negative breast cancer patients. Methylene blue and indocyanine green were injected locally before surgery. Sentinel lymph nodes were grouped based on fluorescence intensity and methylene blue staining. A binary logistic regression model was established using 285 lymph node groups to predict metastatic risk. Results: A total of 475 lymph nodes were identified, with 33 being metastatic. The metastatic risk reached 70% for partially blue-stained and weakly fluorescent lymph nodes between 1-2 cm. The model revealed associations between lymph node size, dye staining patterns, and metastatic risks (P<0.05). The AUC of the ROC curve was 0.855. Conclusions: The staining pattern of combined methylene blue and indocyanine green could predict risks of sentinel lymph node metastasis and facilitate rapid intraoperative identification of high-risk lymph nodes. [ABSTRACT FROM AUTHOR]

Breast cancer(BC) is the second most prevalent tumor in the world and one of the most lethal tumors in women. Patients with estrogen receptor-positive breast cancer can obtain significant advantages from endocrine therapies including tamoxifen, aromatase inhibitors, and others. However, the development of primary or acquired drug resistance ultimately leads to discontinuation of treatment with adverse consequences for breast cancer patients, and the underlying mechanisms have not been fully elucidated. Long non-coding RNAs (lncRNAs) play pivotal roles in orchestrating fundamental biochemical and cellular processes. They exert regulatory control over various processes including epigenetics, gene transcription, posttranscriptional modifications, and translation. Additionally, they influence key biological events like cell cycle progression, cell differentiation, and development. For the past few years, the relationship between lncRNAs and endocrine resistance has gained increasing attention, leading to a surge in related studies. LncRNAs mediate tamoxifen resistance in cancer by utilizing a variety of molecular mechanisms, including enhanced estrogen receptor (ER) signaling, inhibition of apoptosis, autophagy, exosome-mediated transfer, epigenetic alterations, epithelial-to-mesenchymal transition, and acting as competitive endogenous RNAs(ceRNAs). In this comprehensive review, we systematically summarize the critical role and intricate molecular mechanisms by which lncRNAs influence the development of tamoxifen resistance in breast cancer. Furthermore, we propose the potential clinical significance of lncRNAs as innovative therapeutic targets and prognostic biomarkers for breast cancer. [ABSTRACT FROM AUTHOR]

At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm³ in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients. [ABSTRACT FROM AUTHOR]

Introduction: Metastatic breast cancer (MBC) presents an enduring and significant challenge for affected women, requiring sustained commitment over the years. Case Presentation: This paper presents a case of a woman affected by bone and visceral MBC with a very long 20-year survival, excellent quality of life, and high resilience. She is now 51 years old and underwent quadrantectomy for breast cancer in 2005, and in 2013, she developed a recurrence with bone and liver metastases. Despite the widespread stage of the disease with visceral compromise, the patient was treated with a multidisciplinary approach that included surgery, chemotherapy, radiotherapy, hormone therapy, bone target agents, metabolic radiotherapy, and ozone therapy for medication-related osteonecrosis of the jaw. Multidisciplinary management results in a complete clinical and metabolic response to treatment in a visceral metastatic setting. Conclusion: This report supports the possibility of achieving unusual survival outcomes in patients with MBC. This study also highlights the importance of resilience in breast cancer patients who continue to manage their disease and pursue treatment for over 2 decades. Understanding these resilience factors can improve clinical practice and support patients’ long-term care. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NAC) for breast cancer enables pathological complete response (pCR) in patients initially diagnosed with axillary lymph node metastases, potentially obviating the need for axillary lymph node dissection (ALND). Current targeted axillary dissection (TAD) techniques, guided by traditional tissue markers placed prior to NAC, face challenges such as marker loss and high costs. Carbon nanoparticle suspension injection (CNSI) offers a stable and reliable alternative for marking, which could enhance the TAD procedure. This study aims to evaluate the feasibility and accuracy of different TAD strategies using CNSIs and to explore their clinical utility in locally advanced breast cancer. Methods: This prospective, multicenter, randomized controlled trial will enroll 126 biopsy-proven breast cancer patients with suspicious axillary lymph node metastases (cN1-2a) who achieve ycN0 status following NAC. Participants will be randomized in a 1:1:1 ratio to undergo TAD guided by: [1] conventional tissue clips (CG-TAD); [2] CNSI lymph node marking (CN-LNM); or [3] peritumoral CNSI mapping (PCN-MAP). Primary endpoints include retrieval rate of marked lymph nodes, number of sentinel and marked lymph nodes, concordance rates, and complication rates. Secondary endpoints encompass regional and distant recurrence rates, survival outcomes, surgical duration, postoperative complications, quality of life scores, and margin status in breast-conserving surgery. Statistical analyses will adhere strictly to the CONSORT guidelines. Discussion: This study aims to evaluate the feasibility and accuracy of CNSI for targeted axillary dissection in breast cancer patients following neoadjuvant chemotherapy and to explore its clinical significance in reducing surgical complications and costs, as well as improving surgical precision. Trial registration: Clinicaltrials.gov, NCT04744506, Registered 27 December 2020, Updated 24 September 2024. Protocol Version Ver 1.2, 17/9/2024. [ABSTRACT FROM AUTHOR]

