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.

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.

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.

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.

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.

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.

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.

The cancer-testis gene,MEIOB,sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.

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.

Excellent effects and possible mechanisms of action of a new antibody–drug conjugate against EGFR-positive triple-negative breast cancer

Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted therapeutics.Epidermal growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in TNBC.LR004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our laboratory.This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action.Methods:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by HIC-HPLC.The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western blotting.MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation.The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion assays.Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo.Briefly,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 cells.Then they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,respectively.Tumor sizes and the body weights of mice were measured every 4 d.The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry.Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR,ERK,MEK phosphorylation and tumor stemness marker gene expression.Results:LR004-VC-MMAE with a DAR of 4.02 were obtained.The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells(P<0.01).LR004-VC-MMAE inhibited the proliferation of EGFRpositive TNBC cells,and the ICvalues of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were(0.13±0.02)nmol/L and(0.66±0.06)nmol/L,respectively,which were significantly lower than that of cells treated with MMAE[(3.20±0.60)nmol/L,P<0.01,and(6.60±0.50)nmol/L,P<0.001].LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells.Moreover,LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability.In TNBC xenograft models,LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36.Surprisingly,tumor recurrence was not observed until the end of the experiment on day 52.In a mechanistic study,we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G/M phase in MDAMB-468[(34±5)%vs.(12±2)%,P<0.001]and MDA-MB-231[(27±4)%vs.(18±3)%,P<0.01]cells.LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4,Sox2,KLF4 and EpCAM.Conclusions:LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes.It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.

Clinical Application of Lobaplatin Combined with Docetaxel in Adjuvant Chemotherapy for Triple-Negative Breast Cancer in Elderly Patients

To investigate the adverse reactions and efficacy of docetaxel combined with lobaplatin in adjuvant chemotherapy for triple-negative breast cancer in elderly patients.A total of 96 elderly triple-negative breast cancer patients admitted to our hospital from January 2008 to December 2011 were randomly divided into two groups.A group of 56 patients received docetaxel 75 mg·m^(-2),intravenous drip,d1;lobaplatin 30 mg·m^(-2),intravenous drip,d1;21 days repeat,a total of 6 cycles.A group of 40 patients received chemotherapy for 6 cycles with an anthracycline-containing(TEC)regimen.Comparison of adverse reactions and 5-year diseasefree survival in both groups.The incidence of thrombocytopenia was significantly higher in 56 patients with TL regimen than those with TCE-containing anthracyclines(P=0.005).But the incidence of cardiotoxicity was 32.5%in the TEC group.And the difference was statistically significant(P=0.008).The 5-year disease-free survival rate was 73.2%in the TL group and 67.5%in the TEC group.There was no statistical difference.Docetaxel combined with lobaplatin in the treatment of elderly triple-negative breast cancer has no significant difference in efficacy compared with traditional anthracycline-containing drugs,but it can avoid the cardiotoxicity caused by anthracyclines.It’s a new option for elderly TNBC adjuvant chemotherapy,suggesting to expand the sample content for further research.

Insulin receptor is implicated in triple-negative breast cancer by decreasing cell mobility

Triple-negative breast cancer(TNBC)has a poor prognosis and typically earlier onset of metastasis in comparison with other breast cancer subtypes.It has been reported that insulin receptor(INSR)is downregulated in TNBC,however,its clinical significance and functions in TNBC remain to be elucidated.In this study,we found that INSR expression was significantly downregulated in TNBC,and overexpression of INSR suppressed cell migration and invasion in TNBC.In addition,the survival rate of breast cancer patients with low INSR expression was lower than that of patients with high INSR expression.INSR expression was significantly correlated with lymph node metastasis,clinical tumor stages,ER status,PR status,and the proliferation index Ki-67 expression.In summary,our study suggests that INSR may serve as a biomarker for breast cancer prognosis and it may be a potential target for TNBC treatment.

