Effects of psychological intervention on negative emotions and psychological resilience in breast cancer patients after radical mastectomy

Breast cancer(BC)is the most common malignant tumor in women,and the treatment process not only results in physical pain but also significant psychological distress in patients.Psychological intervention(PI)has been recognized as an important approach in treating postoperative psychological disorders in BC patients.It has been proven that PI has a significant therapeutic effect on postoperative psychological disorders,improving patients'negative emotions,enhancing their psychological resilience,and effectively enhancing their quality of life and treatment compliance.

Personalized and continuous care intervention affects rehabilitation,living quality,and negative emotions of patients with breast cancer

BACKGROUND Breast cancer is among the most common malignancies worldwide.With progress in treatment methods and levels,the overall survival period has been prolonged,and the demand for quality care has increased.AIM To investigate the effect of individualized and continuous care intervention in patients with breast cancer.METHODS Two hundred patients with breast cancer who received systemic therapy at The First Affiliated Hospital of Hebei North University(January 2021 to July 2023)were retrospectively selected as research participants.Among them,134 received routine care intervention(routing group)and 66 received personalized and continuous care(intervention group).Self-rating anxiety scale(SAS),self-rating depression scale(SDS),and Functional Assessment of Cancer Therapy-Breast(FACT-B)scores,including limb shoulder joint activity,complication rate,and care satisfaction,were compared between both groups after care.RESULTS SAS and SDS scores were lower in the intervention group than in the routing group at one and three months after care.The total FACT-B scores and five dimensions in the intervention group were higher than those in the routing group at three months of care.The range of motion of shoulder anteflexion,posterior extension,abduction,internal rotation,and external rotation in the intervention group was higher than that in the routing group one month after care.The incidence of postoperative complications was 18.18%lower in the intervention group than in the routing group(34.33%;P<0.05).Satisfaction with care was 90.91% higher in the intervention group than in the routing group(78.36%;P<0.05).CONCLUSION Personalized and continuous care can alleviate negative emotions in patients with breast cancer,quicken rehabilitation of limb function,decrease the incidence of complications,and improve living quality and care satisfaction.

Systemic treatment strategies for triple-negative breast cancer

Triple-negative breast cancer(TNBC) is defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2(EGFR2). Most TNBC has a basal-like molecular phenotype by gene expression profiling and shares clinical and pathological features with hereditary BRCA1 related breast cancers. This review evaluates the activity of available chemotherapy and targeted agents in TNBC. A systematic review of PubM ed and conference databases was carried out to identify randomised clinical trials reporting outcomes in women with TNBC treated with chemotherapy and targeted agents. Our review identified TNBC studies of chemotherapy and targeted agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth and survival pathways. TNBC is sensitive to taxanes and anthracyclins. Platinum agents are effective in TNBC patients with BRCA1 mutation, either alone or in combination with poly adenosine diphosphate polymerase 1 inhibitors. Combinations of ixabepilone and capecitabine have added to progression-free survival(PFS) without survival benefit in metastatic TNBC. Antiangiogenic agents, tyrosine kinase inhibitors and EGFR inhibitorsin combination with chemotherapy produced only modest gains in PFS and had little impact on survival. TNBC subgroups respond differentially to specific targeted agents. In future, the treatment needs to be tailored for a specific patient, depending on the molecular characteristics of their malignancy. TNBC being a chemosensitive entity, combination with targeted agents have not produced substantial improvements in outcomes. Appropriate patient selection with rationale combinations of targeted agents is needed for success.

Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing

Objective:To compare the efficacy of platinum-and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer(TNBC)and analyze the relationship between their efficacy and BRCA gene status.Methods:Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology,Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy.A total of 114 patients had BRCA1/2 gene tested by next generation sequencing(NGS)using peripheral blood,and we analyzed the correlation between their efficacy and BRCA1/2 gene status.Results:Non-platinum-based chemotherapy(NPCT)was administered to 129 and platinum-based chemotherapy(PBCT)to 91 study patients.The clinical benefit rate(CBR)and median progression-free survival(PFS)were not statistically different between NPCT and PBCT groups.The median overall survival(OS)was 30.0 and 22.5 months for PBCT and NPCT group,respectively[P=0.090,hazard ratios(HR)=0.703].BRCA status was assessed in 114 patients,14 of whom had deleterious germline BRCA1/2(g BRCA)mutations(seven in each group).In PBCT group,the CBR was 85.7%and 35.1%for patients with and without deleterious g BRCA mutations,respectively(P=0.039).The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious g BRCA mutations,respectively(P=0.001,P=0.161,respectively).Patients in PBCT group had significantly greater rates of grade 3-4 anemia(5.5%vs.0%)and thrombocytopenia(8.8%vs.0%),whereas palmar-plantar erythrodysesthesia(12.4%vs.0%)and peripheral neuropathy(8.6%vs.1.1%)occurred more frequently in NPCT group.Conclusions:Platinum-based regimens are more effective in patients with deleterious g BRCA mutations,but no difference in patients without BRCA gene mutations,so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect.And we recommend that patients with advanced TNBC should have BRCA gene test.

