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.

Stability and variability of molecular subtypes:comparative analysis of primary and metastatic triple-negative breast cancer

Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.

A Prognostic Model Based on Colony Stimulating Factors-related Genes in Triple-negative Breast Cancer

Objective Triple-negative breast cancer(TNBC)is the breast cancer subtype with the worst prognosis,and lacks effective therapeutic targets.Colony stimulating factors(CSFs)are cytokines that can regulate the production of blood cells and stimulate the growth and development of immune cells,playing an important role in the malignant progression of TNBC.This article aims to construct a novel prognostic model based on the expression of colony stimulating factors-related genes(CRGs),and analyze the sensitivity of TNBC patients to immunotherapy and drug therapy.Methods We downloaded CRGs from public databases and screened for differentially expressed CRGs between normal and TNBC tissues in the TCGA-BRCA database.Through LASSO Cox regression analysis,we constructed a prognostic model and stratified TNBC patients into high-risk and low-risk groups based on the colony stimulating factors-related genes risk score(CRRS).We further analyzed the correlation between CRRS and patient prognosis,clinical features,tumor microenvironment(TME)in both high-risk and low-risk groups,and evaluated the relationship between CRRS and sensitivity to immunotherapy and drug therapy.Results We identified 842 differentially expressed CRGs in breast cancer tissues of TNBC patients and selected 13 CRGs for constructing the prognostic model.Kaplan-Meier survival curves,time-dependent receiver operating characteristic curves,and other analyses confirmed that TNBC patients with high CRRS had shorter overall survival,and the predictive ability of CRRS prognostic model was further validated using the GEO dataset.Nomogram combining clinical features confirmed that CRRS was an independent factor for the prognosis of TNBC patients.Moreover,patients in the high-risk group had lower levels of immune infiltration in the TME and were sensitive to chemotherapeutic drugs such as 5-fluorouracil,ipatasertib,and paclitaxel.Conclusion We have developed a CRRS-based prognostic model composed of 13 differentially expressed CRGs,which may serve as a useful tool for predicting the prognosis of TNBC patients and guiding clinical treatment.Moreover,the key genes within this model may represent potential molecular targets for future therapies of TNBC.

Turning foes to friends:Advanced“in situ nanovaccine”with dual immunoregulation for enhanced immunotherapy of metastatic triple-negative breast cancer

As a“cold tumor”,triple-negative breast cancer(TNBC)exhibits limited responsiveness to current immunotherapy.How to enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC remain a formidable challenge.Herein,an“in situ nanovaccine”Au/CuNDs-R848 was designed for imagingguided photothermal therapy(PTT)/chemodynamic therapy(CDT)synergistic therapy to trigger dual immunoregulatory effects on TNBC.On the one hand,Au/CuNDs-R848 served as a promising photothermal agent and nanozyme,achieving PTT and photothermal-enhanced CDT against the primary tumor of TNBC.Meanwhile,the released antigens and damage-associated molecular patterns(DAMPs)promoted the maturation of dendritic cells(DCs)and facilitated the infiltration of T lymphocytes.Thus,Au/CuNDs-R848 played a role as an“in situ nanovaccine”to enhance the immunogenicity of TNBC by inducing immunogenic cell death(ICD).On the other hand,the nanovaccine suppressed the myeloid-derived suppressor cells(MDSCs),thereby reversing the immunosuppressive microenvironment.Through the dual immunoregulation,“cold tumor”was transformed into a“hot tumor”,not only implementing a“turning foes to friends”therapeutic strategy but also enhancing immunotherapy against metastatic TNBC.Furthermore,Au/CuNDs-R848 acted as an excellent nanoprobe,enabling high-resolution near-infrared fluorescence and computed tomography imaging for precise visualization of TNBC.This feature offers potential applications in clinical cancer detection and surgical guidance.Collectively,this work provides an effective strategy for enhancing immune response and offers novel insights into the potential clinical applications for tumor immunotherapy.