Advanced breast cancer, as well as ineffective treatments leading to surviving cancer cells, can result in the dissemination of these malignant cells from the primary tumor to distant organs. Recent research has shown that microRNA 200c (miR‐200c) can hamper certain steps of the invasion–metastasis cascade. However, it is still unclear whether miR‐200c expression alone is sufficient to prevent breast cancer cells from metastasis formation. Hence, we performed a xenograft mouse experiment with inducible miR‐200c expression in MDA‐MB 231 cells. The ex vivo analysis of metastatic sites in a multitude of organs, including lung, liver, brain, and spleen, revealed a dramatically reduced metastatic burden in mice with miR‐200c‐expressing tumors. A fundamental prerequisite for metastasis formation is the motility of cancer cells and, therefore, their migration. Consequently, we analyzed the effect of miR‐200c on collective‐ and single‐cell migration in vitro, utilizing MDA‐MB 231 and MCF7 cell systems with genetically modified miR‐200c expression. Analysis of collective‐cell migration revealed confluence‐dependent motility of cells with altered miR‐200c expression. Additionally, scratch assays showed an enhanced predisposition of miR‐200c‐negative cells to leave cell clusters. The in‐between stage of collective‐ and single‐cell migration was validated using transwell assays, which showed reduced migration of miR‐200c‐positive cells. Finally, to measure migration at the single‐cell level, a novel assay on dumbbell‐shaped micropatterns was performed, which revealed that miR‐200c critically determines confined cell motility. All of these results demonstrate that sole expression of miR‐200c impedes metastasis formation in vivo and migration in vitro and highlights miR‐200c as a metastasis suppressor in breast cancer. [ABSTRACT FROM AUTHOR]

Brain metastasis, a serious complication of cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor AXL. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis. [Display omitted] • Brain metastases initiate with distinct tumor architectures and stromal interfaces • Perivascular and spheroidal micrometastases elicit different microglial responses • Breast cancer cell-derived tenascin C (TNC) drives spheroidal colony growth • TNC triggers a disease-associated microglia state via type I interferon response Gan et al. reveal distinct tumor architectures, stromal interfaces, and tumor-intrinsic mechanisms that are preferentially adopted by prevalent brain metastases during the initiation of colonization. These findings highlight critical spatial and microenvironmental features that can be leveraged to target minimal residual disease in the brain. [ABSTRACT FROM AUTHOR]

Breast cancer remains a significant health concern, with triple-negative breast cancer (TNBC) being an aggressive subtype with poor prognosis. Epithelial-mesenchymal transition (EMT) is important in early-stage tumor to invasive malignancy progression. Snail, a central EMT component, is tightly regulated and may be subjected to proteasomal degradation. We report a novel proteasomal independent pathway involving chaperone-mediated autophagy (CMA) in Snail degradation, mediated via its cytosolic interaction with HSC70 and lysosomal targeting, which prevented its accumulation in luminal-type breast cancer cells. Conversely, Snail predominantly localized to the nucleus, thus evading CMA-mediated degradation in TNBC cells. Starvation-induced CMA activation downregulated Snail in TNBC cells by promoting cytoplasmic translocation. Evasion of CMA-mediated Snail degradation induced EMT, and enhanced metastatic potential of luminal-type breast cancer cells. Our findings elucidate a previously unrecognized role of CMA in Snail regulation, highlight its significance in breast cancer, and provide a potential therapeutic target for clinical interventions. [ABSTRACT FROM AUTHOR]

Background: Breast cancer metastasis remains the leading cause of cancer-related deaths in women worldwide. Infiltration of tumor-associated macrophages (TAMs) in the tumor stroma is known to be correlated with reduced overall survival. The inhibitors of TAMs are sought after for reprogramming the tumor microenvironment. Signal transducer and activator of transcription 3 (STAT3) is well known to contribute in pro-tumoral properties of TAMs. 2-Methoxyestradiol (2ME2), a potent anticancer and antiangiogenic agent, has been in clinical trials for treatment of breast cancer. Here, we investigated the potential of 2ME2 in modulating the pro-tumoral effects of TAMs in breast cancer. Methods: THP-1-derived macrophages were polarized to macrophages with or without 2ME2. The effect of 2ME2 on macrophage surface markers and anti-inflammatory genes was determined by Western blotting, flow cytometry, immunofluorescence, qRT‒PCR. The concentration of cytokines secreted by cells was monitored by ELISA. The effect of M2 macrophages on malignant properties of breast cancer cells was determined using colony formation, wound healing, transwell, and gelatin zymography assays. An orthotopic model of breast cancer was used to determine the effect of 2ME2 on macrophage polarization and metastasis in vivo. Results: First, our study found that polarization of monocytes to alternatively activated M2 macrophages is associated with the reorganization of the microtubule cytoskeleton. At lower concentrations, 2ME2 treatment depolymerized microtubules and reduced the expression of CD206 and CD163, suggesting that it inhibits the polarization of macrophages to M2 phenotype. However, the M1 polarization was not significantly affected at these concentrations. Importantly, 2ME2 inhibited the expression of several anti-inflammatory cytokines and growth factors, including CCL18, TGF-β, IL-10, FNT, arginase, CXCL12, MMP9, and VEGF-A, and hindered the metastasis-promoting effects of M2 macrophages. Concurrently, 2ME2 treatment reduced the expression of CD163 in tumors and inhibited lung metastasis in the orthotopic breast cancer model. Mechanistically, 2ME2 treatment reduced the phosphorylation and nuclear translocation of STAT3, an effect which was abrogated by colivelin. Conclusions: Our study presents novel findings on mechanism of 2ME2 from the perspective of its effects on the polarization of the TAMs via the STAT3 signaling in breast cancer. Altogether, the data supports further clinical investigation of 2ME2 and its derivatives as therapeutic agents to modulate the tumor microenvironment and immune response in breast carcinoma. [ABSTRACT FROM AUTHOR]

