BACKGROUND There is currently no effective targeted therapy for advanced HER2-negative gastric cancer(GC).While immunotherapy combined with chemotherapy is the first-line treatment for GC,patient survival outcomes rem...BACKGROUND There is currently no effective targeted therapy for advanced HER2-negative gastric cancer(GC).While immunotherapy combined with chemotherapy is the first-line treatment for GC,patient survival outcomes remain highly hetero-geneous,highlighting the urgent need for reliable predictive biomarkers.The fibrinogen-to-albumin ratio(FAR)integrates both inflammation(elevated fibrinogen levels)and nutritional status(reduced albumin levels).Although FAR has been associated with immunotherapy resistance in various solid tumors,its prognostic value in GC patients receiving immunochemotherapy remains unclear.AIM To assess the predictive value of the FAR in the long-term prognosis of advanced HER2-negative GC patients receiving sintilimab-based immunotherapy combined with chemotherapy.METHODS This retrospective study included 260 patients with unresectable or metastatic HER2-negative GC who received sintilimab plus chemotherapy from 2021 to 2024.Pre-treatment FAR values were calculated,and the optimal cutoff value was determined using receiver operating characteristic curve analysis.The association between the FAR and overall survival(OS)and progression-free survival(PFS)was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models.Independent prognostic factors were identified by multivariate Cox regression analysis based on OS,and a nomogram model was constructed incorporating FAR.The concordance index(C-index)and calibration curves were used to assess the predictive performance and calibration of the model.RESULTS Patients with high FAR(≥0.08)had significantly shorter median PFS[7.80 months(6.40-8.30)vs 10.00 months(9.30-11.20),P<0.001]and OS[14.20 months(12.20-16.60)vs 19.50 months(18.80-22.00),P<0.001]compared to the group with low FAR(<0.08).Moreover,the group with high FAR had a significantly lower objective response rate(10.22%vs 19.51%,P=0.034)and disease control rate(34.31%vs 49.59%,P=0.013).The incidence of adverse events did not significantly differ between the two groups(P>0.05).Multivariate analysis confirmed the FAR as an independent prognostic factor for OS(HR=2.33,95%CI:1.59-3.43,P<0.001).The nomogram model,incorporating FAR,Eastern Cooperative Oncology Group performance status,programmed cell death ligand 1 expression,tumor stage,and body mass index,demonstrated strong predictive accuracy,with an internal validation C-index of 0.73(95%CI:0.66-0.79).The calibration curve showed a high consistency between predicted and actual survival rates.CONCLUSION Patients with low FAR had significantly better prognostic outcomes than those with high FAR when receiving immunochemotherapy.Thus,FAR may serve as a valuable prognostic biomarker for predicting survival outcomes in patients with advanced HER2-negative GC.展开更多
Objective:Breast cancer(BC)with chest wall metastasis(CWM)usually shows rich neovascularization.This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2(HER2)-negative advanced B...Objective:Breast cancer(BC)with chest wall metastasis(CWM)usually shows rich neovascularization.This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2(HER2)-negative advanced BC involving CWM.Methods:This trial involved four centers in China and was conducted from September 2016 to March 2020.Patients received apatinib 500 mg/d[either alone or with endocrine therapy if hormone receptor-positive(HR+)]until disease progression or unacceptable toxicity.Progression-free survival(PFS)was the primary endpoint.Results:We evaluated 26 patients for efficacy.The median PFS(mPFS)and median overall survival(mOS)were4.9[range:2.0-28.5;95%confidence interval(95%CI):2.1-8.3]months and 18(range:3-55;95%CI:12.9-23.1)months,respectively.The objective response rate(ORR)was 42.3%(11/26),and the disease-control rate was76.9%(20/26).In the subgroup analysis,HR+patients compared with HR-negative patients had significantly improved mPFS of 7.0(95%CI:2.2-11.8)months vs.2.3(95%CI:1.2-3.4)months,respectively(P=0.001);and mPFS in patients without or with chest wall radiotherapy was 6.4(95%CI:1.6-19.5)months vs.3.0(95%CI:1.3-4.6)months,respectively(P=0.041).In the multivariate analysis,HR+status was the only independent predictive factor for favorable PFS(P=0.014).Conclusions:Apatinib was highly effective for BC patients with CWM,especially when combined with endocrine therapy.PFS improved significantly in patients with HR+status who did not receive chest wall radiotherapy.However,adverse events were serious and should be carefully monitored from the beginning of apatinib treatment.展开更多