Bibliometric analysis of phosphoglycerate kinase 1 expression in breast cancer and its distinct upregulation in triple-negative breast cancer

BACKGROUND Phosphoglycerate kinase 1(PGK1)has been identified as a possible biomarker for breast cancer(BC)and may play a role in the development and advancement of triple-negative BC(TNBC).AIM To explore the PGK1 and BC research status and PGK1 expression and mecha-nism differences among TNBC,non-TNBC,and normal breast tissue.METHODS PGK1 and BC related literature was downloaded from Web of Science Core Co-llection Core Collection.Publication counts,key-word frequency,cooperation networks,and theme trends were analyzed.Normal breast,TNBC,and non-TNBC mRNA data were gathered,and differentially expressed genes obtained.Area under the summary receiver operating characteristic curves,sensitivity and specificity of PGK1 expression were determined.Kaplan Meier revealed PGK1’s prognostic implication.PGK1 co-expressed genes were explored,and Gene Onto-logy,Kyoto Encyclopedia of Genes and Genomes,and Disease Ontology applied.Protein-protein interaction networks were constructed.Hub genes identified.RESULTS PGK1 and BC related publications have surged since 2020,with China leading the way.The most frequent keyword was“Expression”.Collaborative networks were found among co-citations,countries,institutions,and authors.PGK1 expression and BC progression were research hotspots,and PGK1 expression and BC survival were research frontiers.In 16 TNBC vs non-cancerous breast and 15 TNBC vs non-TNBC datasets,PGK1 mRNA levels were higher in 1159 TNBC than 1205 non-cancerous breast cases[standardized mean differences(SMD):0.85,95%confidence interval(95%CI):0.54-1.16,I²=86%,P<0.001].PGK1 expression was higher in 1520 TNBC than 7072 non-TNBC cases(SMD:0.25,95%CI:0.03-0.47,I²=91%,P=0.02).Recurrence free survival was lower in PGK1-high-expression than PGK1-low-expression group(hazard ratio:1.282,P=0.023).PGK1 co-expressed genes were concentrated in ATP metabolic process,HIF-1 signaling,and glycolysis/gluconeogenesis pathways.CONCLUSION PGK1 expression is a research hotspot and frontier direction in the BC field.PGK1 may play a strong role in promoting cancer in TNBC by mediating metabolism and HIF-1 signaling pathways.

Targeting triple-negative breast cancer:A clinical perspective

Triple-negative breast cancer(TNBC)is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer.TNBC accounts for approximately 10%–15%of all diagnosed breast cancer cases and represents a high unmet need in the field.Up to just a few years ago,chemotherapy was the only systemic treatment option for this subtype(1).To date,TNBC is considered a heterogeneous disease.One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases,in which Lehman et al.proposed six subtypes of TNBC as follows:two basal-like(BL1 and BL2)subtypes,a mesenchymal(M)subtype,a mesenchymal stem-like(MSL)subtype,an immunomodulatory(IM)subtype,and a luminal androgen receptor(LAR)subtype(2).Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes(TILs)or stromal cells.According to this finding,the classification of TNBC has been revised into the following four subtypes:basal 1,basal 2,LAR,and mesenchymal subtypes(3).Over the last years,several new strategies have been investigated for the treatment of patients with TNBC.Among them,immunotherapy,antibody drug conjugates,new chemotherapy agents,and targeted therapy have been and are currently being developed.The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.

Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer

Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.

Primary acinic cell carcinoma of the breast: A case report and review of literature