Breast cancer stands as the foremost malignant tumor among women globally, with postoperative recurrence and metastasis significantly impacting patient prognosis. While metastasis to various sites has been reported, gastric involvement remains uncommon. Presenting a case of gastric metastasis a decade post-breast cancer surgery, we underscore the rarity of this occurrence. Our patient, an elderly woman, underwent left breast modified radical surgery ten years prior, followed by adjuvant chemotherapy, maintaining favorable health until experiencing abdominal discomfort two months ago. Contrast-enhanced computed tomography (CT) of the chest and upper abdomen unveiled diffuse abnormal enhancement in the gastric body and sinus wall. Subsequent gastroscopy revealed an ulcer near the gastric antrum, with immunohistochemical staining confirming invasive lobular carcinoma metastasis from the breast. We further conducted an extensive review of 23 cases with detailed information retrieved from PubMed, elucidating clinicopathological, endoscopic features, diagnostic modalities, and contemporary treatment strategies for breast-stomach metastasis. Our findings underscore the imperative of regular postoperative surveillance for breast cancer patients. Timely detection, accurate diagnosis, and appropriate intervention are paramount in managing gastric metastasis, significantly influencing patient outcomes. [ABSTRACT FROM AUTHOR]

Breast cancer continues to be an important health issue around the world, with timely screening being important in improving survival and therapy. Here is a presentation of PolyBreastVit, a novel hybrid deep learning (DL) model for the automatic detection and classification of breast cancer in ultrasound images that combines PolyNet with Vision Transformer (ViT). The above model is trained and validated on a dataset of 880 high‐definition images collected from 500 female subjects aged between 25 and 75 years on three classes: benign, malignant, and normal. For the enhancement of the proposed model's accuracy, thorough data augmentation and preprocessing have been performed. The performance of PolyBreastVit is evaluated against several well‐known DL models such as VGG‐16, Inception V3, and ResNet‐50 using accuracy, precision, recall, F1, AUC, and other standard metrics. These findings support the evidence that PolyBreastVit manages to outperform those classical models in the task of breast cancer classification in every aspect. This paper presents the latest development of breast cancer diagnostic tools through medical imaging incorporating convolutional neural networks (CNNs) and transformer models for radiologists. [ABSTRACT FROM AUTHOR]

Background : Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case–control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. Methods: In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into "active" and "insufficiently active" to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. Results: Compared to "insufficiently active" patients, "active" individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p =.0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be "active" at baseline revealed significantly fewer AEs compared to "insufficiently" active patients. In detail, both severe and non-severe AEs occurred less frequently in the "active" patients group. In line with that, QoL and fatigue were better in physical "active" patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. Conclusions: Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients' QoL and fatigue. Trial registration: EUPAS9462. Registered 30th October 2012 "retrospectively registered." [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most commonly diagnosed cancer worldwide. Although major treatments represented by chemotherapy have shown effectiveness at the initial period, recurrence and metastasis still occur later after treatments. The alternation of the tumor microenvironment by chemotherapy is confirmed as a trigger of the elevated proliferation and migration of the remaining tumor cells. Methods: Using bioinformatic methods, differential gene expression analysis was used to determine DEGs between post-chemotherapy and pre-chemotherapy samples of breast cancer patients, followed by survival analysis and ELISA analysis of the potential key genes. An in vitro model of 2 breast cancer cells lines was used to demonstrate the role of VWF in the evasion and migration of breast cancer cells, using cell migration, evasion and wound healing assays, PCR and molecular docking analysis. Results: 19 hub genes were further identified using GO and KEGG pathway analyses and WGCNA. The 5 secreted protein-coding genes with reported carcinogenesis effects (VWF, SVEP1, DPT, ADIPOQ, and LPL) were further analyzed in breast cancer patients and VWF was identified as a potential key regulator in the anthracycline-based chemotherapy-exacerbated metastasis. It was further confirmed that anthracycline-based chemotherapeutics doxorubicin exacerbated VWF upregulation and the evasion and migration of breast cancer cells. Based on molecular docking analysis and previous study, berberine was used as an inhibitor of VWF, and showed an effective inhibition of the doxorubicin-exacerbated VWF upregulation, migration and evasion in breast cancer. Conclusions: Doxorubicin-exacerbated evasion and migration through VWF upregulation. Berberine as an inhibitor of VWF was able to reversed the doxorubicin-exacerbated VWF upregulation and evasion and migration in breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: Cellular senescence can be induced in mammalian tissues by multiple stimuli, including aging, oncogene activation and loss of tumor suppressor genes, and various types of stresses. While senescence is a tumor suppressing mechanism when induced within premalignant or malignant tumor cells, senescent cells can promote cancer development through increased secretion of growth factors, cytokines, chemokines, extracellular matrix, and degradative enzymes, collectively known as senescence-associated secretory phenotype (SASP). Previous studies indicated that senescent cells, through SASP factors, stimulate tumor cell invasion that is a critical step in cancer cell metastasis. Methods: In the current study, we investigated the effect of senescent cells on the motility of breast cancer cells, which is another key step in cancer cell metastasis. We analyzed the motility of breast cancer cells co-cultured with senescent cells in vitro and metastasis of the breast cancer cells co-injected with senescent cells in orthotopic xenograft models. We also delineated the signaling pathway mediating the effect of senescent cells on cancer cell motility. Results: Our results indicate that senescent cells stimulated the migration of breast cancer cells through secretion of GM-CSF and bFGF, which in turn induced activation of the JNK pathway in cancer cells. More importantly, senescent cells promoted breast cancer metastasis, with a minimum effect on the primary tumor growth, in orthotopic xenograft mouse models. Conclusions: These results have revealed an additional mechanism by which senescent cells promote tumor cell metastasis and tumor progression, and will potentially lead to identification of novel targets for cancer therapies that suppress metastasis, the major cause of cancer mortality. [ABSTRACT FROM AUTHOR]