Platinum is essential in neoadjuvant treatment of triple-negative breast cancer: a network meta-analysis

Objective:This study aimed to assess the efficacy and safety of various neoadjuvant regimens for patients diagnosed with early-stage or locally advanced triple-negative breast cancer(TNBC).Methods:Medline,EMBASE,Cochrane Library,and Web of Science were searched in May 2020 to identify randomized controlled trials(RCTs).Bayesian network meta-analysis(NMA)was performed(Registration:PROSPERO CRD42020223012).Results:A total of 35 RCTs involving 8,424 participants were reviewed,of which 22 RCTs with 5,203 patients were included in this NMA focusing on pathologic complete response(pCR).An anthracycline-taxane-based(AT)regimen combined with a platinum(ATPt)[odds ratio(OR)=2.04,95%credible interval(CrI):1.69,2.48]regimen,and a docetaxel regimen combined with a carboplatin(TCb;OR=2.16,95%CrI:1.20,3.91)regimen improved pCR beyond that with AT only.AT and ATPt combined with targeted therapy[including bevacizumab(Bev),veliparib,atezolizumab,or pembrolizumab]also improved pCR.Five RCTs included in this NMA reported serious adverse events(SAEs)or grade≥3 AEs.TCb was associated with fewer grade≥3 AEs than was AT(OR=0.66,95%CrI:0.23,1.72)alone.In contrast,ATPt,AT+Bev,ATPt+Bev,ATPt+veliparib,and ATPt+pembrolizumab were associated with more SAEs than was AT alone.Conclusions:In patients with TNBC,platinum-based neoadjuvant regimens ATPt and TCb increase pCR beyond that with AT alone,but TCb appears to be better tolerated than either AT or ATPt.Platinum-based regimens combined with targeted therapies(Bev,PARPi,and PD-1/PD-L1 inhibitor)also improve the pCR rate beyond that with AT alone,but this benefit is accompanied by greater toxicity.

Inhibition of growth and metastasis of triple-negative breast cancer targeted by Traditional Chinese Medicine Tubeimu in orthotopic mice models

Objective： Triple-negative breast cancer（TNBC） is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu（TBM）, the rhizome of Bolbostemma paniculatum（Maxim.） Franquet, is one of the Chinese medicinal herbs used for breast diseases since the ancient times. The present study evaluated the efficacy, especially the anti-metastatic effects of the dichloromethane extract of Tubeimu（ETBM） on TNBC orthotopic mouse models and cell lines.Methods： We applied real-time imaging on florescent orthotopic TNBC mice model and tested cell migration and invasion abilities with MDA-MB-231 cell line. Digital gene expression sequencing was performed and Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis applied to explore the pathways influenced by ETBM.Moreover, quantitative real-time polymerase chain reactions（q RT-PCR） and Western blot were delivered to confirm the gene expression changes.Results： ETBM exhibited noticeable control on tumor metastasis and growth of TNBC tumors with no obvious toxicity. In compliance with this, it also showed inhibition of cell migration and invasion in vitro. Its impact on the changed biological behavior in TNBC may be a result of decreased expression of integrin β1（ITGβ1）, integrin β8（ITGβ8） and Rho GTPase activating protein 5（ARHGAP5）, which disabled the focal adhesion pathway and caused change in cell morphology.Conclusions： This study reveals that ETBM has anti-metastatic effects on MDA-MB-231-GFP tumor and may lead to a new therapeutic agent for the integrative treatment of highly invasive TNBC.

