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.

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.

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.

Treatment for triple-negative breast cancer

Triple-negative breast cancers (TNBCs) neither express estrogen receptor and progesterone receptor nor over- express human epidermal growth factor receptor-2. Because of the special molecular features, triple-negative breast cancer is not either sensitive to endocrine therapy or targeted therapy of trastuzumab. There has not been standard treatment regimen for triple-negative breast cancer yet and chemotherapy has still been the chief therapy currently. However, with the great progress of oncology and molecular biology, the understanding of the natural history, pathophysiology and molecular features of this disease has been greatly improved, and a growing number of novel and effective therapies and discoveries of new biological targets for this phenotype of breast cancers have been reported, which provide new insights into therapeutic strategies for the women suffering from it.

Violence against Women with Breast Neoplasms

The aim of this study is to assess the occurrence and type of violence suffered by women with breast cancer in the High Complexity Care Unit of a municipality in the South of Minas and patients in a support group of the University of the South of Minas Gerais. For that aim, a descriptive-exploratory methodology was applied through the quantitative method. Data were collected through a semi-structured form applied in individual interviews over a period of three months. We interviewed 57 patients and among those, 20 women （35.08%） reported having experienced some form of violence at some stage of their life, and the most frequently mentioned was the psychological violence followed by physical aggression. Although it was possible to identify that violence against affected these women, complaints against the aggressor were not affected.

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.

Dose-dense paclitaxel plus carboplatin vs.epirubicin and cyclophosphamide with paclitaxel as adjuvant chemotherapy for high-risk triple-negative breast cancer

Objective:The objective of this open-label,randomized study was to compare dose-dense paclitaxel plus carboplatin(PCdd)with dose-dense epirubicin and cyclophosphamide followed by paclitaxel(ECdd-P)as an adjuvant chemotherapy for early triple-negative breast cancer(TNBC).Methods:We included Chinese patients with high recurrence risk TNBC who underwent primary breast cancer surgery.They were randomly assigned to receive PCdd[paclitaxel 150 mg/m2 on d 1 and carboplatin,the area under the curve,(AUC)=3 on d 2]or ECdd-P(epirubicin 80 mg/m2 divided in 2 d and cyclophosphamide 600 mg/m2 on d 1 for 4 cycles followed by paclitaxel 175 mg/m2 on d 1 for 4 cycles)every 2 weeks with granulocyte colony-stimulating factor(G-CSF)support.The primary endpoint was 3-year disease-free survival(DFS);the secondary endpoints were overall survival(OS)and safety.Results:The intent-to-treat population included 143 patients(70 in the PCdd arm and 73 in the ECdd-P arm).Compared with the ECdd-P arm,the PCdd arm had significantly higher 3-year DFS[93.9%vs.79.1%;hazard ratio(HR)=0.310;95%confidence interval(95%CI),0.137-0.704;log-rank,P=0.005]and OS(98.5%vs.92.9%;HR=0.142;95%CI,0.060-0.825;log-rank,P=0.028).Worse neutropenia(grade 3/4)was found in the ECdd-P than the PCdd arm(47.9%V5.21.4%,P=0.001).Conclusions:PCdd was superior to ECdd-P as an adjuvant chemotherapy for early TNBC with respect to improving the 3-year DFS and OS.PCdd also yielded lower hematological toxicity.Thus,PCdd might be a preferred regimen for early TNBC patients with a high recurrence risk.

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.

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.

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.

Targeted inhibition of Notch1 gene enhances the killing effects of Paclitaxel on triple-negative breast cancer cells

Objective:To study the influence of targeted inhibition of Notch1 gene on the killing effects of Paclitaxel on triple-negative breast cancer cells.Methods:The triple-negative [estrogen receptor(ER)/progesterone receptor(PR)/human epidermal growth factor receptor 2(Her2)] breast cancer cell line MDA-MB-231 and ER/PR/HER-2-positive breast cancer cell line MCF-7 were cultured,transfected with Notch1-si RNA-overexpression plasmid and blank plasmid,and treated with different concentrations of paclitaxel,and then the cell proliferation activity and apoptosis rate as well as the m RNA expression of Caspase-3,Caspase-9 and Bcl-2 were determined.Results:Paclitaxel could decrease the MDA-MB-231 and MCF-7 cell proliferation activity as well as Bcl-2 mRNA expression,and increase MDA-MB-231 and MCF-7 cell apoptosis rate as well as Caspase-3 and Caspase-9 mRNA expression in dosedependent manners;with the same dose of paclitaxel treatment,the inhibitory effects on MDAMB-231 cell proliferation activity and Bcl-2 m RNA expression as well as the promoting effects on MDA-MB-231 cell apoptosis and mR NA expression of Caspase-3 and Caspase-9 were weaker than those on MCF-7 cell;after 0.5 μM paclitaxel combined with Notch1-siRNA treatment,MDA-MB-231 cell proliferation activity and Bcl-2 mRNA expression were significantly lower than those after 0.5 μM paclitaxel combined with control plasmid treatment while cell apoptosis rate and mR NA expression of Caspase-3 and Caspase-9 were higher than those after 0.5 μM paclitaxel combined with control plasmid treatment.Conclusions:Targeted inhibition of Notch1 gene may enhance the killing effects of paclitaxel on triple-negative breast cancer cells by up-regulating the expression of Caspase-3 and Caspase-9 and inhibiting the expression of Bcl-2.

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.