The Role of Breast Cancer Cells in Bone Metastasis: Suitable Seeds for Nourishing Soil.

PURPOSE OF REVIEW: The purpose of this review was to describe the characteristics of breast cancer cells prone to developing bone metastasis and determine how they are regulated by the bone microenvironment. RECENT FINDINGS: The bone is a site of frequent breast cancer metastasis. Bone metastasis accounts for 70% of advanced breast cancer cases and remains incurable. It can lead to skeletal-related events, such as bone fracture and pain, and seriously affect the quality of life of patients. Breast cancer cells escape from the primary lesion and spread to the bone marrow in the early stages. They can then enter the dormant state and restore tumourigenicity after several years to develop overt metastasis. In the last few years, an increasing number of studies have reported on the factors promoting bone metastasis of breast cancer cells, both at the primary and metastatic sites. Identifying factors associated with bone metastasis aids in the early recognition of bone metastasis tendency. How to target these factors and minimize the side effects on the bone remains to be further explored.

ARHGAP39 is a prognostic biomarker involved in immune infiltration in breast cancer.

BACKGROUND: Current studies on the role of ARHGAP39 mainly focused on its effect on neurodevelopment. However, there are few studies on the comprehensive analysis of ARHGAP39 in breast cancer. METHODS: ARHGAP39 expression level was analyzed based on the Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database and validated by qPCR in various cell lines and tumor tissues. The prognostic value was analyzed using Kaplan-Meier curve analysis. CCK-8 and transwell assays were conducted to identify the biological function of ARHGAP39 in tumorigenesis. Signaling pathways related to ARHGAP39 expression were identified by the GO and KEGG enrichment analysis and gene set enrichment analysis (GSEA). The correlations between ARHGAP39 and cancer immune infiltrates were investigated via TIMER, CIBERSORT, ESTIMATE and tumor-immune system interactions database (TISIDB). RESULTS: ARHGAP39 was overexpressed in breast cancer and associated with poor survival outcomes. In vitro experiments revealed that ARHGAP39 could facilitate the proliferation, migration, and invasion capability of breast cancer cells. GSEA analysis showed that the main enrichment pathways of ARHGAP39 was immunity-related pathways. Considering the immune infiltration level, ARHGAP39 was negatively associated with infiltrating levels of CD8 + T cell and macrophage, and positively associated with CD4 + T cell. Furthermore, ARHGAP39 was significantly negatively correlated with immune score, stromal score, and ESTIMATE score. CONCLUSIONS: Our findings suggested that ARHGAP39 can be used as a potential therapeutic target and prognostic biomarker in breast cancer. ARHGAP39 was indeed a determinant factor of immune infiltration.

Long non-coding RNA-CTD-2108O9.1 represses breast cancer metastasis by influencing leukemia inhibitory factor receptor.

Breast cancer (BC) is an aggressive malignant disease in women worldwide with a high tendency to metastasize. However, important biomarkers for BC metastasis remain largely undefined. In the present study, we identified that long non-coding RNA-CTD-2108O9.1 is downregulated in BC tissues and cells and acts as a metastatic inhibitor of BC. Mechanistic investigation determined that lncRNA-CTD-2108O9.1 represses metastasis by targeting leukemia inhibitory factor receptor (LIFR), which is designated as a metastasis suppressor in BC. Our study characterizes a significant tumor suppressor active in BC metastasis repression through the known metastasis inhibitor LIFR.

ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis.