Narrowing the focus:Therapeutic cell surface targets for refractory triple-negative breast cancer

Triple-negative breast cancer(TNBC)is defined as a type of breast cancer with lack of expression of estrogen receptor,progesterone receptor and human epidermal growth factor 2 protein.In comparison to other types of breast cancer,TNBC characterizes for its aggressive behavior,more prone to early recurrence and a disease with poor response to molecular target therapy.Although TNBC is identified in only 25%-30%of American breast cancer cases annually,these tumors continue to be a therapeutic challenge for clinicians for several reasons:Tumor heterogeneity,limited and toxic systemic therapy options,and often resistance to current standard therapy,characterized by progressive disease on treatment,residual tumor after cytotoxic chemotherapy,and early recurrence after complete surgical excision.Cell-surface targeted therapies have been successful for breast cancer in general,however there are currently no approved cell-surface targeted therapies specifically indicated for TNBC.Recently,several cell-surface targets have been identified as candidates for treatment of TNBC and associated targeted therapies are in development.The purpose of this work is to review the current clinical challenges posed by TNBC,the therapeutic approaches currently in use,and provide an overview of developing cell surface targeting approaches to improve outcomes for treatment resistant TNBC.

P53 gene could be a new effective therapeutic target in triple-negative breast cancer: a Meta-analysis

Objective： The aim of this study was to explore the relationship between p53 gene and triple-negative breast cancer （TNBC）, and determine that whether p53 gene could be a new effective therapeutic target. Methods： We identified studies with quantitative data on the relation of p53 gene and TNBC through searching 12 databases online （Oct. 1999-Oct. 2012） and reviewing the references, which were written in English or Chinese. Summary estimates of odds ratio （OR） was calculated using the fixed-effects model or the random-effects model as appropriate. Results： We identified 12 eligible stud- ies with 1532 cases of TNBC patients and 6329 controls of non-TNBC patients. The test for homogeneity resulted in X^2 = 200.16 （P 〈 0.05）, it showed significant heterogeneity so that a random effect model was applied. Our results showed that the expression of p53 gene could be much stronger in TNBC group than that in non-TNBC group [OR = 2.10, 95% confidence interval （CI） = 1.21-3.65]. In ethnicity-subgroup analysis, we found that in Caucasian group, the expression of p53 gene were stronger in TNBC group （OR = 2.60, 95% CI = 1.21-5.57）, but there was no statistical significance in Asian group （OR = 1.69, 95% CI = 0.83-3.45）. Conclusion： P53 gene could be an effective predictor and a good therapeutic target for TNBC patients in the future, especially in Caucasian. Further researches focusing on p53 gene would gain a breakthrough in the treatment of TNBC.

Analysis of the Clinicopathologic Features and Prognosis in Triple-Negative Breast Cancer

OBJECTIVE To investigate the clinical and pathological features,as well as prognosis in triple-negative breast cancer patients.METHODS A total of 509 cases of operable breast cancer from January,2002 to June,2002 treated in the Cancer Hospital of Tianjin Medical University were analyzed.The Her-2,ER and PR status was determined using immunohistochemistry.Of the total cases,one group was identifi ed as triple negative breast cancer,ie defi ned as ER,PR and Her-2 negative.The other group was non-triple-negative breast cancer.Clinicopathologic features of the groups were compared and 5-year disease-free survival(DFS) analyzed by the Kaplan-Meier method.RESULTS Of the total cases,21.4%(109/509) of cases were found to be triple-negative while 78.6%(400/509) were non-triple-negative.The triple negative group had higher incidence rates than the non-triple-negative group of the medullary type and Grade Ⅲ tumors(P < 0.05).There was no other difference in the clinicopathologic features between the 2 groups.From follow-up to June,2007,21.1%(23/109) of the triple-negative group and 12.7%(51/400) of the non-triple negative group had a local recurrence or distant metastasis,resulting in a signifi cant difference(P < 0.05).In the triple-negative group and non-triple-negative group,5-year DFS were 78.9% and 87.3% respectively.There was a statistically signifi cant difference between the 2 groups(P = 0.031).CONCLUSION Compared with non-triple-negative breast cancer,triple-negative breast cancer patients have an increased likehood of a local recurrence or distant metastasis and a poorer prognosis.

