Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase Ⅱ single-arm study

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Clinicopathological features,psychological status,and prognosis of 33 patients with occult breast cancer

BACKGROUND Occult breast cancer(OBC)has traditionally been considered to be a carcinoma of unknown primary origin with a favorable prognosis and can be treated as stage II-III breast cancer.Due to the small number of cases and limited clinical experience,treatments vary greatly around the world and no standardized treatment has yet been established.AIM To investigate the clinicopathological features,psychological status and prognostic features of patients with OBC.METHODS The clinicopathological data of 33 OBC patients diagnosed and treated in the Affiliated Hospital of Xuzhou Medical University and Xuzhou Central Hospital from November 2015 to November 2022 were retrospectively analyzed.The psychological status of OBC patients was evaluated by the Self-rating Anxiety Scale and Self-rating Depression Scale.Patients’emotions,stress perception and psychological resilience were evaluated by the Positive and Negative Affect Schedule,the Chinese Perceived Stress Scale,and the Connor-Davidson Resilience Scale(CD-RISC),respectively.Patient survival was calculated using the Kaplan-Meier method,and survival curves were plotted for analysis with the log-rank test.Univariate and multivariate survival analyses were performed using the Cox regression model.RESULTS The 33 OBC patients included 32 females and 1 male.Of the 33 patients,30(91%)had axillary tumors,3(9%)had a neck mass as the primary symptom;18(54.5%)had estrogen receptor-positive tumors,17(51.5%)had progesterone receptor-positive tumors,and 18(54.5%)had Her-2-positive tumors;24(72.7%)received surgical treatment,including 18 patients who underwent modified radical mastectomy,1 patient who underwent breast-conserving surgery plus axillary lymph node dissection(ALND),and 5 patients who underwent ALND alone;12 patients received preoperative neoadjuvant therapy.All 30 patients developed anxiety and depression,with low positive affect scores and high negative affect scores,accompanied by a high stress level and poor psychological resilience.There were no differences in the psychological status of patients according to age,body mass index,or menopausal status.The overall survival and disease-free survival(DFS)of all the patients were 83.3%and 55.7%,respectively.Univariate analysis demonstrated that the initial tumor site(P=0.021)and node stage(P=0.020)were factors that may affect patient prognosis.The 5-year DFS rate of OBC patients who received radiotherapy was greater(P<0.001),while the use of different surgical methods(P=0.687)had no statistically significant effect on patient outcomes.Multivariate analysis revealed that radiotherapy(P=0.031)was an independent prognostic factor.Receiving radiotherapy had a significant effect on the CD-RISC score(P=0.02).CONCLUSION OBC is a rare breast disease whose diagnosis and treatment are currently controversial.There was no significant difference in the efficacy of other less invasive surgical procedures compared to those of modified radical mastectomy.In addition,radiotherapy can significantly improve patient outcomes.We should pay attention to the psychological state of patients while they receive antitumor therapy.

Navigating breast cancer brain metastasis:Risk factors,prognostic indicators,and treatment perspectives

In this editorial,we comment on the article by Chen et al.We specifically focus on the risk factors,prognostic factors,and management of brain metastasis(BM)in breast cancer(BC).BC is the second most common cancer to have BM after lung cancer.Independent risk factors for BM in BC are:HER-2 positive BC,triplenegative BC,and germline BRCA mutation.Other factors associated with BM are lung metastasis,age less than 40 years,and African and American ancestry.Even though risk factors associated with BM in BC are elucidated,there is a lack of data on predictive models for BM in BC.Few studies have been made to formulate predictive models or nomograms to address this issue,where age,grade of tumor,HER-2 receptor status,and number of metastatic sites(1 vs>1)were predictive of BM in metastatic BC.However,none have been used in clinical practice.National Comprehensive Cancer Network recommends screening of BM in advanced BC only when the patient is symptomatic or suspicious of central nervous system symptoms;routine screening for BM in BC is not recommended in the guidelines.BM decreases the quality of life and will have a significant psychological impact.Further studies are required for designing validated nomograms or predictive models for BM in BC;these models can be used in the future to develop treatment approaches to prevent BM,which improves the quality of life and overall survival.