OBJECTIVE: Mitochondrial fatty acid oxidation is a metabolic pathway whose dysregulation is recognized as a critical factor in various cancers, because it sustains cancer cell survival, proliferation, and metastasis. The acyl-CoA synthetase long-chain (ACSL) family is known to activate long-chain fatty acids, yet the specific role of ACSL3 in breast cancer has not been determined. METHODS: We assessed the prognostic value of ACSL3 in breast cancer by using data from tumor samples. Gain-of-function and loss-of-function assays were also conducted to determine the roles and downstream regulatory mechanisms of ACSL3 in vitro and in vivo. RESULTS: ACSL3 expression was notably downregulated in breast cancer tissues compared with normal tissues, and this phenotype correlated with improved survival outcomes. Functional experiments revealed that ACSL3 knockdown in breast cancer cells promoted cell proliferation, migration, and epithelial-mesenchymal transition. Mechanistically, ACSL3 was found to inhibit ß-oxidation and the formation of associated byproducts, thereby suppressing malignant behavior in breast cancer. Importantly, ACSL3 was found to interact with YES proto-oncogene 1, a member of the Src family of tyrosine kinases, and to suppress its activation through phosphorylation at Tyr419. The decrease in activated YES1 consequently inhibited YAP1 nuclear colocalization and transcriptional complex formation, and the expression of its downstream genes in breast cancer cell nuclei. CONCLUSIONS: ACSL3 suppresses breast cancer progression by impeding lipid metabolism reprogramming, and inhibiting malignant behaviors through phospho-YES1 mediated inhibition of YAP1 and its downstream pathways. These findings suggest that ACSL3 may serve as a potential biomarker and target for comprehensive therapeutic strategies for breast cancer.

Development of an obesity-related multi-gene prognostic model incorporating clinical characteristics in luminal breast cancer.

Despite adjuvant chemotherapy and endocrine therapy in luminal breast cancer (LBC), relapses are common. Addressing this, we aim to develop a prognostic model to refine adjuvant therapy strategies, particularly for patients at high recurrence risk. Notably, obesity profoundly affects the tumor microenvironment (TME) of LBC. However, it is unclear whether obesity-related biological features can effectively screen high-risk patients. Utilizing weighted gene coexpression network analysis (WGCNA) on RNA sequencing (RNAseq) data, we identified seven obese LBC genes (OLGs) closely associated with patient prognosis. Subsequently, we developed a luminal obesity-gene clinical prognostic index (LOG-CPI), combining a 7-gene signature, TNM staging, and age. Its predictive efficacy was confirmed across validation datasets and a clinical cohort (5-year accuracy = 0.828, 0.760, 0.751, and 0.792, respectively). LOG-CPI emerges as a promising predictor for clinical prognosis and treatment response, helping distinguish molecular and immunological features in LBC patients and guiding clinical practice by identifying varying prognoses.

Understanding the mechanisms underlying obesity in remodeling the breast tumor immune microenvironment: from the perspective of inflammation.

Obesity is a well-known modifiable risk factor for breast cancer and is considered a poor prognostic factor in pre- and post-menopausal women. While the systemic effects of obesity have been extensively studied, less is known about the mechanisms underlying obesity-associated cancer risk and the local consequences of obesity. Thus, obesity-induced inflammation has become the focus of research interest. Biologically, the development of cancer involves a complex interaction with numerous components. As the tumor immune microenvironment changes due to obesity-triggered inflammation, an increase in infiltration occurs for proinflammatory cytokines and adipokines, as well as adipocytes, immune cells, and tumor cells in the expanded adipose tissue. Complicated cellular-molecular crosstalk networks change critical pathways, mediate metabolic and immune function reprogramming, and have a significant role in tumor metastasis, proliferation, resistance, angiogenesis, and tumorigenesis. This review summarizes recent research findings on how inflammatory mediators in the in situ tumor microenvironment regulate the occurrence and development of breast cancer in the context of obesity. We analyzed the heterogeneity and potential mechanisms of the breast cancer immune microenvironment from the perspective of inflammation to provide a reference for the clinical transformation of precision targeted cancer therapy.

A generalized non-linear model predicting efficacy of neoadjuvant therapy in HER2+ breast cancer.

Neoadjuvant therapy (NAT) is currently recommended to patients with human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) that typically exhibit a poor prognosis. The tumor immune microenvironment profoundly affects the efficacy of NAT. However, the correlation between tumor-infiltrating lymphocytes or their specific subpopulations and the response to NAT in HER2+ BC remains largely unknown. In our study, the immune infiltration status of 295 patients was classified as "immune-rich" or "immune-poor" phenotypes. The "immune-rich" phenotype was significantly positively related to pathological complete response (pCR). Ten genes were correlated with both pCR and the immune phenotype based on the results of spline and logistic regression. We constructed a generalized non-linear model combining linear and non-linear gene effects and successfully validated its predictive power using an internal and external validation set (AUC = 0.819, 0.797; respectively) and a clinical set (accuracy = 0.75).