Cytotoxicity Study of Gold Nanoparticles on the Basal-Like Triple-Negative HCC-1937 Breast Cancer Cell Line

The Triple Negative “Basal-like” breast cancer (TNBL) tumours have a high proliferative capacity and develop a resistance phenotype associated with metastases. However, the management of TNBL carcinomas is still not standardized. Among the promising trails, gold nanoparticles could be a relevant tool for the development of a targeted treatment for this breast cancer subtype in monotherapy, associated and/or conjugated with other drugs. In this work, we report the cytotoxicity impact of gold nanoparticles wrapped in Poly-Ethylene Glycol (PEG) on the TNBL HCC-1937 breast cancer cell line. PEG-coated gold nanoparticles (PEG-Au NPs) were synthesized by a two-step method using a reduction process followed by a post-functionalization called PEGylation. PEG-Au NPs were characterized using transmission electron microscopy and X-ray diffraction. The gold content of the samples was determined using atomic absorption spectrometer. The cytotoxicity tests were performed using Sulforhodamine B survival test and resazurin viability test. PEG-Au NPs impact analysis on HCC1937 TNBL cell line showed a clear toxic action of type dose dependent and at long term. These PEGylated gold nanoparticles present a promising tool for the development of tumor-specific radiosensitizing vectors, with or without the association of other treatment strategies.

Expression and significance of Shh,Gli1 and β-catenin in triple-negative breast cancer tissues

Objective:To detect the expression of Shh,Gli1 and β-catenin in triple negative breast cancer tissues and paracancer breast tissues by qRT-PCR and immunohistochemistry and to analyze their correlation with clinicopathological features.Methods:(1)qRT-PCR was used to detect the mRNA expression of Shh,Gli1 and β-catenin in 30 cases of triple negative breast cancer and their paracancer breast tissues,and the correlation among them was analyzed.(2)The expression of Shh,Gli1 and β-catenin proteins in 30 triple negative breast cancer and their paracancer breast tissues was detected by immunohistochemistry,and their correlation with clinicopathological features was analyzed.Results:(1)Shh mRNA expression(1.2334±0.27867),Gli1 mRNA expression(1.2135±0.20636)and β-catenin mRNA expression(1.1421±0.32330)in triple negative breast cancer tissues were higher than that in paracancer breast tissues,i.e.,Shh mRNA expression(1.0022±0.06721),Gli1 mRNA expression(1.0003±0.02420)and β-catenin mRNA expression(1.0033±0.07920)were significantly different(p<.05).There was a significantly positive correlation between the mRNA expression of Shh and Gli1(r=.989,p<.001),and between the mRNA expression of Shh and β-catenin(r=.868,p<.001).There was a significantly positive correlation between the mRNA expression of Gli1 and β-catenin expression(r=.869,p<.001).(2)The positive expression rates of Shh,Gli1 and β-catenin in triple negative breast cancer tissues were 93.3%(28/30),96.7%(29/30)and 93.3%(28/30),respectively,which were higher than those in paracancer tissues 60%(18/30),73.3%(22/30)and 73.3%(22/30),the differences were statistically significant(p<0.05).There was a significantly positive correlation between the mRNA expression of Shh and Gli1(r=.958,p<.001),and between the mRNA expression of Shh and β-catenin(r=.952,p<.001).There was a significantly positive correlation between the mRNA expression of Gli1 and β-catenin expression(r=.927,p<.001).The expression of Shh,Gli1 and β-catenin protein in triple negative breast cancer was not correlated with age and tumor size(p>.05),but Shh was positively correlated with histological grade(G)(r=.774,p<.001).Furthermore,Gli1 was positively correlated with histological grade(r=.757,p<.001).β-catenin was positively correlated with histological grade(r=.739,p<.001).Shh was positively correlated with TNM staging(r=.460,p=.010).Gli1 was positively correlated with TNM staging(r=.414,p=.023).β-catenin was positively correlated with TNM staging(r=.404,p=.027).Shh was positively correlated with lymph node metastasis(r=.540,p=.002).Gli1 was positively correlated with lymph node metastasis(r=.515,p=.004).β-catenin was positively correlated with lymph node metastasis(r=.559,p=.001).Conclusions:(1)The up-regulated expression of Shh,Gli1 and β-catenin proteins in triple negative breast cancer suggests that Shh,Gli1 and β-catenin proteins are involved in tumor genesis.The combined detection of the three proteins may provide a theoretical basis for the diagnosis and prognosis evaluation of triple negative breast cancer.(2)Shh was positively correlated with Gli1 protein expression and β-catenin protein expression.Gli1 was positively correlated with β-catenin protein expression,suggesting that the three types of proteins play a synergistic role in the occurrence and development of TNBC.There may be crosstalk in the Wnt/β-catenin and Hedgehog signaling pathways in TNBC,which may provide a new approach for the treatment of TNBC.(3)The expression of Shh,Gli1 and β-catenin proteins was correlated with the degree of differentiation,TNM staging and lymph node metastasis of triple negative breast cancer,but not correlated with age and tumor size.Therefore,it was predicted that the three types of proteins were related to the invasion,metastasis and prognosis of TNBC.