Breast cancer metastasis is associated with a poor prognosis and a high rate of mortality. Cathepsin L (CTSL) is a lysosomal cysteine protease that promotes tumor metastasis by degrading the extracellular matrix. Gene set enrichment analysis revealed that CTSL expression was higher in tumorous than in non-tumorous tissues of breast cancer patients and that high-level CTSL expression correlated positively with the epithelial-mesenchymal transition. Therefore, we hypothesized that inhibiting CTSL activity in tumor cells would prevent metastasis. In this study, we characterized the inhibitory activity of SnuCalCpI15, the I29 domain of a CTSL-like cysteine protease from Calotropis procera R. Br., and revealed that the propeptide stereoselectively inhibited CTSL in a reversible slow-binding manner, with an inhibitory constant (Ki) value of 1.38 ± 0.71 nM, indicating its potency as an exogenous inhibitor in anti-cancer therapy. SnuCalCpI15 was localized intracellularly in MDA-MB-231 breast cancer cells and suppressed tumor cell migration and invasion. These results demonstrate the potential of SnuCalCpI15 as a novel agent to prevent breast cancer metastasis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Palbociclib is indicated for the treatment of hormone receptor-positive, HER2- negative, advanced or metastatic breast cancer in adults. When patients have a minimum of grade 3 neutropenia, the prescribing information for palbociclib recommends therapy interruption to allow for absolute neutrophil count recovery. OBJECTIVE: To identify the incidence of febrile neutropenia (FN) in the setting of grade 3 or 4 neutropenia in patients receiving palbociclib. METHODS: This retrospective cohort study included patients aged =18 years who had grade 3 or 4 neutropenia while receiving palbociclib at a single health system (Geisinger Health System) from January 1, 2018, to December 31, 2020. The primary outcome of this study was the incidence of FN, which was defined as a single body temperature of >38.3°C (101°F) or a temperature of >38°C (100.4°F) sustained for >1 hour within 7 days of having grade 3 or 4 neutropenia. Statistical testing was performed using XRealStats (2022). RESULTS: Grade 3 or 4 neutropenia occurred in 80 (40%) of 200 total patients who received palbociclib, with a total of 387 occurrences. Of those 387 occurrences, 370 were occurrences of grade 3 neutropenia compared with 17 occurrences of grade 4 neutropenia. FN occurred in 10 (2.7%) patients with grade 3 neutropenia whereas there were no occurrences of FN in patients with grade 4 neutropenia (relative risk, 1.0189; 95% confidence interval, 0.0621-16.7109; P=1). Of the 80 patients, 72 (90%) patients received pharmacist-managed medication therapy disease management (MTDM) services. The median occurrence of grade 3 neutropenia in patients followed by the MTDM service was 2 compared with 3.5 for those followed by physicians only. A subgroup analysis of the 10 occurrences of FN revealed that pharmacists identified neutropenia in 80% of occurrences before illness and assessed medication restart for 60% of those patients. CONCLUSION: In patients who received palbociclib, the relationship between the incidence of FN in the setting of grade 3 or 4 neutropenia was nonsignificant. Pharmacist-managed MTDM services contribute to the recognition of neutropenia and FN, resulting in improved patient outcomes. [ABSTRACT FROM AUTHOR]

Objective: CDK4/6 inhibitors (CDK4/6is) in combination with endocrine therapy have secured a central role in the treatment of hormone receptor (HR)-positive advanced breast cancer (ABC) and have transformed the therapeutic landscape. Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects. Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2 (HER2)- ABC. Methods: This retrospective study enrolled 82 patients with HR+/HER2- ABC who were treated with cross-line CDK4/6is (abemaciclib, palbociclib, ribociclib, and dalpiciclib) after progression with another CDK4/6i. The primary endpoint was progressionfree survival (PFS) according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included toxicity, objective response rate, disease control rate, and overall survival. Adverse events (AEs) were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events, as promulgated by the U.S. Department of Health and Human Services. Results: Eighty-two HR+/HER2- ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled. The median age of the patients was 60 years. The median PFS of all patients was 7.6 months (95% CI, 5.9-9.2). Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS. Notably, patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months. The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i, then to a subsequent CDK4/6i merits further investigation. Hematologic toxicity was the most common grade = 3 AEs. No instances of fatal safety events were observed. Conclusions: Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2- ABC, which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy. [ABSTRACT FROM AUTHOR]