Chronic stress-induced immune dysregulation in breast cancer: Implications of psychosocial factors.

Chronic stress refers to continuous emotional changes and psychological pressure that individuals experience when they are unable to adjust and stabilize the internal environment over an extended period. It can increase the pressure on endocrine mediators and cytokines in the circulation, as well as tissues throughout the hypothalamic-pituitary-adrenaline (HPA) axis and sympathetic nervous system (SNS); thus, evolving the internal environment of the tumor. This review assesses several key issues, involving psychosocial factors, and integrates clinical, cellular, and molecular studies-as well as the latest research progress-to provide a mechanistic understanding regarding breast oncopsychology. We propose that chronic stress contributes to large individual diferences in the prognosis of breast cancer survivors because they change the basic physiological processes of the endocrine and immune systems, which in turn regulate tumor growth. The study of psychological and physiological reactions of breast cancer patients suggests a new idea for psychological intervention and clinical treatment for breast cancer patients.

Predicting Pathological Complete Response in Breast Cancer After Two Cycles of Neoadjuvant Chemotherapy by Tumor Reduction Rate: A Retrospective Case-Control Study.

PURPOSE: We aimed to identify effectiveness-associated indicators and evaluate the optimal tumor reduction rate (TRR) after two cycles of neoadjuvant chemotherapy (NAC) in patients with invasive breast cancer. METHODS: This retrospective case-control study included patients who underwent at least four cycles of NAC at the Department of Breast Surgery between February 2013 and February 2020. A regression nomogram model for predicting pathological responses was constructed based on potential indicators. RESULTS: A total of 784 patients were included, of whom 170 (21.68%) reported pathological complete response (pCR) after NAC and 614 (78.32%) had residual invasive tumors. The clinical T stage, clinical N stage, molecular subtype, and TRR were identified as independent predictors of pCR. Patients with a TRR > 35% were more likely to achieve pCR (odds ratio, 5.396; 95% confidence interval [CI], 3.299-8.825). The receiver operating characteristic (ROC) curve was plotted using the probability value, and the area under the ROC curve was 0.892 (95% CI, 0.863-0.922). CONCLUSION: TRR > 35% is predictive of pCR after two cycles of NAC, and an early evaluation model using a nomogram based on five indicators, age, clinical T stage, clinical N stage, molecular subtype, and TRR, is applicable in patients with invasive breast cancer.

A machine learning model to predict efficacy of neoadjuvant therapy in breast cancer based on dynamic changes in systemic immunity.

OBJECTIVE: Neoadjuvant therapy (NAT) has been widely implemented as an essential treatment to improve therapeutic efficacy in patients with locally-advanced cancer to reduce tumor burden and prolong survival, particularly for human epidermal growth receptor 2-positive and triple-negative breast cancer. The role of peripheral immune components in predicting therapeutic responses has received limited attention. Herein we determined the relationship between dynamic changes in peripheral immune indices and therapeutic responses during NAT administration. METHODS: Peripheral immune index data were collected from 134 patients before and after NAT. Logistic regression and machine learning algorithms were applied to the feature selection and model construction processes, respectively. RESULTS: Peripheral immune status with a greater number of CD3+ T cells before and after NAT, and a greater number of CD8+ T cells, fewer CD4+ T cells, and fewer NK cells after NAT was significantly related to a pathological complete response (P < 0.05). The post-NAT NK cell-to-pre-NAT NK cell ratio was negatively correlated with the response to NAT (HR = 0.13, P = 0.008). Based on the results of logistic regression, 14 reliable features (P < 0.05) were selected to construct the machine learning model. The random forest model exhibited the best power to predict efficacy of NAT among 10 machine learning model approaches (AUC = 0.733). CONCLUSIONS: Statistically significant relationships between several specific immune indices and the efficacy of NAT were revealed. A random forest model based on dynamic changes in peripheral immune indices showed robust performance in predicting NAT efficacy.