Biomarkers in triple negative breast cancer:A review

Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triplenegative. Characteristic feature of triple negative breast cancer(TNBC) is that it lacks expression of oestrogen,progesterone and human epidermal growth factor receptor-2/neu receptors. They comprise 15%-20% of all breast cancers. We did a systematic review of Pub Med and conference databases to identify studies published on biomarkers in TNBC. We included studies with biomarkers including: Epidermal growth factor receptor,vascular endothelial growth factor,c-Myc,C-kit and basal cytokeratins,Poly(ADP-ribose) polymerase-1,p53,tyrosinase kinases,m-TOR,heat and shock proteins and TOP-2A in TNBC. We also looked for studies published on synthetic lethality and inhibition of angiogenesis,growth,and survival pathways. TNBC is a complex disease subtype with many subclasses. Majority TNBC have a basal-like molecular phenotype by gene expression profiling. Their clinical and pathologic features overlap with hereditary BRCA1 related breast cancers. Management of these tumours is a challenge to the clinician because of its aggressive behaviour,poor outcome,and absence of targeted therapies. As the complexity of this disease is being simplified over time new targets are also being discovered for the treatment of this disease. There are many biomarkers in TNBC being used in clinical practice. Biomarkers may be useful as prognostic or predictive indicators as well as suggest possible targets for novel therapies. Many targeted agents are being studied for treatment of TNBC.

Triple negative breast cancer: special histological types and emerging therapeutic methods

Triple negative breast cancer(TN BC)is a complex and malignant breast cancer subtype that lacks expression of the estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor 2(H ER2),thereby making therapeutic targeting difficult.TNBC is generally considered to have high malignancy and poor prognosis.However,patients diagnosed with certain rare histomorphologic subtypes of TNBC have better prognosis than those diagnosed with typical triple negative breast cancer.In addition,with the discovery and development of novel treatment targets such as the androgen receptor(AR),PI3K/AKT/mTOR and AMPK signaling pathways,as well as emerging immunotherapies,the therapeutic options for TNBC are increasing.In this paper,we review the literature on various histological types of TNBC and focus on newly developed therapeutic strategies that target and potentially affect molecular pathways or emerging oncogenes,thus providing a basis for future tailored therapies focused on the mutational aspects of TNBC.

Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo

OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate.

Non-anthracycline-containing docetaxel and cyclophosphamide regimen is associated with sustained worse outcome compared with docetaxel, anthracycline and cyclophosphamide in neoadjuvant treatment of triple negative and HER2-positive breast cancer patients:

Objective： A previous study demonstrated that non-anthracycline-containing docetaxel plus cyclophosphamide（TC） regimen was inferior to docetaxel, anthracycline and cyclophosphamide（TAC） in neoadjuvant treatment of triple-negative breast cancer（TNBC） and human epidermal growth factor receptor-2-（HER2）-positive breast cancer in a short-term follow-up. Herein, long-term follow-up survival outcomes have been investigated.Methods： TNBC or HER2-positive patients were randomized to receive 6 cycles of TC or TAC neoadjuvant treatment. The primary endpoint was pathological complete remission（p CR）. Secondary endpoints included clinical response rate, event-free survival（EFS）, and overall survival（OS）.Results： A cohort of 96 patients consisted of 45 in TC and 51 in TAC arm. With a median follow-up period of53（range, 8-76） months, the patients achieving p CR post neoadjuvant chemotherapy exhibited superior EFS and OS than patients without p CR（P〈0.05）. TAC treatment resulted in consistently better EFS than TC treatment：the estimated 5-year EFS was 66.1% vs. 29.8%（P=0.002）. Moreover, the estimated 5-year OS was also in favor of TAC： 88.4% vs. 51.6%（P〈0.001）. Multivariable analysis demonstrated that the treatment regimen was an independent prognostic factor, and patients treated with TAC had a superior EFS [hazard ratio（HR）, 0.48; 95%confidence interval（95% CI）, 0.26-0.90; P=0.021] and OS（HR, 0.20; 95% CI, 0.08-0.60; P=0.003）.Conclusions： The updated long-term follow-up data demonstrated a sustained benefit in EFS and OS from anthracycline-containing TAC treatment, indicating that anthracycline is an essential and effective drug in this clinical trial.

