Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway.

BACKGROUND: Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. Non-coding RNAs (ncRNAs) are enriched in exosomes, which participated in generation, progression, and resistance of BC. However, the mechanism underlying the chemoresistance and metastasis in BC cells mediated by the BC-derived exosomal ncRNAs remained to be elucidated. METHODS: The effects of PTX-induced exosomal circBACH1 on BC cell function were assessed using RNA Binding Protein Immunoprecipitation (RIP), dual luciferase reporter gene, tube formation, CCK-8, and Western Blot assays. The circBACH1 and miR-217 expression levels were detected using quantitative real-time PCR (RT-qPCR) and Immunohistochemistry (IHC) assays in BC tissues and precancerous tissues of BC patients. RESULTS: CircBACH1 expression was increased in paclitaxel-treated BC-derived exosomes (PTX-EXO) and BC tissue. PTX-EXO was shown to promote PTX-resistance and angiogenesis through upregulation circBACH1. Downregulation of circBACH1 improved PTX-sensitiveness by suppressing the cell viability, stemness, migration, and angiogenesis of BC cells. Moreover, we found that miR-217 interacted with circBACH1 and targeted GTPase-activating SH3 domain-binding protein 2 (G3BP2) in BC cells. CircBACH1 combined miR-217 cotransfection suppressed the expression of G3BP2 proteins compared with circBACH1 treatment in MCF-7 cells. In addition, downregulation of G3BP2 suppressed BC cell migration. CONCLUSIONS: These results demonstrated that PTX-induced exosomal circBACH1 promoted stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.

γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.

Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate γδT (γδT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and γδT17 polarization in human tumors. Activated inf-DCs induced γδT17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, γδT17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC-γδT17-PMN-MDSC regulatory axis in human CRC that correlates MDSC-meditated immunosuppression with tumor-elicited inflammation. These findings suggest that γδT17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction.

Systemic Analysis of the Prognosis-Related RNA Alternative Splicing Signals in Melanoma.

BACKGROUND Alternative splicing (AS), the mechanism underlying the occurrence of protein diversity, may result in cancer genesis and development when it becomes out of control, as suggested by a growing number of studies. However, systemically analyze of AS events at the genome-wide level for skin cutaneous melanoma (SKCM) is still in a preliminary phase. This study aimed to systemically analyze the bioinformatics of the AS events at a genome-wide level using The Cancer Genome Atlas (TCGA) SKCM data. MATERIAL AND METHODS The SpliceSeq tool was used to analyze the AS profiles for SKCM clinical specimens from the TCGA database. The association between AS events and overall survival was analyzed by Cox regression analysis. AS event intersections and a gene interaction network were established by UpSet plot. A multivariate survival model was used to establish a feature genes prognosis model. RESULTS A total of 103 SKCM patients with full clinical parameters available were included in this study. We established an AS network that investigated the relationship between AS events and clinical prognosis information. Furthermore, 4 underlying feature genes of SKCM (MCF2L, HARS, TFR2, and RALGPS1) were found in the AS network. We performed function analysis as well as correlation analysis of AS events with gene expression. Using the multivariate survival model, we further confirmed the 4 genes that impacted the classifying SKCM prognosis at the level of AS events as well as gene expression, especially in wild-type SKCM. CONCLUSIONS AS events could be ideal indicators for SKCM prognosis. The key feature gene MCF2L played an important role in wild-type SKCM.

Prognostic Value and Clinicopathologic Features of Platelet Distribution Width in Cancer: A Meta-Analysis.