BACKGROUND In the current World Health Organization classification,acinic cell carcinoma(AcCC)of the breast is considered a rare histological subtype of triple-negative breast cancer.Because of the few reports in the literature,data concerning clinical outcomes are limited.Here,we report a case of AcCC of the breast in a 48-year-old woman.A 48-year-old woman with a mass in her right breast came to our hospital for further diagnosis.Mammography and an ultrasound(US)scan showed a mass in the upper inner side of the right breast.She then underwent surgery to resect the mass in her right breast.Postoperative pathological examination revealed that the tumor had abundant acinar-like structures formed by tumor cells with prominent eosinophilic granules in the cytoplasm,consistent with acinar cell carcinoma.The results of immunohistochemical analysis supported the diagnosis of breast acinar cell carcinoma.Two months later,she underwent breast-conserving surgery and sentinel lymph node biopsy.The pTNM stage was T2N0M0.After surgery,the patient received 30 radiotherapy sessions.The patient was followed up for a period of one year,and no recurrence was found.AcCC of the breast is a rare type of malignant tumor.Because it is usually asym-ptomatic and can be detected by imaging studies,routine breast US or mamm-ograms are important.However,there are no characteristic diagnostic imaging findings or clinical manifestations,so immunohistochemical examination is critical for an accurate diagnosis of AcCC of the breast.

Polo-like kinase 1 as a biomarker predicts the prognosis and immunotherapy of breast invasive carcinoma patients

Invasive breast carcinoma(BRCA)is associated with poor prognosis and high risk of mortality.Therefore,it is critical to identify novel biomarkers for the prognostic assessment of BRCA.Methods:The expression data of polo-like kinase 1(PLK1)in BRCA and the corresponding clinical information were extracted from TCGA and GEO databases.PLK1 expression was validated in diverse breast cancer cell lines by quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting.Single sample gene set enrichment analysis(ssGSEA)was performed to evaluate immune infiltration in the BRCA microenvironment,and the random forest(RF)and support vector machine(SVM)algorithms were used to screen for the hub infiltrating cells and calculate the immunophenoscore(IPS).The RF algorithm and COX regression model were applied to calculate survival risk scores based on the PLK1 expression and immune cell infiltration.Finally,a prognostic nomogram was constructed with the risk score and pathological stage,and its clinical potential was evaluated by plotting calibration charts and DCA curves.The application of the nomogram was further validated in an immunotherapy cohort.Results:PLK1 expression was significantly higher in the tumor samples in TCGA-BRCA cohort.Furthermore,PLK1 expression level,age and stage were identified as independent prognostic factors of BRCA.While the IPS was unaffected by PLK1 expression,the TMB and MATH scores were higher in the PLK1-high group,and the TIDE scores were higher for the PLK1-low patients.We also identified 6 immune cell types with high infiltration,along with 11 immune cell types with low infiltration in the PLK1-high tumors.A risk score was devised using PLK1 expression and hub immune cells,which predicted the prognosis of BRCA patients.In addition,a nomogram was constructed based on the risk score and pathological staging,and showed good predictive performance.Conclusions:PLK1 expression and immune cell infiltration can predict post-immunotherapy prognosis of BRCA patients.

Identification of an immune classifier for predicting the prognosis and therapeutic response in triple-negative breast cancer

Triple-negative breast cancer(TNBC)poses a significant challenge due to the lack of reliable prognostic gene signatures and an understanding of its immune behavior.Methods:We analyzed clinical information and mRNA expression data from 162 TNBC patients in TCGA-BRCA and 320 patients in METABRIC-BRCA.Utilizing weighted gene coexpression network analysis,we pinpointed 34 TNBC immune genes linked to survival.The least absolute shrinkage and selection operator Cox regression method identified key TNBC immune candidates for prognosis prediction.We calculated chemotherapy sensitivity scores using the“pRRophetic”package in R software and assessed immunotherapy response using the Tumor Immune Dysfunction and Exclusion algorithm.Results:In this study,34 survival-related TNBC immune gene expression profiles were identified.A least absolute shrinkage and selection operator-Cox regression model was used and 15 candidates were prioritized,with a concomitant establishment of a robust risk immune classifier.The high-risk TNBC immune groups showed increased sensitivity to therapeutic agents like RO-3306,Tamoxifen,Sunitinib,JNK Inhibitor VIII,XMD11-85h,BX-912,and Tivozanib.An analysis of the Search Tool for Interaction of Chemicals database revealed the associations between the high-risk group and signaling pathways,such as those involving Rap1,Ras,and PI3K-Akt.The low-risk group showed a higher immunotherapy response rate,as observed through the tumor immune dysfunction and exclusion analysis in the TCGA-TNBC and METABRIC-TNBC cohorts.Conclusion:This study provides insights into the immune complexities of TNBC,paving the way for novel diagnostic approaches and precision treatment methods that exploit its immunological intricacies,thus offering hope for improved management and outcomes of this challenging disease.