Eribulin in breast cancer:Current insights and therapeutic perspectives

Eribulin is a non-taxane synthetic analogue approved in many countries as thirdline treatment for the treatment of patients with metastatic breast cancer.In addition to its mitotic property,eribulin has non-mitotic properties including but not limited to,its ability to induce phenotypic reversal of epithelial to mesenchymal transition,vascular remodelling,reduction in immunosuppressive tumour microenvironment.Since approval,there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types,including hormone receptor positive,HER2 positive and triple negative breast cancer,many demonstrating promising activity.This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent,its toxicity profile,and potential future directions.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Methanolic extract of Ephedra alata inhibits breast cancer cells in vitro and in vivo

Objective:To determine the anticancer potential of the methanolic extract from Ephedra alata against breast cancer both in vitro and in vivo.Methods:The effects of the methanolic extract of Ephedra alata on the viability,migration as well as apoptosis of breast cancer 4T1 cells were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,Transwell assay,and annexin V-FITC staining assay,respectively.Histological examination was also carried out.Moreover,a murine breast cancer model was established to evaluate the inhibitory effect of the extract.Biochemical parameters including hepatic and non-hepatic enzymes,malondialdehyde,and glutathione were investigated.Results:The methanolic extract of Ephedra alata showed a strong anti-proliferative and anti-migratory activity against 4T1 cells in a dose-dependent manner.It also induced apoptosis in 4T1 cells.In an in vivo mouse model,the extract markedly inhibited tumor growth,reduced malondialdehyde,and hepatic and non-hepatic enzymes as well as increased glutathione level.Conclusions:The methanolic extract of Ephedra alata inhibits breast cancer in vitro and in vivo,which may be a promising anticancer agent.

Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer

Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive.It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.Methods:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators.Then,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.Results:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific functions.We discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and CBX3.Moreover,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation.Notably,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.Conclusions:Our work deciphered the extensive regulation among hundreds of epigenetic regulators.The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

Circular RNAs in breast cancer diagnosis,treatment and prognosis

Breast cancer has surpassed lung cancer to become the most common malignancy worldwide.The incidence rate and mortality rate of breast cancer continue to rise,which leads to a great burden on public health.Circular RNAs(circRNAs),a new class of noncoding RNAs(ncRNAs),have been recognized as important oncogenes or suppressors in regulating cancer initiation and progression.In breast cancer,circRNAs have significant roles in tumorigenesis,recurrence and multidrug resistance that are mediated by various mechanisms.Therefore,circRNAs may serve as promising targets of therapeutic strategies for breast cancer management.This study reviews the most recent studies about the biosynthesis and characteristics of circRNAs in diagnosis,treatment and prognosis evaluation,as well as the value of circRNAs in clinical applications as biomarkers or therapeutic targets in breast cancer.Understanding the mechanisms by which circRNAs function could help transform basic research into clinical applications and facilitate the development of novel circRNA-based therapeutic strategies for breast cancer treatment.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Anti-PD1 antibody and not anti-LAG-3 antibody improves the antitumor effect of photodynamic therapy for treating metastatic breast cancer

Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

Advances in regional nodal management of early-stage breast cancer

With the continuous improvement of systemic treatment, reasonable local regional control of early-stage breast cancer can be translated into survival benefits. The optimization of regional nodal management in patients with limited sentinel lymph node(SLN) metastasis needs to be weighed by surgical complications, regional recurrence risk, and lymph node status, as well as other escalating treatment(systemic/radiotherapy) that may result from deescalating surgery. With the effective support and supplementation of systemic therapy and radiotherapy, the management of axillary surgery is developing in a de-escalating trend. The widespread application of neoadjuvant therapy has contributed to optimizing the management of patients with clinically node-negative/imaging nodepositive disease. In clinical practice, it is necessary to consider the residual tumor burden of regional lymph nodes when formulating the optimal irradiation fields in patients with limited positive SLN without axillary lymph node dissection. The combined application of genomic tests and American College of Surgeons Oncology Group Z0011/AMAROS criteria could provide patients with a better strategy of dual de-escalation treatment, which includes the de-escalation of both axillary surgery and systemic treatment. In the era of sentinel lymph node biopsy(SLNB), the regional nodal management of breast cancer should adhere to the concept of “updating ideas, making bold assumptions, and carefully seeking proof”, make full use of the benefits of systemic therapy and radiotherapy to reduce the scope of surgery and complications, and expand the “net benefit” of efficacy and quality of life. This review discusses the optimization of regional nodal management in the era of SLNB, in order to provide reference information for clinicians.