BACKGROUND The association between platelet distribution width (PDW) and cancer has been evaluated by a few studies, but the influence of PDW on cancer prognosis is unclear. Therefore, we conducted the present meta-analysis. MATERIAL AND METHODS We identified relevant research using identical search strategies. The influence of PDW level on cancer prognosis, as well as clinical characteristics, was analyzed. RESULTS A total of 11 studies comprising 2625 cancer patients were included in our meta-analysis. The results suggested that high PDW level was obviously related to poor OS (HR=1.54, 95%CI 1.18-2.00), especially for breast cancer (HR=1.21, 95%CI 1.07-1.36) and pharyngolaryngeal cancer (HR=3.06, 95%CI 1.68-5.57). Furthermore, high PDW was obviously related to poor OS both in older and younger subgroups, with combined HR estimates of 1.58 (95%CI 1.15-2.16) and 1.64 (95%CI 1.19-2.26), respectively. High PDW level was notably related to poor OS in the cut-off value ³16% subgroup (HR=1.84, 95%CI 1.01-3.40). Moreover, high PDW level was obviously associated with lymph node metastasis (OR=1.43, 95%CI 1.04-1.99). CONCLUSIONS The findings of this study suggest that PDW is an effective and convenient indicator of cancer prognosis. Furthermore, high PDW level is obviously associated with lymph node metastasis.

Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-κB-dependent activation of snail and epithelial mesenchymal transition.

BACKGROUND: Lipocalin2 (LCN2) is a secretory protein that is aberrantly expressed in several types of cancer and has been involved in metastatic progression. However, neither mechanisms nor the role that LCN2 plays in the metastasis of colorectal cancer are clear. METHODS: LCN2 expression in colorectal cancer was detected by immunohistochemistry in 400 tissue specimens and Kaplan-Meier survival analysis was performed. In vitro, real-time PCR, western blot, colony formation assay, immunofluorescence assay, wound healing assay, migration and invasion experiment were performed to investigate the effects of LCN2 in epithelial mesenchymal transition (EMT), migration and invasion, respectively. In vivo mouse xenograft and metastasis models were utilized to determine tumorigenicity and metastasis ability, and immunohistochemistry, real-time PCR, western blot were used to evaluate the related protein expression. Luciferase reporter assay was used to explore the role of LCN2 on NF-ĸB promoter. RESULTS: LCN2 was highly expressed in 66.5% of the specimens, and significantly correlated with positive E-cadherin in the membrane and negative nuclear ß-catenin. Higher expression of LCN2 together with negative NF-κB expression was negatively related to nuclear accumulation of snail and predicted favorable prognosis. LCN2 blocked cell proliferation, migration and invasion in vitro and in vivo, and inhibited translocation of NF-κB into nucleus. NF-κB could reverse the effect of LCN2 on EMT and promote snail expression. Rescued snail expression had similar effect without influencing NF-κB activity. CONCLUSION: LCN2 may be an important negative regulator in EMT, invasion and metastasis of CRC via acting as upstream of NF-κB/snail signaling pathway. Thereby combinative manipulation of LCN2 and NF-κB/snail pathway may represent a novel and promising therapeutic approach for the patients with CRC.

Expression of CXCR4 and breast cancer prognosis: a systematic review and meta-analysis.

BACKGROUND: The chemokine receptor CXCR4 plays a significant role in biological processes, as well as in tumorigenesis and the progression of cancer, especially breast cancer. However, the clinical application of CXCR4 for breast cancer prognosis is still very limited. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the relationship between CXCR4 expression and the prognosis of breast cancer. METHODS: A comprehensive search strategy was used to search relevant literature in PubMed, MEDLINE and the ISI Web of Science. The correlation between CXCR4 expression and clinicopathological features and breast cancer prognosis was analyzed. This meta-analysis was carried out using Review Manager 4.2. RESULT: Thirteen eligible studies consisting of 3865 participants were included. We found that breast cancers with CXCR4 expression were associated with lymph node status (pooled RR =1.20, 95% CI: 1.01-1.43, P<0.001) and distant metastasis (pooled RR =1.52, 95% CI: 1.17-1.98, P = 0.125). CXCR4 overexpression was significantly associated with disease free survival (DFS) (RR = 0.77, 95% CI = 0.70-0.86, P = 0.554) and overall survival (OS) (RR = 0.70, 95% CI = 0.59-0.83, P = 0.329). However, there was no significant association between CXCR4 expression and some clinical parameters of breast cancer, such as tumor category, ER status, PR status, or c-erbB-2 status. CONCLUSION: Our meta-analysis showed that CXCR4 is an efficient prognostic factor for breast cancer. Overexpression of CXCR4 was significantly associated with lymph node status and distant metastasis and indicated poor overall and disease free survival.