PROS1, a clinical prognostic biomarker and tumor suppressor, is associated with immune cell infiltration in breast cancer: A bioinformatics analysis combined with experimental verification.

BACKGROUND: PROS1 is an encoding gene that can generate protein S. This protein is a glycoprotein found in plasma that conducts physiological functions with vitamin K. However, the impact of its expression remains absent in the progression and prognosis of breast cancer (BC). METHODS: In this study, we comprehensively explored the expression of PROS1 in BC and its relationship with BC patient survival, prognosis, and other clinicopathological features. We investigated how PROS1 influenced the malignant biological behavior of BC cells. A series of enrichment analyses were conducted, and the immune landscape was explored in BC affected by PROS1. We also determined correlations between PROS1 and common drug sensitivities used for BC treatments. RESULTS: PROS1 had low expression in BC, which tended to result in poor survival of BC patients. Overexpressed PROS1 inhibited the migration and invasion of BC cells as well as the epithelial-mesenchymal transition process by downregulating SNAIL. Functional enrichment analyses revealed that PROS1 was more active in extracellular matrix (ECM) organization and structural constituent, ECM-receptor interaction, and other pathways with its related genes. PROS1 was also found to affect immune activity, including various immune cells infiltrating BC. BC patients with high PROS1 expression tended to have lower IC50 values of three common medications and obtained better efficacy. CONCLUSIONS: PROS1 can become a promising prognostic factor and a possible therapeutic target in BC patients and suppress BC cell metastatic potential. In addition, PROS1 is a crucial factor in immune infiltration in BC.

KLHL29-mediated DDX3X degradation promotes chemosensitivity by abrogating cell cycle checkpoint in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype and accounts for approximately 15-20% of breast cancer cases. In this study, we identified KLHL29, which is an understudied member of the Kelch-like gene family, as a crucial tumor suppressor that regulates chemosensitivity in TNBC. KLHL29 expression was significantly downregulated in breast cancer tissues compared with adjacent normal tissues, and low levels of KLHL29 were associated with unfavorable prognoses. Ectopic KLHL29 suppressed, while depleting KLHL29 promoted, the growth, proliferation, migration, and invasion of TNBC. Mechanistically, KLHL29 recruited the CUL3 E3-ligase to the RNA-binding protein DDX3X, leading to the proteasomal degradation of the latter. This downregulation of DDX3X resulted in the destabilization of CCND1 mRNA and the consequent cell cycle arrest at G0/G1 phase. Remarkably, the DDX3X inhibitor RK33 combined with platinum-based chemotherapy can synergistically suppress TNBC that usually expresses low levels of KLHL29 and high levels of DDX3X using cancer cell-derived xenograft and patient-derived organoids models. Altogether, we uncovered the potential role for the KLHL29-DDX3X signaling cascade in the regulation of TNBC progression, thus providing a promising combination strategy for overcoming TNBC chemoresistance.

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.

Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O2 environment. Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.

The choice of a neoadjuvant chemotherapy cycle for breast cancer has significance in clinical practice: results from a population-based, real world study.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is currently used in both early stage and locally advanced breast cancers. The survival benefits of standard vs. non-standard NAC cycles are still unclear. This study aimed to investigate the relationship between NAC cycles and survival based on real world data. METHODS: We identified patients diagnosed with invasive primary breast cancers who underwent NAC followed by surgery. Patients who received at least 4 NAC cycles were defined as having received standard cycles, while patients who received less than 4 NAC cycles were defined as having received non-standard cycles. Kaplan-Meier curves and Cox proportional hazard models were used to estimate the disease-free survival (DFS) and overall survival (OS). RESULTS: Of the 1,024 included patients, 700 patients received standard NAC cycles and 324 patients received non-standard NAC cycles. The DFS estimates were 87.1% and 81.0% (P = 0.007) and the OS estimates were 90.0% and 82.6% (P = 0.001) in the standard and non-standard groups, respectively. Using multivariate analyses, patients treated with standard NAC cycles showed significant survival benefits in both DFS [hazard ratio (HR): 0.62, 95% confidence interval (CI): 0.44-0.88] and OS (HR: 0.54, 95% CI: 0.37-0.79). Using stratified analyses, standard NAC cycles were associated with improved DFS (HR: 0.59, 95% CI: 0.36-0.96) and OS (HR: 0.49, 95% CI: 0.28-0.86) in the HER2 positive group. Similar DFS (HR: 0.50, 95% CI: 0.25-0.98) and OS (HR: 0.45, 95% CI: 0.22-0.91) benefits were shown for the triple negative group. CONCLUSIONS: Standard NAC cycles were associated with a significant survival benefit, especially in patients with HER2 positive or triple negative breast cancer.