Objective: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption. Adding ZOL to neoadjuvant chemotherapy has been shown to have potential anticanc...Objective: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption. Adding ZOL to neoadjuvant chemotherapy has been shown to have potential anticancer benefits in women with HER2-negative breast cancer. The objective of the present study was to investigate ZOL’s cost-effectiveness from the perspective of health care payers in Japan. Methods: A Markov model was developed to evaluate the costs and effectiveness associated with ZOL + chemotherapy (CTZ) and chemotherapy (CT) alone over a 10-year time horizon. Monthly transition probabilities were estimated according to JONIE1 (Japan Organization of Neoadjuvant Innovative Expert) Study data and an extrapolated Weibull model. Health outcomes were measured in quality-adjusted life years (QALYs). Costs were calculated using year-2018 Japanese yen (JPY) (1.00 US dollars (USD) = 110.4 JPY). Model robustness was addressed through one-way and probabilistic sensitivity analysis. The costs and QALYs were discounted at a rate of 2% per year. Results: In the base case, the use of CTZ was associated with a gain of 3.94 QALYs. The incremental cost per QALY of the CTZ gain was 681,056.1 JPY (6168.99 USD) per QALY. Conclusion: It is convincing that neoadjuvant CTZ for patients with breast cancer would be expected to have statistically significant clinical efficacy. Addition of ZOL to CT might be a cost-effective option compared with CT alone.展开更多
Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and...Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and it is usually treated with anti-oestrogen drugs. However, the majority of hormone receptor positive metastatic BC patients develop resistance to anti-oestrogen treatments.The need for more down-stream therapies brought to the development of therapeutic strategies inhibiting the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) pathway. Inhibitors of the mTOR have been tested in different clinical trials; everolimus has been Food and Drug Administration approved for the treatment of oestrogen receptor positive/human epidermal growth factor receptor 2 negative BC patients in combination with exemestane in patients who have progressed to anastrozole or letrozole after the encouraging results coming from BOLERO-2 trial. Similar results were obtained by the TAMRAD investigatory study testing tamoxifen in combination with everolimus in advanced BC. This editorial focuses on the results from BOLERO-2, BOLERO 4 and BOLERO-6, which tested the clinical importance of mTOR inhibition. We comment also on the role of phosphatidylinositol 3-kinase-mTOR inhibition as reported in the BELLE-2 and BELLE-3 trials and the future directions for the inhibition of this tumour metabolic axis.展开更多
AIM： To address the role of CD209 in celiac disease （CD） patients. Non-human leukocyte antigen （HLA） genetic factors in CD predisposition are poorly understood, and environmental factors like infectious pathogens...AIM： To address the role of CD209 in celiac disease （CD） patients. Non-human leukocyte antigen （HLA） genetic factors in CD predisposition are poorly understood, and environmental factors like infectious pathogens may play a role. CD209 is a dendritic and macrophage surface molecule involved in pathogen recognition and immune activation. Recently, a functional variant in the promoter of the CD209 gene （-336A/G） has been shown to affect the transcriptional CD209 activity in vitro and it has been associated with a higher susceptibility to/or severity of infection. METHODS： The study population was composed of two case-control cohorts of 103 and 386 CD patients and 312 y 419 healthy controls as well as a panel of 257 celiac families. Genotyping for the -336A/G CD209 promoter polymorphism was performed using a TaqMan 5＇ allelic discrimination assay. HLA-DQ was determined by hybridization with allele specific probes. RESULTS： Initially, the case-control and familial studies did not find any association of the -336 A/G CD209 genetic variant with CD susceptibility. However, the stratification by HLA-DQ2 did reveal a significant association of CD209 promoter polymorphism in the HLA-DQ2 （-） group （carrier A vs GG in DQ2 （-） vs DQ2 （＋） patients （P = 0.026, OR = 3.71）. CONCLUSION： The -336G CD209 allele seems to be involved in CD susceptibility in HLA-DQ2 （-） patients. Our results might suggest a possible role of pathogens in the onset of a minor group of CD patients.展开更多
Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-neg...Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2−)breast cancer remain unclear.Methods:We retrospectively collected mammography records of an HR+/HER2−breast cancer cohort(n=316)with matched clinicopathological,genomic,transcriptomic,and metabolomic data.On the basis of mammographic images,we grouped tumors by calcification status into calcification-negative tumors,tumors with probably benign calcifications,tumors with calcification of lowmoderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy.We then explored the molecular characteristics associated with each calcification status across multiple dimensions.Results:Among the different statuses,tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores,estrogen receptor(ER)pathway activation,lipid metabolism,and sensitivity to endocrine therapy.Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes,elevated lymph node metastasis incidence,Ki-67 staining scores,genomic instability,cell cycle pathway activation,and may benefit from cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors.Conclusions:Our research established links between tumor calcifications and molecular features,thus proposing potential precision treatment strategies for HR+/HER2−breast cancer.展开更多
The purpose of this study was to investigate the efficacy and safety of chidamide combined with paclitaxel liposome in the treatment of advanced HER-2-negative breast cancer.First,41 patients with advanced HER-2-negat...The purpose of this study was to investigate the efficacy and safety of chidamide combined with paclitaxel liposome in the treatment of advanced HER-2-negative breast cancer.First,41 patients with advanced HER-2-negative breast cancer who had received two chemotherapy regimens from May 2017 to November 2017 were randomly selected to receive chidamide combined with paclitaxel liposome treatment(observation group,n=20)or placebo combined with paclitaxel liposome treatment(control group,n=21).The treatment scheme of the observation group was oral chidamide 30mg twice a week for 2 months.In addition,on day 1,the patients were given paclitaxel liposome orally and intravenously administered with 175 mg/m2 for 1 cycle for 21 days and 3 cycles of chemotherapy.The treatment scheme of the control group was oral placebo 30 mg twice a week for 2 months.In addition,the method of paclitaxel liposome administration was the same as the observation group.The response rate(RR),disease control rate(DCR),and progression-free survival(PFS)were compared between the two groups.The results showed that all the 41 patients could be evaluated.In the observation group,CR5,PR7,SD5 and PD3 were obtained.RR was 60.0%and DCR was 85.0%.In the control group,CR3,PR3,SD5 and PD10 were obtained.RR was 28.6%and DCR was 52.4%.RR and DCR in the observation group were better than those in the control group,and the difference was statistically significant(P<0.05).The median PFS of the observation group was 5.2 months,longer than that of the control group(3.1 months,P<0.05).The main adverse reactions in the two groups were gastrointestinal reactions and bone marrow suppression,with grade 1~2 as the main ones.The incidence of leukopenia,thrombocytopenia and nausea and vomiting in the observation group was higher than that in the control group(P<0.05).Therefore,the chidamide combined with paclitaxel liposome is effective in the treatment of advanced HER-2-negative breast cancer,and the adverse reactions can be tolerated.展开更多