A real-world clinicopathological model for predicting pathological complete response to neoadjuvant chemotherapy in breast cancer.

Purpose: This study aimed to develop and validate a clinicopathological model to predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients and identify key prognostic factors. Methods: This retrospective study analyzed data from 279 breast cancer patients who received NAC at Zhejiang Provincial People's Hospital from 2011 to 2021. Additionally, an external validation dataset, comprising 50 patients from Lanxi People's Hospital and Second Affiliated Hospital, Zhejiang University School of Medicine from 2022 to 2023 was utilized for model verification. A multivariate logistic regression model was established incorporating clinical, ultrasound features, circulating tumor cells (CTCs), and pathology variables at baseline and post-NAC. Model performance for predicting pCR was evaluated. Prognostic factors were identified using survival analysis. Results: In the 279 patients enrolled, a pathologic complete response (pCR) rate of 27.96% (78 out of 279) was achieved. The predictive model incorporated independent predictors such as stromal tumor-infiltrating lymphocyte (sTIL) levels, Ki-67 expression, molecular subtype, and ultrasound echo features. The model demonstrated strong predictive accuracy for pCR (C-statistics/AUC 0.874), especially in human epidermal growth factor receptor 2 (HER2)-enriched (C-statistics/AUC 0.878) and triple-negative (C-statistics/AUC 0.870) subtypes, and the model performed well in external validation data set (C-statistics/AUC 0.836). Incorporating circulating tumor cell (CTC) changes post-NAC and tumor size changes further improved predictive performance (C-statistics/AUC 0.945) in the CTC detection subgroup. Key prognostic factors included tumor size >5cm, lymph node metastasis, sTIL levels, estrogen receptor (ER) status and pCR. Despite varied pCR rates, overall prognosis after standard systemic therapy was consistent across molecular subtypes. Conclusion: The developed predictive model showcases robust performance in forecasting pCR in NAC-treated breast cancer patients, marking a step toward more personalized therapeutic strategies in breast cancer.

Neoadjuvant chemotherapy-induced remodeling of human hormonal receptor-positive breast cancer revealed by single-cell RNA sequencing.

Hormone receptor-positive breast cancer (HR+ BC) is known to be relatively insensitive to chemotherapy, and since chemotherapy has remained the major neoadjuvant therapy for HR+ BC, the undetermined mechanism of chemoresistance and how chemotherapy reshapes the immune microenvironment need to be explored by high-throughput technology. By using single-cell RNA sequencing and multiplexed immunofluorescence staining analysis of HR+ BC samples (paired pre- and post-neoadjuvant chemotherapy (NAC)), the levels of previously unrecognized immune cell subsets, including CD8+ T cells with pronounced expression of T-cell development (LMNA) and cytotoxicity (FGFBP2) markers, CD4+ T cells characterized by proliferation marker (ATP1B3) expression and macrophages characterized by CD52 expression, were found to be increased post-NAC, which were predictive of chemosensitivity and their antitumor function was also validated with in vitro experiments. In terms of immune checkpoint expression of CD8+ T cells, we found their changes were inconsistent post-NAC, that LAG3, VSIR were decreased, and PDCD1, HAVCR2, CTLA4, KLRC1 and BTLA were increased. In addition, we have identified novel genomic and transcriptional patterns of chemoresistant cancer cells, both innate and acquired, and have confirmed their prognostic value with TCGA cohorts. By shedding light on the ecosystem of HR+ BC reshaped by chemotherapy, our results uncover valuable candidates for predicting chemosensitivity and overcoming chemoresistance in HR+ BC.

Exploration of prognosis and immunometabolism landscapes in ER+ breast cancer based on a novel lipid metabolism-related signature.