Comparison of three lymph node staging methods for predicting outcome in breast cancer patients with mastectomy.

BACKGROUND: Axillary lymph node (ALN) staging is essential in predicting the clinical outcome of breast cancer (BC) patients. Traditionally, it follows the tumor-node-metastasis (TNM) staging, but its accuracy needs further improvement. METHODS: A total of 9,616 BC patients from the Surveillance, Epidemiology, and End Results (SEER) database and 675 patients from the First Affiliated Hospital of China Medical University underwent mastectomy together with ALN dissection were reviewed. Univariate and multivariate logistic analyses were conducted to find the most meaningful factors relevant to prognosis. RESULTS: After univariate and multivariate analyses, age, race, primary site, radiation, chemotherapy, grade, T-stage, estrogen receptor (ER), progesterone receptor (PR), total number of positive lymph nodes (pN), positive lymph node ratio (LNR) and log odds of positive LNs (LODDS) were found to be significantly associated with overall survival (OS). Using these non-LN risk factors, we further compared the efficacy of three different ALN staging methods in prognosis via nomograms. Harrell's concordance index (C-index) and Akaike Information Criterion (AIC) were used to measure nomogram performance of the ALN staging methods: pN: C-index=0.687 (95% CI: 0.678-0.696), AIC =61,398.24; LNR: C-index =0.691 (95% CI: 0.683-0.701), AIC =61,313.56; and LODDS: C-index =0.691 (95% CI: 0.682-0.700), AIC =61,315.60. We found that the nomogram incorporating LODDS had better predictive ability compared with other two methods. Furthermore, an external validation revealed a C-index of 0.753 (95% CI: 0.690-0.816) for the Asian population, which indicates the nomogram based on LODDS may have universality for both Western and Asian populations. CONCLUSIONS: Compared with pN and LNR, LODDS showed higher homeostasis in LN evaluation, and showed marked efficacy in evaluating survival differences among patients with negative LN staging. We constructed a BC prognosis model by incorporating highly relevant clinical pathological factors and a new method of LN staging, which may greatly aid in guiding postoperative treatment.

An Immune Model to Predict Prognosis of Breast Cancer Patients Receiving Neoadjuvant Chemotherapy Based on Support Vector Machine.

Tumor microenvironment has been increasingly proved to be crucial during the development of breast cancer. The theory about the conversion of cold and hot tumor attracted the attention to the influences of traditional therapeutic strategies on immune system. Various genetic models have been constructed, although the relation between immune system and local microenvironment still remains unclear. In this study, we tested and collected the immune index of 262 breast cancer patients before and after neoadjuvant chemotherapy. Five indexes were selected and analyzed to form the prediction model, including the ratio values between after and before neoadjuvant chemotherapy of CD4+/CD8+ T cell ratio; lymphosum of T, B, and natural killer (NK) cells; CD3+CD8+ cytotoxic T cell percent; CD16+CD56+ NK cell absolute value; and CD3+CD4+ helper T cell percent. Interestingly, these characters are both the ratio value of immune status after neoadjuvant chemotherapy to the baseline. Then the prediction model was constructed by support vector machine (accuracy rate = 75.71%, area under curve = 0.793). Beyond the prognostic effect and prediction significance, the study instead emphasized the importance of immune status in traditional systemic therapies. The result provided new evidence that the dynamic change of immune status during neoadjuvant chemotherapy should be paid more attention.

Can ACEI/ARB prevent the cardiotoxicity caused by chemotherapy in early-stage breast cancer?-a meta-analysis of randomized controlled trials.