Metastasis to the lymph nodes is one of the most important factors in the poor prognosis of patients with breast cancer; the five-year survival rate for metastatic breast cancer is less than 30%. DNA methylation occurs in the early stages of the development of cancer and also plays an important role in the development of lymphogenous metastases and can serve as a diagnostic and prognostic marker of breast cancer. The lncRNA genes GAS5, HOTAIR, HOTAIRM1, and SSTR5-AS1, presumably hypermethylated in breast cancer and associated with epithelial-mesenchymal transition and metastasis, were bioinformatically selected. Quantitative methyl-specific PCR showed a statistically significant increase in the methylation level of these lncRNA genes in breast tumors compared to the paired norm. Hypermethylation of the HOTAIRM1 and SSTR5-AS1 genes in breast cancer was identified for the first time. Using statistical analysis, positive correlations were established between methylation levels for the GAS5-HOTAIR and SSTR5-AS1-HOTAIRM1 pairs. The result of co-methylation of GAS5 and HOTAIR in breast cancer is consistent with the bioinformatically predicted (using enrichment analysis and the ncPath database) participation of these lncRNAs in the regulation of common signaling pathways and biological processes. The level of methylation of the lncRNA genes HOTAIRM1 and SSTR5-AS1 is associated with indicators of breast cancer progression (stage of the tumor process, tumor size, presence of metastases in the lymph nodes). A model has been proposed for assessing the risk of developing lymphogenous metastases depending on the level of methylation of the HOTAIRM1 gene. Thus, data were obtained on lncRNAs GAS5, HOTAIR, HOTAIRM1, and SSTR5-AS1 and hypermethylation of their genes as factors in the development and progression of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background/aim: Breast cancer is the leading cause of death from cancer for women in age group of 20-59 years. It is responsible for 15% of the cancer related deaths in women. Our study attempts to assess the axillary lymph node status in carcinoma breast using combined clinical and radiological examination. Materials and methods: A prospective study was conducted using 82 patients with proven cases of carcinoma breast over a period of 2 years. Patients were subjected to clinical examination and ultrasonography of axilla. Then the histopathological reports of the axillary lymph nodes were studied following surgery. The accuracy of clinical and radiological examination have been assessed with the histopathological reports of the lymph nodes. Results: It was noted that clinical examination has a sensitivity of 53.52% and specificity of 100% in detecting axillary lymph node metastasis, with a PPV of 100%, NPV of 25%, chi square value of 10.792 and a p -value of 0.001 which is statistically significant. However, ultrasonography of axilla has a sensitivity of 77.46% and specificity of 100% in detecting lymph node metastasis, with a PPV of 100%, NPV of 40.74%, chi square value of 25.879 and a p-value of 0.001 which is statistically significant. Conclusion: Ultasonography is a non invasive, safe, easily available, less expensive and a reliable method of assessing the lymphatic spread of carcinoma breast to the axilla. Axillary lymph node status assessment is an important step in staging and management of carcinoma breast. In our study, it is highly specific and has got good sensitivity. Further studies have to be conducted on a larger scale to set axillary ultrasound as the standard investigation in assessing the axillary nodal involvement in carcinoma breast. [ABSTRACT FROM AUTHOR]

Background: The status of axillary lymph nodes (ALN) plays a critical role in the management of patients with breast cancer. It is an urgent demand to develop highly accurate, non-invasive methods for predicting ALN status Purpose: To evaluate the efficacy of ultrasound radiofrequency (URF) time-series parameters, in combination with clinical data, in predicting ALN metastasis in patients with breast cancer. Material and Methods: We prospectively gathered clinicopathologic and ultrasonic data from patients diagnosed with breast cancer. Various machine-learning (ML) models were developed using all available features to determine the most efficient diagnostic model. Subsequently, distinct prediction models were created using the optimal ML model, and their diagnostic performances were evaluated and compared. Results: The study encompassed 240 patients, of whom 88 had lymph node metastases. A leave-one-out cross-validation (LOOCV) method was used to split the entire dataset into training and testing subsets. The random forest ML model outperformed the other algorithms, with an area under the curve (AUC) of 0.92. Prediction models based on clinical, ultrasonic, URF parameters, clinical + ultrasonic, clinical + URF, and ultrasonic + URF parameters had AUCs of 0.56, 0.79, 0.78, 0.90, 0.80, and 0.84, respectively, in the testing set. The comprehensive diagnostic model (clinical + ultrasonic + URF parameters) demonstrated strong diagnostic capability, with an AUC of 0.94 in the testing set, exceeding any single prediction model. Conclusion: The combined model (clinical + ultrasonic + URF parameters) could be used preoperatively to predict lymph node status, offering valuable input for the design of individualized surgical approaches. [ABSTRACT FROM AUTHOR]