Introduction: Lipid metabolic reprogramming is gaining attention as a hallmark of cancers. Recent mounting evidence indicates that the malignant behavior of breast cancer (BC) is closely related to lipid metabolism. Here, we focus on the estrogen receptor-positive (ER+) subtype, the most common subgroup of BC, to explore immunometabolism landscapes and prognostic significance according to lipid metabolism-related genes (LMRGs). Methods: Samples from The Cancer Genome Atlas (TCGA) database were used as training cohort, and samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), Gene Expression Omnibus (GEO) datasets and our cohort were applied for external validation. The survival-related LMRG molecular pattern and signature were constructed by unsupervised consensus clustering and least absolute shrinkage and selection operator (LASSO) analysis. A lipid metabolism-related clinicopathologic nomogram was established. Gene enrichment and pathway analysis were performed to explore the underlying mechanism. Immune landscapes, immunotherapy and chemotherapy response were further explored. Moreover, the relationship between gene expression and clinicopathological features was assessed by immunohistochemistry. Results: Two LMRG molecular patterns were identified and associated with distinct prognoses and immune cell infiltration. Next, a prognostic signature based on nine survival-related LMRGs was established and validated. The signature was confirmed to be an independent prognostic factor and an optimal nomogram incorporating age and T stage (AUC of 5-year overall survival: 0.778). Pathway enrichment analysis revealed differences in immune activities, lipid biosynthesis and drug metabolism by comparing groups with low- and high-risk scores. Further exploration verified different immune microenvironment profiles, immune checkpoint expression, and sensitivity to immunotherapy and chemotherapy between the two groups. Finally, arachidonate 15-lipoxygenase (ALOX15) was selected as the most prominent differentially expressed gene between the two groups. Its expression was positively related to larger tumor size, more advanced tumor stage and vascular invasion in our cohort (n = 149). Discussion: This is the first lipid metabolism-based signature with value for prognosis prediction and immunotherapy or chemotherapy guidance for ER+ BC.

Integrated transcriptomics, proteomics, and functional analysis to characterize the tissue-specific small extracellular vesicle network of breast cancer.

Small extracellular vesicles (sEVs) are essential mediators of intercellular communication within the tumor microenvironment (TME). Although the biological features of sEVs have been characterized based on in vitro culture models, recent evidence indicates significant differences between sEVs derived from tissue and those derived from in vitro models in terms of both content and biological function. However, comprehensive comparisons and functional analyses are still limited. Here, we collected sEVs from breast cancer tissues (T-sEVs), paired normal tissues (N-sEVs), corresponding plasma (B-sEVs), and tumor organoids (O-sEVs) to characterize their transcriptomic and proteomic profiles. We identified the actual cancer-specific sEV signatures characterized by enriched cell adhesion and immunomodulatory molecules. Furthermore, we revealed the significant contribution of cancer-associated fibroblasts in the sEV network within the TME. In vitro model-derived sEVs did not entirely inherit the extracellular matrix- and immunity regulation-related features of T-sEVs. Also, we demonstrated the greater immunostimulatory ability of T-sEVs on macrophages and CD8+ T cells compared to O-sEVs. Moreover, certain sEV biomarkers derived from noncancer cells in the circulation exhibited promising diagnostic potential. This study provides valuable insights into the functional characteristics of tumor tissue-derived sEVs, highlighting their potential as diagnostic markers and therapeutic agents for breast cancer.

CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer.