Objective:Triple-negative breast cancer(TNBC)is highly aggressive and lacks an effective targeted therapy.This study aimed to elucidate the functions and possible mechanisms of action of zinc finger miz-type containin...Objective:Triple-negative breast cancer(TNBC)is highly aggressive and lacks an effective targeted therapy.This study aimed to elucidate the functions and possible mechanisms of action of zinc finger miz-type containing 2(ZMIZ2)and minichromosome maintenance complex component 3(MCM3)in TNBC progression.Methods:The relationship between ZMIZ2 expression and clinical characteristics of TNBC was investigated.In vitro and in vivo experiments were performed to investigate the role of ZMIZ2 dysregulation in TNBC cell malignant behaviors.The regulatory relationship between ZMIZ2 and MCM3 was also explored.Transcriptome sequencing was performed to elucidate possible mechanisms underlying the ZMIZ2/MCM3 axis in TNBC.Results:High ZMIZ2 expression levels were associated with the malignant degree of TNBC.ZMIZ2 overexpression promoted TNBC cell proliferation,migration,and invasion;inhibited apoptosis;and induced G1 phase cell cycle arrest,whereas knockdown of ZMIZ2 had the opposite effect.ZMIZ2 directly targeted and positively regulated MCM3 expression.MCM3 knockdown reversed the effect of ZMIZ2 overexpression on TNBC tumor growth both in vitro and in vivo.High MCM3 expression levels were linked to the degree of malignancy and poor prognosis in TNBC.The differentially expressed genes associated with the ZMIZ2/MCM3 axis were significantly enriched in multiple pathways,such as the mitogen-activated protein kinase(MAPK),mechanistic target of rapamycin(mTOR),Wnt,and Ras signaling pathways,as verified by The Cancer Genome Atlas data.Conclusions:ZMIZ2 and MCM3 were highly expressed in TNBC.ZMIZ2 promoted the development by positively regulating MCM3 expression.Key pathways,such as the Ras/MAPK,phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mTOR,and Wnt signaling pathways,may be key downstreammechanisms.展开更多
Background:The standard adjuvant chemotherapy for early-stage,high-risk breast cancer includes anthracyclines and taxanes.While anthracycline-based regimens have proven effective in human epidermal growth factor recep...Background:The standard adjuvant chemotherapy for early-stage,high-risk breast cancer includes anthracyclines and taxanes.While anthracycline-based regimens have proven effective in human epidermal growth factor receptor 2(HER2)-positive breast cancer,their efficacy may be reduced in HER2-negative patients due to the lack of co-amplification of DNA topoisomerase IIα,the primary target of anthracyclines.This study compared the efficacy and safety of the regimen of docetaxel,anthracycline,and cyclophosphamide(TAC)versus a novel regimen consisting of docetaxel,cyclophosphamide,and capecitabine(TCX),hypothesizing that replacement of anthracycline with capecitabine could offer superior outcomes in this patient population.Methods:In this open-label,randomized controlled trial,204 patients with pT1-3,node-positive or high-risk node-negative,HER2-negative early-stage breast cancer were enrolled between May 2011 and December 2013(ClinicalTrials.gov:NCT01354522).Patients were randomized 2:1 to TAC(n=136)or TCX(n=68),with treatment administered every 21 days for six cycles.The primary endpoints were disease-free survival(DFS)and overall survival(OS);secondary endpoints included distant disease-free survival(DDFS),disease-specific survival(DSS),and adverse event(AE)rates.Results:With a median follow-up of 124.4(range,19.5-147.8)months,TCX did not significantly improve the 10-year DFS rate over TAC(71.5%±5.6%vs.67.6%±4.0%,P=0.477).However,the 10-year OS rate was significantly higher in the TCX group than in the TAC group(91.0%±3.5%vs.77.2%±3.6%,P=0.009).The TCX group also showed trends toward improved 10-year DDFS rate(82.0%±4.7%vs.69.8%±3.9%,P=0.052)and significantly higher 10-year DSS rate(93.9%±3.0%vs.77.8%±3.6%,P=0.002)compared to the TAC group.Grade 3-4 AEs occurred significantly more often in the TAC group than the TCX group(67.7%vs.42.7%,P=0.001).Conclusion:TCX may provide superior long-term survival and a more favorable safety profile compared to TAC for patients with high-risk HER2-negative breast cancer,warranting further investigation in larger cohorts.展开更多
BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes...BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.展开更多