Introduction: Cancer‐related stigma is a key driver of advanced breast cancer stage in Sub‐Saharan Africa (SSA). We developed and tested the impact of a breast cancer survivor‐led Stigma reduction intervention (SRI) on stigma and treatment adherence of newly diagnosed patients with breast cancer in Tanzania. Methods: Breast cancer survivors were trained on breast cancer knowledge and motivational interviewing. A total of 4 trained survivors delivered a SRI (standardized flipchart breast education talk, personal testimony, and motivational interviewing) to 30 newly diagnosed patients with breast cancer before treatment. Pre‐ and post‐intervention knowledge surveys and stigma scale surveys were analyzed via Fisher's exact test and Wilcoxon rank‐sum tests. A discussion was held with a group of survivors after the intervention period to elicit feedback on their intervention experience. Results: Among the 30 patients, breast cancer knowledge (median overall percent correct) increased from 28% (IQR: 18%–45%) to 85% (IQR: 79%–88%) (p < 0.001) and stigma (median score) decreased from 75 (IQR: 57–81) to 53 (IQR: 44–66) (p < 0.01) following the intervention. All participants were willing to pursue hospital‐based treatment after undergoing the intervention. Eighty‐seven percent (n = 26) initiated treatment at 8‐week follow‐up after the intervention. All survivors endorsed feeling empowered and valued in their role in this intervention. Conclusions: Breast cancer survivors are a powerful group to combat the lack of knowledge and stigma in community and healthcare settings. Expanding the scope and scale of this intervention holds promise for improving treatment‐seeking behavior and ultimately breast cancer outcomes in SSA. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women with multiple risk factors including smoking, genetics, environmental factors, and obesity. Smoking and obesity are the top two risk factors for the development of breast cancer. The effect of obesity on adipose tissue mediates the pathogenesis of breast cancer in the context of obesity. Triple-negative breast cancer (TNBC) is a breast cancer subtype within which the cells lack estrogen, progesterone, and HER2 receptors. TNBC is the deadliest breast cancer subtype. The 5-year survival rates for patients with TNBC are 8–16% lower than the 5-year survival rates for patients with estrogen-receptor-positive breast tumors. In addition, TNBC patients have early relapse rates (3–5 years after diagnosis). Obesity is associated with an increased risk for TNBC, larger TNBC tumors, and increased breast cancer metastasis compared with lean women. Thus, novel therapeutic approaches are warranted to treat TNBC in the context of obesity. In this paper, we show that peritumor breast adipose-derived secretome (ADS) from patients with a high (>30) BMI is a stronger inducer of TNBC cell invasiveness and JAG1 expression than peritumor breast ADS from patients with low (<30) BMI. These findings indicate that patient BMI-associated changes in peritumor AT induce changes in peritumor ADS, which in turn acts on TNBC cells to stimulate JAG1 expression and cancer cell invasiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer who have PIK3CA mutations and have progressed on first-line therapies are considered for treatment with alpelisib alongside endocrine therapy (ET). Combination therapeutic strategies may extend the clinical benefit of alpelisib. This study investigated the potential of onvansertib, a highly specific inhibitor of polo-like kinase 1 (PLK1), to enhance the efficacy of alpelisib in preclinical models of HR+ breast cancer. Our findings demonstrated that onvansertib synergizes with alpelisib in PIK3CA-mutant HR+ breast cancer cell lines and patient-derived xenografts that are resistant to ET and cyclin-dependent kinase 4/6 inhibitors. The combination inhibited PLK1 and PI3K signaling, induced cell cycle arrest, and triggered apoptotic death in both cell lines and xenograft tumors. Overall, our preclinical data encourage the clinical exploration of this combination for PIK3CA-mutant HR+ metastatic breast cancer patients progressing on standard-of-care therapies. Background: Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is the preferred first-line treatment for hormone receptor-positive (HR+)/HER2- metastatic breast cancer. Although this is beneficial, acquired resistance leads to disease progression, and patients harboring PIK3CA mutations are treated with targeted therapies such as the PI3Kα inhibitor, alpelisib, alongside ET. Drug-associated resistance mechanisms limit the efficacy of alpelisib, highlighting the need for better combination therapies. This study aimed to evaluate the efficacy of combining alpelisib with a highly specific PLK1 inhibitor, onvansertib, in PIK3CA-mutant HR+ breast cancer preclinical models. Methods: We assessed the effect of the alpelisib and onvansertib combination on cell viability, PI3K signaling pathway, cell cycle phase distribution and apoptosis in PI3K-activated HR+ breast cancer cell lines. The antitumor activity of the combination was evaluated in three PIK3CA-mutant HR+ breast cancer patient-derived xenograft (PDX) models, resistant to ET and CDK4/6 inhibitor palbociclib. Pharmacodynamics studies were performed using immunohistochemistry and Simple Western analyses in tumor tissues. Results: The combination synergistically inhibited cell viability, suppressed PI3K signaling, induced G2/M arrest and apoptosis in PI3K-activated cell lines. In the three PDX models, the combination demonstrated superior anti-tumor activity compared to the single agents. Pharmacodynamic studies confirmed the inhibition of both PLK1 and PI3K activity and pronounced apoptosis in the combination-treated tumors. Conclusions: Our findings support that targeting PLK1 and PI3Kα with onvansertib and alpelisib, respectively, may be a promising strategy for patients with PIK3CA-mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation. [ABSTRACT FROM AUTHOR]