PURPOSE: Axillary lymph nodes (LN) are the primary and dominant metastatic sites in breast cancer. However, the interaction between tumor cells and immune cells within metastatic LNs (mLN) remains poorly understood. In our study, we explored the effect of CD24hiCD27+ regulatory B cells (Breg) within mLNs on orchestrating drug resistance of breast cancer cells. EXPERIMENTAL DESIGN: We collected mLN samples from patients with breast cancer who had received standard neoadjuvant therapy (NAT) and analyzed the spatial features of CD24hiCD27+ Bregs through multicolor immunofluorescence staining. The effect of CD24hiCD27+ Bregs on drug resistance of breast cancer cells was evaluated via in vitro experiments. A mouse model with mLNs was used to evaluate the strategies with blocking the interactions between Bregs and breast cancer for improving tumor regression within mLNs. RESULTS: In patients with breast cancer who had received NAT, there is a close spatial correlation between activated CD24hiCD27+ Bregs and residual tumor cells within mLNs. Mechanistically, CD24hiCD27+ Bregs greatly enhance the acquisition of multidrug resistance and stem-like features of breast cancer cells by secreting IL6 and TNFα. More importantly, breast cancer cells further promote the activation of CD24hiCD27+ Bregs via CD40L-dependent and PD-L1-dependent proximal signals, forming a positive feedback pattern. PD-L1 blockade significantly attenuates the drug resistance of breast cancer cells induced by CD24hiCD27+ Bregs, and addition of anti-PD-L1 antibody to chemotherapy improves tumor cell remission in mLNs. CONCLUSIONS: Our study reveals the pivotal role of CD24hiCD27+ Bregs in promoting drug resistance by interacting with breast cancer cells in mLNs, providing novel evidence for an improved strategy of chemoimmunotherapy combination for patients with breast cancer with mLNs.

Crosstalk between the peripheral nervous system and breast cancer influences tumor progression.

Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve growth and branching by secreting neuroactive molecules, including neurotrophins and axon guidance molecules (AGMs). Sympathetic nerves promote breast cancer progression, while parasympathetic and sensory nerves mainly have anti-tumor effects in the progression of breast cancer. Specifically, peripheral nerves can influence the progression of breast cancer by secreting neurotransmitters not only directly binding to the corresponding receptors of BCCs, but also indirectly acting on immune cells to modulate anti-tumor immunity. In this review, we summarize the crosstalk between breast cancer and peripheral nerves and the roles of important neuroactive molecules in the progression of breast cancer. In addition, we summarize indicators, including nerve fiber density and perineural invasion (PNI), that may help determine the prognosis of breast cancer based on current research results, as well as potential therapeutic approaches, such as ß-blockers and retroviral-mediated genetic neuroengineering techniques, that may enhance the prognosis of breast cancer. In addition, we propose suggestions for future research priorities based on a current lack of knowledge in this area.

High PANX1 Expression Leads to Neutrophil Recruitment and the Formation of a High Adenosine Immunosuppressive Tumor Microenvironment in Basal-like Breast Cancer.

Background: A high adenosine level is an important characteristic of the tumor microenvironment (TME) in breast cancer. Pannexin 1 (PANX1) can release intracellular ATP to the extracellular space and elevate extracellular ATP (exATP) levels under physiological conditions. Methods: We performed public database bioinformatics analysis, surgical specimen histological validation, RNA sequencing, and exATP/extracellular adenosine (exADO) assays to reveal the role of PANX1 in regulating the immune microenvironment of basal-like breast cancer. Results: Our results revealed that PANX1 acted as a poor prognostic factor for breast cancer and had high expression in basal-like breast cancer. PANX1 expression was positively correlated with exATP and exADO levels in basal-like breast cancer TME. PANX1 expression was also positively correlated with tumor-associated neutrophil (TAN) infiltration in breast cancer TME and TANs highly expressed ENTPD1 (CD39)/NT5E (CD73). Conclusions: This study suggests that high PANX1 expression is associated with high TAN infiltration and adenosine production to induce local immunosuppression in basal-like breast cancer TME.

Case report: Individualized treatment of advanced breast cancer with the use of the patient-derived tumor-like cell cluster model.