Overview of recent advances in metastatic triple negative breast cancer

Metastatic triple negative breast cancer(TNBC)has an aggressive phenotype with a predilection for visceral organs and brain.Best responses to chemotherapy are predominately in the first line.Recent studies have demonstrated improved progression free survival with the combination of atezolizumab/pembrolizumab and chemotherapy in programmed death-ligand 1 positive metastatic TNBC.However,a recent trial in a similar population showed no benefit for atezolizumab and paclitaxel which led to a Food and Drug Administration alert.Two phase III trials(OLYMPIAD and BROCADE3)demonstrated a benefit in progression free survival(PFS)but not overall survival in patients with BRCAassociated metastatic TNBC treated with Olaparib or Talazoparib respectively.For those treated with Talazoparib,the time to deterioration in health related-quality of life was also longer compared to chemotherapy.The BROCADE3 trial demonstrated that the combination of a platinum and veliparib increased PFS in first-line metastatic TNBC but at the cost of increased toxicity.There are no headto-head comparisons of a poly(adenosine diphosphate-ribose)polymerase inhibitors(PARPi)and platinums.There are unanswered questions regarding the role of PARPi maintenance after platinum therapy as is standard of care in BRCAassociated ovarian cancer.Other areas of therapeutic interest include targeting aberrations in the phosphoinositide 3-kinase pathway,protein kinase B,mammalian target of rapamycin or utilising antibody drug conjugates.This review focusses on recent and emerging therapeutic options in metastatic TNBC.We searched PubMed,clinicaltrials.gov and recent international meetings from American Society of Clinical Oncology,San Antonio Breast Cancer Conference and the European Society of Medical Oncology.

Metronomic chemotherapy for non-metastatic triple negative breast cancer: Selection is the key

Triple negative breast cancer(TNBC) accounts for 15%-20% of all breast cancer, and is still defined as what it is not. Currently, TNBC is the only type of breast cancer for which there are no approved targeted therapies and maximum tolerated dose chemotherapy with taxanes and anthracycline-containing regimens is still the standard of care in both the neoadjuvant and adjuvant settings. In the last years, metronomic chemotherapy(MC) is being explored as an alternative to improve outcomes in TNBC. In the neoadjuvant setting, purely metronomic and hybrid approaches have been developed with the objective of increasing complete pathologic response(p CR) and prolonging disease free survival. These regimens proved to be very effective achieving pC R rates between 47%-60%, but at the cost of great toxicity. In the adjuvant setting, MC is used to intensify adjuvant chemotherapy and, more promisingly, as maintenance therapy for high-risk patients, especially those with no pC R after neoadjuvant chemotherapy. Considering the dismal prognosis of TNBC, any strategy that potentially improves outcomes, specially being the oral agents broadly available and inexpensive, should be considered and certainly warrants further exploration. Finally, the benefit of MC needs to be validated in properly designed clinical trials were the selection of the population is the key.

RNA-seq analysis identified hormone-related genes associated with prognosis of triple negative breast cancer

Triple negative breast cancer(TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we performed a comprehensive differential analysis of 165 TNBC samples by integrating RNA-seq data of breast tumor tissues and adjacent normal tissues from both our cohort and The Cancer Genome Atlas(TCGA). Pathway enrichment analysis was conducted to evaluate the biological function of TNBC-specific expressed genes. Further multivariate Cox proportional hazard regression was performed to evaluate the effect of these genes on TNBC prognosis. In this report, we identified a total of 148 TNBC-specific expressed genes that were primarily enriched in mammary gland morphogenesis and hormone levels related pathways, suggesting that mammary gland morphogenesis might play a unique role in TNBC patients differing from other breast cancer types. Further survival analysis revealed that nine genes(FSIP1, ADCY5, FSD1, HMSD, CMTM5, AFF3, CYP2 A7, ATP1 A2,and C11 orf86) were significantly associated with the prognosis of TNBC patients, while three of them(ADCY5,CYP2 A7, and ATP1 A2) were involved in the hormone-related pathways. These findings indicated the vital role of the hormone-related genes in TNBC tumorigenesis and may provide some independent prognostic markers as well as novel therapeutic targets for TNBC.