BACKGROUND: Administration of anthracycline-based chemotherapy with or without trastuzumab is recognized as standard care for breast cancer, but it is associated with a decline in left ventricular ejection fraction (LVEF). Angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB) might decrease this cardiac dysfunction caused by the anti-cancer therapy. We sought to evaluate the prophylactic effects of the cardioprotective agents ACEI/ARB for early-stage breast cancer. METHODS: We systematically searched the electronic databases Cochrane, PubMed, and Embase for randomized controlled trials (RCTs) evaluating the effect of ACEI/ARB. This meta-analysis calculated weighted mean differences with 95% CI, for ejection fraction and pooled odds ratios (OR) with 95% CI, for cardiac events. Pooled analyses were used in a random-effect model. The primary endpoint was the change of LVEF in the ACEI/ARB group versus the control group from baseline through completion of the studies. RESULTS: our meta-analysis includes 5 studies encompassing 702 early-stage breast cancer patients. There was statistically significant diversity in the magnitude of the change of mean LVEF in patients receiving ACEI/ARB compared with control groups, with a mean difference of 4.08% (95% CI: 0.8% to 7.35%, P=0.01). However, regarding patient outcomes, ACEI/ARB did not significantly reduce the risk of cardiac events (OR 0.91, 95% CI: 0.62 to 1.34, P=0.64) or increase the incidence of hypotension events as compared with controls (OR 2.72, 95% CI: 0.69 to 10.73, P=0.15). CONCLUSIONS: Our study suggests that ACEI/ARB significantly attenuate the cardiac dysfunction caused by anthracycline-based chemotherapy and/or trastuzumab. Further studies are required to confirm the effectiveness of this cardioprotective agent.

Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer.

PURPOSE: Combining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy. METHODS: RCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes. RESULTS: We demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS. CONCLUSION: We conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.

Exploring the Metabolic Vulnerabilities of Epithelial-Mesenchymal Transition in Breast Cancer.

Metastasis and drug resistance are the leading causes of death for breast cancer patients. Epithelial-mesenchymal transition (EMT), a transition from polarized epithelial cells to motile mesenchymal cells mediated by a series of activation signals, confers breast tumor cells with enhanced stem cell, invasive, and metastatic properties. Metabolic reprogramming is an emerging hallmark of cancer cells, which have a complex mutual effect with EMT process. Under hypoxic and nutrient-deprived conditions, metabolic rewiring can rapidly provide ATP and sufficient metabolic intermediates for fueling breast cancer metastasis and progression. In this review, we primarily focus on how these altered metabolic phenotypes of breast tumor cells activate the EMT transcription factors and induce the EMT process to further promote metastasis and resistance to therapy. This review is divided to glucose, lipid, and amino acid metabolism to explore for potential metabolic vulnerabilities, which may provide new insights for blocking the EMT process in breast cancer.

Metabolic Reprogramming in Triple-Negative Breast Cancer.

Metabolic reprogramming is an emerging hallmark of cancer cells, in which cancer cells exhibit distinct metabolic phenotypes to fuel their proliferation and progression. The significant advancements made in the area of metabolic reprogramming make possible new strategies for overcoming malignant cancer, including triple-negative breast cancer. Triple-negative breast cancer (TNBC) is associated with high histologic grade, aggressive phenotype, and poor prognosis. Even though triple-negative breast cancer patients benefit from standard chemotherapy, they still face high recurrence rates and are more likely to develop resistance to chemotherapeutic drugs. Therefore, there is an urgent need to explore vulnerabilities of triple-negative breast cancer and develop novel therapeutic drugs to improve clinical outcomes for triple-negative breast cancer patients. Metabolic reprogramming may provide promising therapeutic targets for the treatment of triple-negative breast cancer. In this paper, we primarily discuss how triple-negative breast cancer cells reprogram their metabolic phenotype and that of stromal cells in the microenvironment to survive under nutrient-poor conditions. Considering that metastasis and chemoresistance are the main contributors to mortality in triple-negative breast cancer patients, we also focus on the role of metabolic adaption in mediating metastasis and chemoresistance of triple-negative breast cancer tumors.