Identification of a seven-gene signature and establishment of a prognostic nomogram predicting overall survival of triple-negative breast

Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancersubtype characterized by the absence of expression of estrogen receptor (ER), progesteronereceptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC exhibitsresistance to hormone and HER2-targeted therapy, along with a higher incidence ofrecurrence and poorer prognosis. Therefore, exploring the molecular features of TNBC andconstructing prognostic models are of significant importance for personalized treatmentstrategies. Methods: In this research, bioinformatics approaches were utilized to screendifferentially expressed genes in 405 TNBC cases and 128 normal tissue samples from 8 GEOdatasets. Key core genes and signaling pathways were further identified. Additionally, aprognostic model incorporating seven genes was established using clinical and pathologicalinformation from 169 TNBC cases in the TCGA dataset, and its predictive performance wasevaluated. Results: Functional analysis revealed dysregulated biological processes such asDNA replication, cell cycle, and mitotic chromosome separation in TNBC. Protein-proteininteraction network analysis identified ten core genes, including BUB1, BUB1B, CDK1,CDC20, CDCA8, CCNB1, CCNB2, KIF2C, NDC80, and CENPF. A prognostic model consistingof seven genes (EXO1, SHCBP1, ABRACL, DMD, THRB, DCDC2, and APOD) was establishedusing a step-wise Cox regression analysis. The model demonstrated good predictiveperformance in distinguishing patients' risk. Conclusion: This research provides importantinsights into the molecular characteristics of TNBC and establishes a reliable prognosticmodel for understanding its pathogenesis and predicting prognosis. These findingscontribute to the advancement of personalized treatment for TNBC.

Clinical Value of cfDNA Content in Peripheral Blood of Patients with Triple-Negative Breast Cancer

Objective:To explore the value of circulating free(cfDNA)content in the clinical diagnosis and treatment of triple-negative breast cancer(TNBC).Methods:A total of 39 TNBC patients,45 non-TNBC patients,and 50 healthy individuals admitted to the Baoding First Central Hospital during 2019-2022 were recruited.The clinical data,peripheral blood cfDNA concentration,and clinicopathological indicators of the patients were observed and analyzed.Results:The difference in clinical indicators such as age,age range,tumor size,clinical stage,and lymph node metastasis between patients with TNBC and non-TNBC was insignificant(P>0.05).The cfDNA concentrations(ng/mL)of the TNBC group,non-TNBC group,and healthy group were 24.12±4.98,15.36±4.12,and 3.12±1.02,respectively,and they are statistically different(P<0.05).The difference in cfDNA concentration was insignificant between TNBC patients with tumors≤2 cm and>2 cm(P>0.05)but was significant between TNBC patients with clinical stages I+II and III+IV(P<0.05).The cfDNA concentration in TNBC patients with lymph node metastasis was significantly higher than those without lymph node metastasis(P<0.05).Conclusion:cfDNA has an important application value in the diagnosis and treatment of breast cancer.By detecting the cfDNA level and its gene variation,valuable information about the progress and treatment effects of breast cancer can be obtained.This non-invasive detection method has a wide range of applications and can be used for early screening,auxiliary diagnosis,efficacy evaluation,and recurrence monitoring of breast cancer.

Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

Breast cancer has been shown to live in the tumor microenvironment, which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells. Diverse components of the breast cancer microenvironment, such as suppressive immune cells, re-programmed fibroblast cells, altered extracellular matrix (ECM) and certain soluble factors, synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis. Among these components, stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, whereas the ECM features biochemical and biomechanical changes. However, triple-negative breast cancer (TNBC), the most aggressive subtype of this disease that lacks effective therapies available for other subtypes, is considered to feature a unique microenvironment distinct from that of other subtypes, especially compared to Luminal A subtype. Because these changes are now considered to significantly impact breast cancer development and progression, these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC. In this review, we focus on the composition of the TNBC microenvironment, concomitant distinct biological alteration, specific interplay between various cell types and TNBC cells, and the prognostic implications of these findings.