Efficacy and prognostic factors of neoadjuvant chemotherapy for triple-negative breast cancer

BACKGROUND Breast cancer mainly occurs in young and premenopausal women;its incidence is increasing annually. Patients with triple-negative breast cancer(TNBC) have relatively high recurrence and transfer rates during the operation and 3 years after postoperative adjuvant chemotherapy. Currently, the treatment for patients with TNBC is mainly based on a comprehensive combination of surgery and chemotherapy. Therefore, identifying additional effective treatments to improve patient prognosis is important.AIM To explore and discuss the effects and prognostic factors of neoadjuvant chemotherapy in TNBC.METHODS In total, 118 patients diagnosed with TNBC from January 2016 to January 2020 in our hospital were selected and divided into the observation(n = 60) and control(n = 58) groups according to therapeutic regimen. The control group received routine chemotherapy, and the observation group received neoadjuvant chemotherapy. The therapeutic effects of the two groups were observed, and the survival of patients was followed up.RESULTS The karyopherin A2(KPNA2)-positive and SRY-related HMG box-2(SOX2)-positive expression rates of patients with TNBC with intravascular tumor thrombus and tumor-node-metastasis(TNM) stage IV were 92.00% and 91.67% and 96.00% and 95.83%, respectively, which were significantly higher than those of patients with no intravascular tumor thrombus and TNM stage Ⅲ(P < 0.05). KPNA2 was positively associated with SOX2 expression(rs = 0.514, P < 0.50). The short-term curative effect of the observation group was better than that of the control group(P < 0.05), and the total effective rate was 58.33%. After treatment, carcinoembryonic antigen, cancer antigen(CA) 19-9, and CA125 Levels in the observation group were 11.40 ± 2.32 mg/L, 19.92 ± 3.42 kU/L, and 54.30 ± 12.28 kU/L, respectively, which were significantly lower than those in the control group(P < 0.05). The median survival time of the observation group was 33 mo(95%CI: 31.21-34.79), which was significantly longer than that of the control group(P < 0.05). TNM stage, degree of differentiation, lymph node metastasis, KPNA2 and SOX2 expressions, and treatment plan were prognostic factors of TNBC(relative risk = 1.575, 1.380, 1.366, 1.433, 1.411, and 0.581, respectively, P < 0.05).CONCLUSION Neoadjuvant chemotherapy for TNBC treatment can achieve good curative effects. TNM stage, differentiation degree, lymph node metastasis, KPNA2 and SOX2 expressions, and treatment plan are prognostic factors of TNBC.

Nomogram for predicting overall survival in Chinese triple-negative breast cancer patients after surgery

BACKGROUND There are few nomograms for the prognosis of Chinese patients with triplenegative breast cancer(TNBC).AIM To construct and validate a nomogram for overall survival(OS)of Chinese TNBC patients after surgery.METHODS This study used the data of SEER*stat 8.3.5 and selected Chinese patients with TNBC operated on between 2010 and 2015.Univariate and multivariate Cox proportional hazard regression models were used.The identified variables were integrated to form a predictive nomogram and risk stratification model;it was assessed with C-indexes and calibration curves.RESULTS The median and maximal OS of the 336 patients was 39 and 83 mo,respectively.The multivariate analysis showed that age(P=0.043),marital status(P=0.040),tumor localization(P=0.030),grade(P=0.035),T classification(P=0.012),and N classification(P=0.002)were independent prognostic factors.The six variables were combined to construct a 1-,3-and 5-year OS nomogram.The C-indexes of the nomogram to predict OS were 0.766 and compared to the seventh edition staging system,which was higher(0.766 vs 0.707,P<0.001).In order to categorize patients into different prognostic groups,a risk stratification model was created.There was a significant difference between the Kaplan–Meier curves of the entire cohort and each disease stage according to the nomogram.CONCLUSION The nomogram provided prognostic superiority over the traditional tumor,node and metastasis system.It could help clinicians make individual OS or risk predictions for Chinese TNBC patients after surgery.