Breast cancer is one of the most common tumors in women. Despite various treatments, the survival of patients with advanced breast cancer is still disappointing. Furthermore, finding an effective individualized treatment for different kinds of patients is a thorny problem. Patient-derived tumor-like cell clusters were reported to be used for personalized drug testing in cancer therapy and had a prediction accuracy of 93%. However, there is still a lack of case reports about its application in the individualized treatment of breast cancer patients. Here, we described four cases of individualized treatment for advanced breast cancer using the patient-derived tumor-like cell cluster model (PTC model). In these four cases, the PTC model showed a good predictive effect. The tumor size was reduced significantly or even disappeared completely through clinical, radiological, or pathological evaluation with the help of the PTC model for selecting an individualized therapy regimen. Furthermore, the drug sensitivity test results of the PTC model were consistent with pathological molecular typing and the actual clinical drug resistance of the patients. In summary, our case report first evaluated the application value of the PTC model in advanced breast cancer, and the PTC model might be used as an efficient tool for drug resistance screening and for selecting a better personalized treatment, although further study is needed to prove the validity and stability of the PTC model in drug screening.

A comprehensive comparison of circulating tumor cells and breast imaging modalities as screening tools for breast cancer in Chinese women.

Background: Circulating tumor cells (CTCs) have been recognized as a sensitive biomarker for breast cancer (BC). This study aimed to comprehensively compare CTC with imaging modalities, including ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging (MRI) in screening for BC in Chinese women. Methods: Three hundred forty-three participants were enrolled in this study, including 102 treatment-naive BC patients, 177 with breast benign diseases (BBD) and 64 healthy female patients. All participants underwent CTC testing and at least one of the following examinations, ultrasonography, mammography, and MRI at the Second Affiliated Hospital of Zhejiang University between December 2017 and November 2020. CTCs were quantitatively assessed using cell counting (CTC detection rate/counts) and categorically examined using a cutoff value (CTC classification). The diagnostic power of CTC tests and imaging modalities, including accuracy and capability to predict clinicopathological characteristics of BC, were evaluated and compared. Results: CTC classification with a cutoff value of 2 showed a "good" diagnostic accuracy of 0.889 for early- to mid-stage BC comparable to breast imaging modalities using Breast Imaging-Reporting and Data System (BI-RADS). MRI demonstrated the highest sensitivity of 0.872 for BC, and CTC classification had the highest specificity of 0.938. A relatively low sensitivity was found for mammography in this cohort of patients. Successful detection of BC by CTC detection rate/counts, but not CTC classification, correlated with two important clinicopathological features, American Joint Committee on Cancer (AJCC) stage and tumor-node-metastasis (TNM) stage. The detection power of certain imaging modalities was also associated with AJCC stage (ultrasonography, p = 0.0438 and MRI, p = 0.0422) and lymph node metastasis (ultrasonography, 0.0157). There were clear correlations between CTC tests (counts or classification) and imaging BI-RADS scoring system in detecting positive BC cases (p < 0.05). Further correlation analysis suggested that CTC quantity, but not CTC classification, had the capability to predict clinicopathological traits of BC that were identified by ultrasonography. Conclusions: CTC tests have a diagnostic potency comparable to breast imaging modalities, and may be used as an alternative screening tool for BC.

Treatment patterns, effectiveness, and patient-reported outcomes of palbociclib therapy in Chinese patients with advanced breast cancer: A multicenter ambispective real-world study.

BACKGROUND: Palbociclib was the only available cyclin-dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient-reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real-world China. METHODS: An ambispective cohort study was conducted on patients with advanced HR+HER2- breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items [EORTC QLQ-C30] and EuroQoL 5 dimensions [EQ-5D]) were analyzed. The Kaplan-Meier method was used to visualize and estimate the median progression-free survival (mPFS). Log-rank tests, Cox regressions, t tests, and chi-square tests were performed for comparison. RESULTS: A total of 190 patients (median follow-up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first- (n = 83), second- (n = 41) and subsequent-line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p < 0.01). The outcome was worse for patients who failed to meet the inclusion criteria of PALOMA-3 than for those who met the criteria (later-line: 6.0 months vs. 9.0 months). The most common adverse events (AEs) were neutropenia (74.2%; grade 3/4: 30.0%), fatigue (48.4%), anemia (32.6%), and thrombocytopenia (22.1%). PRO data suggested that palbociclib plus ET significantly improved cognitive and emotional function, pain symptoms, and overall quality of life. CONCLUSIONS: Palbociclib is effective for front-line use and for treating endocrine-sensitive patients in real-world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA-2/3 trials.

