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.

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.

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.

Predicting the Prognosis and Immunotherapeutic Response of Triple-Negative Breast Cancer by Constructing a Prognostic Model Based on CD8+T Cell-Related Immune Genes

Objective Triple-negative breast cancer(TNBC)poses a significant challenge for treatment efficacy.CD8+T cells,which are pivotal immune cells,can be effectively analyzed for differential gene expression across diverse cell populations owing to rapid advancements in sequencing technology.By leveraging these genes,our objective was to develop a prognostic model that accurately predicts the prognosis of patients with TNBC and their responsiveness to immunotherapy.Methods Sample information and clinical data of TNBC were sourced from The Cancer Genome Atlas and METABRIC databases.In the initial stage,we identified 67 differentially expressed genes associated with immune response in CD8+T cells.Subsequently,we narrowed our focus to three key genes,namely CXCL13,GBP2,and GZMB,which were used to construct a prognostic model.The accuracy of the model was assessed using the validation set data and receiver operating characteristic(ROC)curves.Furthermore,we employed various methods,including Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway,immune infiltration,and correlation analyses with CD274(PD-L1)to explore the model's predictive efficacy in immunotherapeutic responses.Additionally,we investigated the potential underlying biological pathways that contribute to divergent treatment responses.Results We successfully developed a model capable of predicting the prognosis of patients with TNBC.The areas under the curve(AUC)values for the 1-,3-,and 5-year survival predictions were 0.618,0.652,and 0.826,respectively.Employing this risk model,we stratified the samples into high-and low-risk groups.Through KEGG enrichment analysis,we observed that the high-risk group predominantly exhibited enrichment in metabolism-related pathways such as drug and chlorophyll metabolism,whereas the low-risk group demonstrated significant enrichment in cytokine pathways.Furthermore,immune landscape analysis revealed noteworthy variations between(PD-L1)expression and risk scores,indicating that our model effectively predicted the response of patients to immune-based treatments.Conclusion Our study demonstrates the potential of CXCL13,GBP2,and GZMB as prognostic indicators of clinical outcomes and immunotherapy responses in patients with TNBC.These findings provide valuable insights and novel avenues for developing immunotherapeutic approaches targeting TNBC.

ROR2 promotes invasion and chemoresistance of triple-negative breast cancer cells by activating PI3K/AKT/mTOR signaling

Objective:This study aimed to investigate the role of receptor tyrosine kinase-like orphan receptor 2(ROR2)in triple-negative breast cancer(TNBC).Methods:ROR2 expression in primary TNBC and metastatic TNBC tissues was analyzed by immunohistochemical staining and PCR.ROR2 expression in TNBC cell lines was detected by PCR and Western blot analysis.The migration,invasion and chemosensitivity of TNBC cells with overexpression or knockdown of ROR2 were examined.Results:ROR2 expression was high in metastatic TNBC tissues.ROR2 knockdown suppressed the migration,invasion and chemoresistance of TNBC cells.ROR2 overexpression in MDA-MB-435 cells promoted the migration,invasion,and chemoresistance.Moreover,ROR2 knockdown in HC1599 and MDA-MB-435 adriamycin-resistant cells enhanced chemosensitivity to adriamycin.ROR2 could activate PI3K/AKT/mTOR signaling in TNBC cells.Conclusion:ROR2 is upregulated and promotes metastatic phenotypes of TNBC by activating PI3K/AKT/mTOR signaling.

Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis

BACKGROUND The association between tumor-infiltrating lymphocyte(TIL)levels and the res-ponse to neoadjuvant therapy(NAT)in patients with triple-negative breast cancer(TNBC)remains unclear.AIM To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients.METHODS A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31,2023.The correlation between TIL levels and the NAT pathologic com-plete response(pCR)in TNBC patients was assessed using a systematic review and meta-analysis.Subgroup analysis,sensitivity analysis,and publication bias analysis were also conducted.RESULTS A total of 32 studies were included in this meta-analysis.The overall meta-ana-lysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup(48.0%vs 27.7%)(risk ratio 2.01;95%confidence interval 1.77-2.29;P<0.001,I2=56%).Subgroup analysis revealed that the between-study hetero-geneity originated from differences in study design,TIL level cutoffs,and study populations.Publication bias could have existed in the included studies.The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols(all P≤0.01),and there was no significant between-protocol difference in the statistics among the different NAT protocols(P=0.29).Additionally,sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded.CONCLUSION TILs can serve as a predictor of the response to NAT treatment in TNBC patients.TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs,and this predictive capability is con-sistent across different NAT regimens.

Unveiling the therapeutic potential:KBU2046 halts triple-negative breast cancer cell migration by constricting TGF-β1 activation in vitro

Background:Triple-negative breast cancer(TNBC)is a heterogeneous,recurring cancer characterized by a high rate of metastasis,poor prognosis,and lack of efficient therapies.KBU2046,a small molecule inhibitor,can inhibit cell motility in malignant tumors,including breast cancer.However,the specific targets and the corresponding mechanism of its function remain unclear.Methods:In this study,we employed(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium)(MTS)assay and transwell assay to investigate the impact of KBU2046 on the proliferation and migration of TNBC cells in vitro.RNA-Seq was used to explore the targets of KBU2046 that inhibit the motility of TNBC.Finally,confirmed the predicted important signaling pathways through RT-qPCR and western blotting.Results:In this study,we found that KBU2046 functioned as a novel transforming growth factor-β(TGF-β1)inhibitor,effectively suppressing tumor cell motility in vitro.Mechanistically,it directly down-regulated leucine-rich repeat-containing 8 family,member E(LRRC8E),latent TGFβ-binding protein 3(LTBP3),dynein light chain 1(DNAL1),and MAF family of bZIP transcription factors(MAFF)genes,along with reduced protein expression of the integrin family.Additionally,KBU2046 decreased phosphorylation levels of Raf and ERK.This deactivation of the ERK signaling pathway impeded cancer invasion and metastasis.Conclusions:In summary,these findings advocate for the utilization of TGF-β1 as a diagnostic and prognostic biomarker and as a therapeutic target in TNBC.Furthermore,our data underscore the potential of KBU2046 as a novel therapeutic strategy for combating cancer metastasis.

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.

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.

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.

Hot issues in triple-negative breast cancer

Triple-negative breast cancer(TNBC)is an aggressive disease with a poor prognosis.Several clinical trials have demonstrated future prospects for patients with TNBC based on improved long-term survival;however,there are still TNBC challenges,such as molecular classification and treatment optimization.Invited by Cancer Biology&Medicine,we would like to discuss four hot topics in TNBC and suggest some potential solutions(Figure 1).

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Background:Unresectable locally advanced or metastatic triple-negative(hormone-receptor-negative and human epidermal growth factor receptor 2[HER2]-negative)breast cancer is an aggressive disease with poor outcomes.Nanoparticle albumin-bound(nab)-paclitaxel may enhance the anticancer activity of atezolizumab.

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.

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.

Hexadecanoic acid-enriched extract of Halymenia durvillei induces apoptotic and autophagic death of human triple-negative breast cancer cells by upregulating ER stress

Objective:To investigate the effect of the hexane solvent fraction of Halymenia durvillei(HDHE)on triple-negative breast cancer.Methods:The phytochemical profile of HDHE was investigated by GC-MS.The cytotoxicity of HDHE against MDA-MB-231 cells was determined.The apoptotic and autophagic effects of HDHE were analyzed.The expression of molecular markers controlling apoptosis,autophagy,DNA damage,and endoplasmic reticulum(ER)stress was determined.Results:HDHE contains a mixture of fatty acids,mainly hexadecanoic acid.HDHE at a cytotoxic concentration induced apoptotic death of MDA-MB-231 cells through mitochondrial membrane dysfunction,and induction of apoptosis markers,and increased the expression of proteins related to DNA damage response.HDHE also induced the expression of LC-3,a marker of autophagic cell death at a cytotoxic concentration.Moreover,HDHE modulated the expression of ER stress genes.Conclusions:The hexadecanoic acid-enriched extract of Halymenia durvillei promotes apoptosis and autophagy of human triple-negative breast cancer cells.This extract may be further explored as an anticancer agent for triple-negative breast cancer.