Current approaches in treatment of triple-negative breast cancer

Triple-negative breast cancer(TNBC) is diagnosed more frequently in younger and premenopausal women and is highly prevalent in African American women. TNBC is a term derived from tumors that are characterized by the absence of ER, Pg R, and HER2. So patients with TNBC do not benefit from hormonal or trastuzumab-based therapies. TNBCs are biologically aggressive, although some reports suggest that they respond to chemotherapy better than other types of breast cancer, prognosis remains poor. This is due to: shortened disease-free interval in the adjuvant and neoadjuvant setting and a more aggressive course in the metastatic setting.

Ultra-sensitive Nanoprobe Modified with Tumor Cell Membrane for UCL/MRI/PET Multimodality Precise Imaging of Triple-Negative Breast Cancer

Triple-negative breast cancer(TNBC)is a subtype of breast cancer in which the estrogen receptor and progesterone receptor are not expressed,and human epidermal growth factor receptor 2 is not amplified or overexpressed either,which make the clinical diagnosis and treatment very challenging.Molecular imaging can provide an effective way to diagnose TNBC.Upconversion nanoparticles(UCNPs),are a promising new generation of molecular imaging probes.However,UCNPs still need to be improved for tumor-targeting ability and biocompatibility.This study describes a novel probe based on cancer cell membrane-coated upconversion nanoparticles(CCm-UCNPs),owing to the low immunogenicity and homologous-targeting ability of cancer cell membranes,and modified multifunctional UCNPs.This probe exhibits excellent performance in breast cancer molecular classification and TNBC diagnosis through UCL/MRI/PET tri-modality imaging in vivo.By using this probe,MDA-MB-231 was successfully differentiated between MCF-7 tumor models in vivo.Based on the tumor imaging and molecular classification results,the probe is also expected to be modified for drug delivery in the future,contributing to the treatment of TNBC.The combination of nanoparticles with biomimetic cell membranes has the potential for multiple clinical applications.

Cancer stem-like cells directly participate in vasculogenic mimicry channels in triple-negative breast cancer

Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.

Adjuvant treatment for triple-negative breast cancer: a retrospective study of immunotherapy with autologous cytokine-induced killer cells in 294 patients

Objective: To examine the efficacy and safety of a sequential combination of chemotherapy and autologous cytokine-induced killer(CIK) cell treatment in triple-negative breast cancer(TNBC) patients.Methods: A total of 294 post-surgery TNBC patients participated in the research from January 1, 2009 to January 1, 2015. After adjuvant chemotherapy, autologous CIK cells were introduced in 147 cases(CIK group), while adjuvant chemotherapy alone was used to treat the remaining 147 cases(control group). The major endpoints of the investigation were the disease-free survival(DFS) and overall survival(OS). Additionally, the side effects of the treatment were evaluated.Results: In the CIK group, the DFS and OS intervals of the patients were significantly longer than those of the control group(DFS:P = 0.047;OS: P = 0.007). The multivariate analysis demonstrated that the TNM(tumor-node-metastasis) stage and adjuvant CIK treatment were independent prognostic factors for both DFS [hazard ratio(HR)= 0.520, 95% confidence interval(CI):0.271-0.998, P = 0.049;HR = 1.449, 95% CI:1.118-1.877, P = 0.005, respectively] and OS(HR=0.414, 95% CI:0.190-0.903, P = 0.027;HR= 1.581, 95% CI:1.204-2.077, P = 0.001, respectively) in patients with TNBC. Additionally, longer DFS and OS intervals were associated with increased number of CIK treatment cycles(DFS: P = 0.020;OS: P = 0.040). The majority of the patients who benefitted from CIK cell therapy were relatively early-stage TNBC patients.Conclusion: Chemotherapy in combination with adjuvant CIK could be used to lower the relapse and metastasis rate, thus effectively extending the survival time of TNBC patients, especially those at early stages.