Purpose: Bromodomain-containing protein 7 (BRD7) is downregulated and functions as a tumor suppressor in many types of cancers including breast cancer, and the dysregulation of BRD7 expression is closely related to the development and progression of breast cancer. Whereas little attention has been focused on the regulation of BRD7 protein levels in breast cancer, which needs to be further elucidated. Methods: The protein stability of BRD7 in breast cancer cells and BRD7 protein level in breast cancer tissues was examined by Western Blotting. The potential E3 ubiquitin ligase proteins that interact with the BRD7 was screened by coimmunoprecipitation combined with mass spectrometry analysis in MDA-MB-231 cells. We proved the interaction between BRD7 and tripartite motif containing 28 (TRIM28) through Co-Immunoprecipitation (Co-IP) and immunofluorescence assays. Co-IP and ubiquitination assay were used to explore the specific binding domain between BRD7 and TRIM28 and the ubiquitination site of BRD7. The effects of TRIM28 on the BRD7 protein stability and ubiquitination level was investigated by qPCR, Western Blot and Co-IP assay. CCK-8 and clone formation assays were carried out to assess the effect of TRIM28 on proliferation ability of breast cancer ells. Transwell assay and wound healing assay were used to investigate the effect of TRIM28 on breast cancer cell invasion and migration. Flow cytometry was used to detect the effect of TRIM28 on cell cycle and apoptosis of breast cancer cells. In addition, we confirmed effect of TRIM28 on tumor growth and metastasis by xenograft and metastatic mouse models. We designed some recovery assays to explore the role of recovery BRD7 in TRIM28-mediated promotion of malignant progression of breast cancer in vivo and in vitro. Finally, the clinical significance of TRIM28 and BRD7 was proved by immunohistochemistry. Results: In this study, we demonstrated that BRD7 was an unstable protein and might be regulated by ubiquitination in breast cancer; furthermore, we found that the Coiled-Coil region of TRIM28 could directly bind to N-terminal of BRD7, and TRIM28 mediates BRD7 ubiquitination and degradation dependent on K21 by acting as a potential E3 ubiquitin ligase. Moreover, TRIM28 promoted cell proliferation, migration, invasion, xenograft tumor growth and metastasis, thus playing an oncogenic role in breast cancer. Furthermore, the restoration of BRD7 expression in breast cancer significantly reversed the promotional effects of TRIM28 on malignant progression both in vitro and in vivo. In addition, TRIM28 was highly expressed in the biopsy tissues of breast cancer, and its expression was negatively correlated with BRD7 expression and positively correlated with TNM stage and poor prognosis of BC patients. Conclusions: Our findings provide a novel mechanism by which TRIM28 significantly facilitates BRD7 ubiquitination and degradation, thus promoting breast cancer malignant progression. Targeting the TRIM28/BRD7 axis might be a novel potential strategy for the clinical diagnosis and treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) have been implicated in the pathology of various inflammatory conditions. In cancer, NETs have been demonstrated to induce systemic inflammation, impair peripheral vessel and organ function and promote metastasis. Here we show that the plasma level of NETs is significantly higher in patients with metastatic breast cancer compared to those with local disease, or those that were considered cured at a 5‐year follow‐up, confirming NETs as interesting therapeutic targets in metastatic breast cancer. Administration of DNase I is one strategy to eliminate NETs but long‐term treatment requires repeated injections and species‐specific versions of the enzyme. To enhance administration and therapeutic efficacy, we have developed an adeno‐associated virus (AAV) vector system for delivery of murine DNase I and addressed its potential to counteract cancer‐associated pathology in the murine MMTV‐PyMT model for metastatic mammary carcinoma. The AAV vector is comprised of capsid KP1 and an expression cassette encoding hyperactive murine DNase I (AAV‐mDNase I) under the control of a liver‐specific promotor. This AAV‐mDNase I vector could support elevated expression and serum activity of murine DNase I over at least 8 months. Neutrophil Gelatinase‐Associated Lipocalin (NGAL), a biomarker for kidney hypoperfusion that is upregulated in urine from MMTV‐PyMT mice, was suppressed in mice receiving AAV‐mDNase I compared to an AAV‐null control group. Furthermore, the proportion of mice that developed lung metastasis was reduced in the AAV‐mDNase I group. Altogether, our data indicate that AAV‐mDNase I has the potential to reduce cancer‐associated impairment of renal function and development of metastasis. We conclude that AAV‐mDNase I could represent a promising therapeutic strategy in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Objective: In highly aggressive malignant cancers including breast cancer, vasculogenic mimicry (VM) is the potential of tumor cells to generate a vascular channel network for delivering blood to tumor cells. Detection of genes involved in this process is critical to designing targeted therapy against breast cancer metastasis. In this study, we evaluated the roles of FAK and ILK in the progression of VM in metastatic breast tumor cells. Results: Primary (4T1T), and highly metastatic (4T1B and 4T1L) breast tumor cells were isolated from cancerous mice. The potential of cancer cells to organize themselves into vascular-like structures (VM) has been evaluated with in vitro assessment. The expression of ILK and FAK were examined using real-time polymerase chain reaction. We confirmed the high ability of metastatic tumor cells in vascular-like structure formation. In molecular analysis, our data showed that ILK and FAK expression was significantly elevated in metastatic breast tumor cells. These results indicated that the higher potential of metastatic tumor cells in vascular-like structure formation may be related to higher expression of ILK and FAK. Analysis of molecular features of metastatic tumor cells could be utilized to create a targeted therapeutic strategy against metastasis in breast cancer. [ABSTRACT FROM AUTHOR]