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.

Unfavorable Pathological Complete Response Rate of Neoadjuvant Chemotherapy Epirubicin plus Taxanes for Locally Advanced Triple-negative Breast Cancer

Anthracycline-Taxane chemotherapy is widely used in neoadjuvant treatment for breast cancers. However, there is limited data reported in patients with triple negative breast cancer （TNBC）. Here, we evaluated the pathologic responses and survival of neoadjuvant epirubicin and taxanes chemotherapy in patients with locally advanced TNBC to provide some useful information for clinical practice. A total of 43 patients with locally advanced TNBC were enrolled in this study. Patients were administered with epirubicin 75 mg/m^2 plus paclitaxel 175 mg/m^2 or docetaxel 75 mg/m^2 every 3 weeks for at least 2 cycles. The primary endpoint was pathologic complete response （pCR）, which was defined as no residual invasive cancer, or only carcinoma in situ in both the excised breast and axillary lymph node, while relapse-free survival （RFS） and overall survival （OS） were secondary endpoints. Thirty-nine （90.7%） patients were at clinical stages II B-IIIC. Thirty-seven （86%） completed 4-6 cycles of preop- erative chemotherapy, and objective response rate （ORR） was 81.4% （35/43）. Forty-two patients un- derwent radical surgery subsequently. The pCR rate was 14.3% （6/42）. The most common adverse events in neoadjuvant chemotherapy were nausea/vomiting （88.4%, 38/43） and neutropenia （88.4%）. After a median follow-up period of 34.0 months, 3-year RFS and OS rate was 53.6% and 80.1%, respectively. All events of recurrence and death occurred in non-pCR patients, in whom the 3-year RFS and OS rates were 44.3% and 76.6%, respectively. This study suggest that neoadjuvant chemotherapy with epirubicin plus taxanes has a relatively low pCR rate and high early recurrence risk in locally ad- vanced TNBC, which indicates the necessity for more efficacious treatment. Further study is needed to validate these results.

The advance of adjuvant treatment for triple-negative breast cancer

Triple-negative breast cancer(TNBC)is a subtype of breast cancer characterized by its highly aggressive behavior,early recurrence,and poor outcomes,when compared with other subtypes.Due to the absence of the estrogen receptor,progesterone receptor,and human epidermal growth factor receptor 2 expression,TNBC lacks meaningful biomarkers and an effective therapeutic strategy.Chemotherapy remains the main adjuvant treatment for patients with TNBC.Anthracycline/taxane-based regimens are the standard of care in adjuvant settings.The addition of capecitabine or platinum may offer extra benefits to patients with TNBC,but at the cost of increased toxicity or adverse events.Dose-dense chemotherapy may enhance treatment efficacy in patients who are able to tolerate the treatment regimen,especially in high-risk patients.As a heterogenous disease,TNBC can be classified into several molecular subtypes according to genomic or transcriptional features,which may indicate potential targets for more precise and individualized treatment strategies.With our increased understanding of signal pathways associated with TNBC,as well as the discovery of novel biomarkers indicative of TNBC prognosis,several new therapeutic options are under investigation,and some have already reported good results.In this review,we summarized the current conventional therapeutic strategies and emerging clinical trials regarding adjuvant treatment for TNBC.Furthermore,we evaluated the prognostic value of several potential targets and the progress of targeted therapy in TNBC,both in neoadjuvant and adjuvant settings.