Metabolic reprogramming in triple-negative breast cancer

Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with other breast cancer subtypes,have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment.Metabolic reprogramming,an emerging hallmark of cancer,is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands;maintain the redox balance;and further promote oncogenic signaling,cell proliferation,and metastasis.Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC.Here,we review the metabolic reprogramming of glycolysis,oxidative phosphorylation,amino acid metabolism,lipid metabolism,and other branched pathways in TNBC and explore opportunities for new biomarkers,imaging modalities,and metabolically targeted therapies.

Capecitabine maintenance therapy for XT chemotherapy-sensitive patients with metastatic triple-negative breast cancer

Objective： To investigate the efficacy and safety of capecitabine maintenance therapy（MT） after initial capecitabine plus docetaxel（XT） chemotherapy in patients with metastatic triple-negative breast cancer（m TNBC）.Methods： Fifty-five m TNBC patients treated with XT chemotherapy between May 2007 and June 2013 were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, capecitabine was continued for 32 patients（MT）, while 23 patients remained without any treatment（nonMT）. We compared progression-free survival（PFS） and safety of both groups.Results： The median PFS of 55 patients was 8.1 months, overall median PFS time of 32 patients in the capecitabine MT group and 23 in the non-MT group was 10.1 vs. 6.7 months（P=0.032）, respectively. When compared PFS time of maintenance treatment, single-agent capecitabine prolonged PFS by 7.1 months, for non-MT patients, the PFS without any treatment was 3.1 months, and this between-group difference was statistically significant（P=0.003）. Adverse events, including of hematologic toxicity, gastrointestinal toxicities, hand-foot syndrome and abnormal liver function were not significantly different between two groups.Conclusions： After initial disease control was achieved with the XT combination chemotherapy, capecitabine MT can significantly prolong PFS time with a favorable safety profile in m TNBC patients.

Histo-and clinico-pathological analysis of a large series of triple-negative breast cancer in a single center in China:Evidences on necessity of histological subtyping and grading

Objective: To investigate histo-pathological distribution and clinico-pathological significance in a large Chinese triple-negative breast cancer(TNBC) patients serials based on the latest understanding of its clinico-pathological diversity, and to provide more information to clinicians to improve precision of individualized treatment of TNBC.Methods: A retrospective analysis was performed on patients with TNBC at Breast Disease Center, Peking University First Hospital between January 2010 and December 2019. Histo-and clinico-pathological characteristics were analyzed by Chi-square test and Student's t-test, and prognoses were calculated using KaplanMeier method and a Cox proportionate hazards model. Bonferroni correction was used to correct for multiple comparison.Results: Conventional type of TNBC(c TNBC) were identified in 73.7% of 582 TNBC, while special type of TNBC(s TNBC) were 26.3%, including 71 apocrine carcinoma, 20 medullary carcinoma, 31 metaplastic carcinoma, 18 invasive lobular carcinoma, 7 invasive micropapillary carcinoma, 5 adenoid cystic carcinoma and 1 acinic cell carcinoma. Compared to s TNBC, c TNBC was associated with high histologic grade(P<0.001) and lower androgen receptor(AR) expression(P<0.001). TNM stage of low-grade c TNBC was significantly lower than that of high-grade c TNBC(P=0.002). Although no significant difference, there was a trend that the rate of 5-year disease-free survival(DFS) and 5-year overall survival(OS) were longer in high-grade c TNBC than in high-grade s TNBC(P=0.091 and 0.518), and were longer in low-grade s TNBC than in high-grade s TNBC(P=0.051 and0.350). Metaplastic carcinomas showed larger tumor size(P=0.008) and higher proliferative Ki67 index(P=0.004)than c TNBCs.Conclusions: Results from our cohort imply that sub-categorization or subtyping and histological grading could be meaningful in pathological evaluation of TNBC, and need to be clarified in more large collections of TNBC.