Public health measures necessitated by the COVID-19 pandemic have affected cancer pathways by halting screening, delaying diagnostic tests and reducing the numbers starting treatment. Specifically, this moves individuals from observed and treated pathways to unobserved and untreated pathways. We introduce a semi-Markov model that includes both, extending an industry-based multiple state model used for life and critical illness insurance. Our model includes events related to cancer diagnosis and progression based on publicly available population data for women aged 65–89 in England and on relevant medical literature. We quantify age-specific excess deaths, for a period up to 5 years, along with years of life expectancy lost and changes in cancer mortality by cancer stage. Our analysis suggests a 3–6% increase in breast cancer deaths, and a 4–6% increase in registrations of advanced breast cancer, robust under sensitivity analysis. This should be applicable to actuarial work in areas where longevity and advanced age morbidity affect healthcare, retirement and insurance. [ABSTRACT FROM AUTHOR]

This article presents a study on the development and validation of an ultrasound-based radiomics nomogram for predicting HER2-low expression breast cancer. The study included 222 patients with breast cancer, and machine learning methods were used to extract radiomics features from ultrasound images. The features were then used to construct a prediction model, which was validated using a training cohort and a test cohort. The nomogram, incorporating radiomics features and clinical risk factors, showed high prediction value for HER2-low expression breast cancer. This non-invasive approach could be useful for early detection and clinical therapy planning. [Extracted from the article]

Recurrent and metastatic breast cancer is frequently treatment resistant. A wealth of evidence suggests that reprogrammed lipid metabolism supports cancer recurrence. Overexpression of the RON and DEK oncoproteins in breast cancer is associated with poor outcome. Both proteins promote cancer metastasis in laboratory models, but their influence on lipid metabolite levels remain unknown. To measure RON- and DEK-dependent steady-state lipid metabolite levels, a nuclear magnetic resonance (NMR)-based approach was utilized. The observed differences identified a lipid metabolism-related gene expression signature that is prognostic of overall survival (OS), distant metastasis-free survival (DMFS), post-progression survival (PPS), and recurrence-free survival (RFS) in patients with breast cancer. RON loss led to decreased cholesterol and sphingomyelin levels, whereas DEK loss increased total fatty acid levels and decreased free glycerol levels. Lipid-related genes were then queried to define a signature that predicts poor outcomes for patients with breast cancer patients. Taken together, RON and DEK differentially regulate lipid metabolism in a manner that predicts and may promote breast cancer metastasis and recurrence. [ABSTRACT FROM AUTHOR]

Introduction: Initial treatment for hormone-receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) typically involves endocrine therapy (ET) combined with different targeted agents. When hormonal therapies fail, until recently, the only option available was chemotherapy (ChT), presenting a significant therapeutic challenge. However, the recent introduction of antibody–drug conjugates (ADCs) has provided new treatment alternatives in this context. Sacituzumab govitecan (SG), a novel trophoblast cell-surface antigen 2 (Trop-2)-targeting ADC, has been evaluated following disease progression to ET and ChT in HR+/HER2- ABC. Areas covered: This review examines the latest clinical trials, including phase I/II and III studies and evaluates the impact of SG on HR+/HER2- ABC. The literature search focused on clinical outcomes, particularly regarding efficacy and safety, comparing them with traditional ChT. Expert opinion: SG has demonstrated to be an effective treatment for patients with HR+/HER2- ABC after progression to ET and cyclin-dependent kinase 4/6 inhibitors (CDKi) in any setting, and at least two ChT-containing regimens in the advanced setting. With a manageable toxicity profile, SG represents a significant advancement in the treatment landscape for this patient population. However, further research is essential to optimize its application and establish long-term benefits. [ABSTRACT FROM AUTHOR]

Breast cancer is a leading cause of female mortality and despite advancements in personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. The estrogen receptor (ER, ESR1) is expressed in two-thirds of all breast cancer, and under endocrine stress, somatic ESR1 mutations arise in approximately 30% of cases that result in endocrine resistance. We and others reported ESR1 fusions as a mechanism of ER-mediated endocrine resistance. ER fusions, which retain the activation function 1- and DNA-binding domains, harbor ESR1 exons 1 to 6 fused to an in-frame gene partner resulting in loss of the ER ligand-binding domain (LBD). We demonstrate that in a no-special type (invasive ductal carcinoma [IDC]-NST) and an invasive lobular carcinoma (ILC) cell line, ER fusions exhibit robust hyperactivation of canonical ER signaling pathways independent of estradiol or antiendocrine therapies. We employ cell line models stably overexpressing ER fusions with concurrent endogenous ER knockdown to minimize endogenous ER influence. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably MYC signaling. Cells expressing the 3′ fusion partners SOX9 and YAP1 consistently demonstrated enhanced growth and cell survival. ILC cells expressing the DAB2 fusion led to enhanced growth, survival, and migration, phenotypes not appreciated in the IDC-NST DAB2 model. Herein, we report that cell line activity is subtype-, fusion-, and assay-specific, suggesting that LBD loss, the fusion partner, and the cellular landscape all influence fusion activities. Therefore, it will be critical to assess fusion frequency in the context of the clinicopathology. [ABSTRACT FROM AUTHOR]