Apigenin is an anoikis sensitizer with strong anti-metastatic properties in experimental breast cancer

Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods.Among 19 tested dietary phytochemicals,the best results were obtained with apigenin,a natural component of celery.Phenotypically,apigenin sensitized breast cancer cells to anoikis,lowered the number of circulating tumor cells,and protected against breast cancer metastasis to lung in mice.Mechanistically,we demonstrated that the thromboxane A_(2)(TXA_(2))-TXA_(2)receptor(TP)axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway.Blockage of TXA_(2)signaling up-regulated p53 as well as its target gene p21,caused a G1 phase arrest,and finally led to apoptosis in breast cancer cells.TXA_(2)level was positively correlated with breast cancer cell anoikis rate,and apigenin significantly inhibited TXA_(2)biosynthesis in vitro and in vivo.Collectively,we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer,and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.

Vaccinia-related kinase 2 variants differentially affect breast cancer growth by regulating kinase activity

Genetic information is transcribed from genomic DNA to mRNA,which is then translated into threedimensional proteins.mRNAs can undergo various post-transcriptional modifications,including RNA editing that alters mRNA sequences,ultimately affecting protein function.In this study,RNA editing was identified at the 499th base(c.499)of human vaccinia-related kinase 2(VRK2).This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine(with adenine base)to valine(with guanine base).Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2,which leads to an increase in tumor cell proliferation.Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein(dysbindin)and results in reducing its stability.Herein,we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valinecontaining VRK2.Dysbindin interacts with cyclin D and thereby regulates its expression and function.The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression,resulting in increased tumor growth and reduction in survival rates.It has also been observed that in patient samples,VRK2 level was elevated in breast cancer tissue compared to normal breast tissue.Additionally,the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue.Therefore,it is concluded that VRK2,especially dependent on the 167th variant amino acid,can be one of the indexes of tumor progression and proliferation.

Machine Learning Techniques Using Deep Instinctive Encoder-Based Feature Extraction for Optimized Breast Cancer Detection

Breast cancer(BC)is one of the leading causes of death among women worldwide,as it has emerged as the most commonly diagnosed malignancy in women.Early detection and effective treatment of BC can help save women’s lives.Developing an efficient technology-based detection system can lead to non-destructive and preliminary cancer detection techniques.This paper proposes a comprehensive framework that can effectively diagnose cancerous cells from benign cells using the Curated Breast Imaging Subset of the Digital Database for Screening Mammography(CBIS-DDSM)data set.The novelty of the proposed framework lies in the integration of various techniques,where the fusion of deep learning(DL),traditional machine learning(ML)techniques,and enhanced classification models have been deployed using the curated dataset.The analysis outcome proves that the proposed enhanced RF(ERF),enhanced DT(EDT)and enhanced LR(ELR)models for BC detection outperformed most of the existing models with impressive results.

A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

Local dose-dense chemotherapy for triple-negative breast cancer via minimally invasive implantation of 3D printed devices

Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals,allowing for promising clinical outcomes with intensive treatment.However,the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance,limiting therapeutic efficacy and clinical benefit.Here,we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with timeprogrammed pulsatile release profiles.The implantable device can control the time between drug releases based on its internal microstructure design,which can be used to control dose density.The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar.Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo.Under the same dose density conditions,device-based chemotherapy shows a higher anticancer effect and less toxic response than intratumoral injection.We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose,number of releases,and treatment duration of the dose-dense AC(doxorubicin and cyclophosphamide)regimen preferred for TNBC treatment.Dose density modulation inhibits tumor growth,metastasis,and the expression of drug resistance-related proteins,including p-glycoprotein and breast cancer resistance protein.To the best of our knowledge,local dose-dense chemotherapy has not been reported,and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men,respectively,worldwide.Although the antitumor activity of chalcones has been extensively studied,the molecular mechanisms of isoliquiritigenin analog 2',4',4-trihydroxychalcone(metochalcone;TEC)against carcinomas remain less well understood.In this study,we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner.TEC induced cell cycle arrest in the S-phase,cell migration inhibition in vitro,and reduced tumor growth in vivo.Moreover,transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways.TEC triggered the senescence-associated secretory phenotype(SASP)by repressing the JAK2/STAT3 axis.The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway,highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.

Ki-67 Change in Anthracyline-containing Neoadjuvant Chemotherapy Response in Breast Cancer

Objective Anthracycline-containing regimens are irreplaceable in neoadjuvant chemotherapy(NAC)for breast cancer(BC)at present.However,30% of early breast cancer(EBC)patients are resistant to anthracycline-containing chemotherapy,leading to poor prognosis and higher mortality.Ki-67 is associated with the prognosis and response to therapy,and it changes after NAC.Methods A total of 105 BC patients who received anthracycline-containing NAC were enrolled.Then,the optimal model of Ki-67 was selected,and its predictive efficacy was analyzed.Immunohistochemistry(IHC)was used to determine the estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER-2)status and Ki-67 level.Fluorescent in situ hybridization(FISH)was used to verify the HER-2 when the IHC score was 2+.Results The post-NAC Ki67 level after treatment with anthracycline drugs was lower than pre-NAC Ki-67(19.6%±23.3%vs.45.6%±23.1%,P<0.001).Furthermore,patients with the Ki-67 decrease had a border line higher pathological complete response(pCR)rate(17.2%vs.0.0%,P=0.068),and a higher overall response rate(ORR)(73.6%vs.27.8%,P<0.001),when compared to patients without the Ki-67 decrease.The ΔKi-67 and ΔKi-67%were valuable markers for the prediction of both the pCR rate and ORR.The area under the curve(AUC)for ΔKi-67 on pCR and ORR was 0.809(0.698-0.921)and 0.755(0.655-0.855),respectively,while the AUC for ΔKi-67% on pCR and ORR was 0.857(0.742-0.972)and 0.720(0.618-0.822),respectively.Multivariate logistic regression model 1 revealed thatΔKi-67 was an independent predictor for both pCR[odds ratio(OR)=61.030,95% confidence interval(CI)=4.709-790.965;P=0.002]and ORR(OR=10.001,95%CI:3.044-32.858;P<0.001).Multivariate logistic regression model 2 revealed thatΔKi-67%was also an independent predictor for both pCR(OR=408.922,95%CI=8.908-18771.224;P=0.002)and ORR(OR=5.419,95%CI=1.842-15.943;P=0.002).Conclusions The present study results suggest thatΔKi67 andΔKi67%are candidate predictors for anthracycline-containing NAC response,and that they may provide various information for further systematic therapy after surgery in clinical practice.

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

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

Reversal of tamoxifen resistance by artemisinin in ER+breast cancer:bioinformatics analysis and experimental validation

Breast cancer is the leading cause of cancer-related deaths in women worldwide,with Hormone Receptor(HR)+being the predominant subtype.Tamoxifen(TAM)serves as the primary treatment for HR+breast cancer.However,drug resistance often leads to recurrence,underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates.Artemisinin(ART)has demonstrated efficacy in inhibiting the growth of drug-resistant cells,positioning art as a viable option for counteracting endocrine resistance.This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation.Five characterized genes(ar,cdkn1a,erbb2,esr1,hsp90aa1)and seven drug-disease crossover genes(cyp2e1,rorc,mapk10,glp1r,egfr,pgr,mgll)were identified using WGCNA crossover analysis.Subsequent functional enrichment analyses were conducted.Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and-sensitized patients.scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells,suggesting artemisinin’s specific impact on tumor cells in estrogen receptor(ER)-positive BC tissues.Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes.These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.