Adjuvant ovarian suppression for premenopausal hormone receptor-positive breast cancer: A network meta-analysis.

BACKGROUND: Ovarian function suppressor (OFS) plus either tamoxifen (TAM) or aromatase inhibitor (AI) could improve the survival outcome for premenopausal hormone receptor-positive (HR+) breast cancer. However, the optimal OFS-based regimen and medication duration remain uncertain. This article aims to systematically evaluate the OFS-based adjuvant endocrine therapy for premenopausal breast cancer. METHODS: We searched several public databases from January 1980 to November 2020. A random model was adopted in this meta-analysis. We used the hazard ratio (HR) with a 95% confidence interval (CI) for the statistical analysis of efficacy. The primary outcome measures included overall survival and disease-free survival. RESULTS: A total of 32 articles with 37,224 cases were included in this network meta-analysis. OFS+TAM improved 5-year disease-free survival (HR -0.09, 95% CI -0.16 to -0.01) and 5-year overall survival (HR -0.18, 95% CI -0.33 to -0.03) compared with TAM monotherapy. For OFS+AI, although the 5-year disease-free survival was improved (HR -0.18, 95% CI -0.29 to -0.08), the 5-year overall survival was not improved (HR -0.13, 95% CI -0.43 to 0.18). In subgroup analysis, both OFS+AI and OFS+TAM showed a protective effect in stage I-III patients compared with stage I-II patients. For the course of therapy, OFS+TAM for 2-years could achieve clinical benefit and the best course of therapy of OFS+AI still waits for further study. CONCLUSIONS: OFS+TAM might be a better option than OFS+AI for premenopausal intensive adjuvant endocrine therapy. Stage III patients are more suitable for the OFS-based therapy. For the medication duration, the 2-years course of OFS+TAM could be effective. This analysis provides helpful information for selecting therapeutic regimen in intensive adjuvant endocrine therapy and identifying the target population.

Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy.

Accumulating evidence showed that cancer stem cells (CSCs) play significant roles in cancer initiation, resistance to therapy, recurrence and metastasis. Cancer stem cells possess the ability of self-renewal and can initiate tumor growth and avoid lethal factors through flexible metabolic reprogramming. Abnormal lipid metabolism has been reported to be involved in the cancer stemness and promote the development of cancer. Lipid metabolism includes lipid uptake, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism leads to ferroptosis of CSCs. In this review, we comprehensively summarized the role of intra- and extracellular lipid signals in cancer stemness, and explored the feasibility of using lipid metabolism-related treatment strategies for future cancer.

Antiangiogenic therapy reverses the immunosuppressive breast cancer microenvironment.

Tumor angiogenesis induces local hypoxia and recruits immunosuppressive cells, whereas hypoxia subsequently promotes tumor angiogenesis. Immunotherapy efficacy depends on the accumulation and activity of tumor-infiltrating immune cells (TIICs). Antangiogenic therapy could improve local perfusion, relieve tumor microenvironment (TME) hypoxia, and reverse the immunosuppressive state. Combining antiangiogenic therapy with immunotherapy might represent a promising option for the treatment of breast cancer. This article discusses the immunosuppressive characteristics of the breast cancer TME and outlines the interaction between the tumor vasculature and the immune system. Combining antiangiogenic therapy with immunotherapy could interrupt abnormal tumor vasculature-immunosuppression crosstalk, increase effector immune cell infiltration, improve immunotherapy effectiveness, and reduce the risk of immune-related adverse events. In addition, we summarize the preclinical research and ongoing clinical research related to the combination of antiangiogenic therapy with immunotherapy, discuss the underlying mechanisms, and provide a view for future developments. The combination of antiangiogenic therapy and immunotherapy could be a potential therapeutic strategy for treatment of breast cancer to promote tumor vasculature normalization and increase the efficiency of immunotherapy.

Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment.

Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron-dependent regulated cell death (ferroptosis) may be a focus of future research.