BRCA1 and EGFR as prognostic biomarkers in triple negative metastatic breast cancer patients treated with cisplatin plus docetaxel

Objective： The triple negative （TN） metastatic breast cancer （MBC） patients are known to have worse prognosis, shorter progressive free survival （PFS）, and overall survival （OS）, that mandates using aggressive chemotherapy regimens. This phase II study aimed at investigating the efficacy and safety of using cisplatin and docetaxel in patients with triple negative metastatic breast cancer, and the possibility of using breast cancer susceptibility genel （BRCA1） expression as a predictive marker of chemotherapy response, and epidermal growth factor receptor （EGFR） as prognostic marker. Method： Between January 2006 and March 2009, 40 eligible patients with TN MBC were included in the study. We examined BRCA1 expression and EGFR protein in their specimens using immunohistochemistry. The patients were treated with cisplatin 75 mg/m2 and docetaxel 75 mg/m2 every 3 weeks, TN measurable MBC patients previously treated with anthracycline in their adjuvant or neo adjuvant settings were included in the study. Results： The median age of the treated patients was 43.5 years. Nearly half of the patients had an ECOG performance status of 0 or 1, and about third of them had one metastatic site. These metastatic sites were predominantly visceral in 80% of the patients. Fifty-five percent of TNMBC stained positive for BRCA1 and sixty-five percent for EGFR. Positivity for both markers was significantly associated with grade III tumors （P = 0.004）, OS, and PFS （P = 0.001 and 0.009） respectively. Overall, the regimen was well tolerated as Gill vomiting and neurological side effects were observed in 20% of the patients. Other toxiciUes were generally mild and medically manageable; with no treatment mortality was recorded. The overall disease control rate （ODCR） was 60%; the median PFS was 8 months, with a median overall OS of 17.5 months; while the median OS among responders was 23 months （95% CI 21.35 to 25.32）. The patients with negative EGFR had a significantly better OR, PFS, and OS than EGFR positive cases. There was no significant difference concerning OR, PFS, and OS, between positive and negative BRCA1 cases, which could be attributed to the better efficacy of cisplatin in the positive BRCA1 cases. Conclusion： This chemotherapy regimen is effective with tolerable toxicity profile, our results point out the importance of BRCA1 expression as predictive marker of chemotherapy response, and EGFR as prognostic marker, which could identify a certain group of patients with more aggressive disease who might benefit from using anti EGFR targeted therapy plus cisplatin.

Triple negative breast cancer: 5 years follow-up

Objective： The aim of the study was to investigate the long-term therapeutic effects of triple negative breast cancers （TNBCs） and find a standardized treatment. Methods： The clinical data and survival status of 69 patients with TNBC were collected, who were treated from 2003 to 2007 at Chongqing Cancer Institute, China. Results： Median observation for 61 months showed the local recurrence rate was 13.0% （9/69）, the overall survival （OS） rate was 76.8% （53/69） and the disease free survival （DFS） rate was 59.4% （41169）. Log-rank univariate survival analysis showed the OS and DFS rates of TNBCs with axillary lymph node metastasis were 38.1% and 23.8%, respectively, and the OS and DFS rates of triple negative breast cancer with axillary lymph node non-metastasis were 93.6% and 75.0%, respectively. There were significant differences comparing with two groups. Indictor analysis of age, menstruation status, tumor size, TNM stage, histological type, neoadjuvant chemotherapy and p53 did not show any prognostic influence. Conclusion： The axillary nodes metastasis is associated with DFS and OS in triple negative breast cancers. Cisplatin-based chemotherapy may be good choice for triple negative breast cancers with metastasis or local recurrence, who received Anthracycline and Taxane-based chemotherapy. Targeted therapies strategies such as EGFR-targeted therapy may be necessary.