Background:Bireociclib(XZP-3287)is a novel selective cyclin-dependent kinase 4 and 6(CDK4/6)inhibitor,with a favorable safety profile demonstrated in preclinical and phase I studies.BRIGHT-1 aimed to further explore t...Background:Bireociclib(XZP-3287)is a novel selective cyclin-dependent kinase 4 and 6(CDK4/6)inhibitor,with a favorable safety profile demonstrated in preclinical and phase I studies.BRIGHT-1 aimed to further explore the efficacy and safety of bireociclib monotherapy in patients with locally advanced,recurrent or metastatic,hormone receptor-positive and human epidermal growth factor receptor 2-negative(HR+/HER2−)breast cancer who had progressed on or after prior chemotherapy and endocrine therapy in advanced settings,without previous exposure to CDK4/6 inhibitors.Methods:In this open-label phase II trial,eligible patients received bireociclib 480 mg twice daily(BID)until disease progression or intolerable toxicities.The primary endpoint was the confirmed objective response rate(ORR)assessed by an independent review committee(IRC).The secondary endpoints included progression-free survival(PFS),investigator-assessed ORR,disease control rate(DCR),clinical benefit rate(CBR),duration of response(DoR),overall survival(OS),safety and the pharmacokinetic properties of bireociclib.Results:A total of 131 patients were enrolled.At data cutoff(July 31,2023),the IRC-assessed ORR was 29.8%(95%confidence interval[CI],22.1%to 38.4%),with a DCR of 73.3%(95%CI,64.8%to 80.6%),CBR of 42.0%(95%CI,33.4%to 50.9%)and a median DoR of 15.2 months(95%CI,9.5 months to not reached).The median PFS was 11.0 months(95%CI,7.3 months to 12.9 months)assessed by the IRC,and the median OS was 29.0 months(95%CI,24.9 months to not reached).The most frequently reported treatment-emergent adverse events(TEAEs)of any grade were diarrhea(93.1%),neutrophil count decreased(87.0%),white blood cell decreased(86.3%),vomiting(78.6%),anemia(72.5%),and platelet count decreased(72.5%).The grade≥3 TEAEs occurred in 109(83.2%)patients.The most common grade≥3 TEAEs were neutrophil count decreased(43.5%),white blood cell decreased(32.8%),hypokalemia(20.6%),and diarrhea(19.1%).Conclusions:Bireociclib monotherapy at 480 mg BID exhibited promising and sustained clinical activity,with no unexpected and acceptable toxicity in patients with recurrent or metastatic HR+/HER2−breast cancer who had progressed on or after previous therapy.Trial registration:Clinicaltrials.gov ID,NCT04539496.展开更多
Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits syntheti...Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase(PARP)inhibitors in ovarian cancer.However,the role of SIC-19 in triplenegative breast cancer(TNBC)and pancreatic cancer(PC)remains poorly defined.This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC.Methods:Cell lines with high SIK2 expression were identified through Western blot analysis.The combination’s impact was evaluated using Cell Counting Kit-8(CCK8),clone formation,and apoptosis assays,as well as in vivo xenograft models.Results:Our findings indicated that the IC50 of SIC-19 was inversely correlated with endogenous SIK2 expression in TNBC and PC cell lines.SIC-19 modulates the homologous recombination repair pathway by suppressing levels of RAD50-pS635,thereby enhancing the sensitivity of TNBC and PC cells,as well as xenografts,to PARP inhibitors.Conclusion:These results underscore the potential of combining PARP inhibitors in combination with SIK2 inhibitors as a novel therapeutic approach to increase PARP inhibition’s effectiveness in treating TNBC and PC.This innovative combination therapy represents a promising approach for overcoming resistance mechanisms and improving the outcomes for patients with these challenging malignancies.展开更多
Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autoph...Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.展开更多
Background： Current understanding of tumor biology suggests that breast cancer is a group of diseases with different intrinsic molecular subtypes. Anatomic staging system alone is insufficient to provide future outco...Background： Current understanding of tumor biology suggests that breast cancer is a group of diseases with different intrinsic molecular subtypes. Anatomic staging system alone is insufficient to provide future outcome information. The American Joint Committee on Cancer （AJCC） expert panel updated the 8th edition of the staging manual with prognostic stage groups by incorporating biomarkers into the anatomic stage groups. In this study, we retrospectively analyzed the data from our center in China using the anatomic and prognostic staging system based on the AJCC 8th edition staging manual. Methods： We reviewed the data from January 2008 to December 2014 for cases with Luminal B Human Epidermal Growth Factor Receptor 2 （HER2）-negative breast cancer in our center. All cases were restaged using the AJCC 8th edition anatomic and prognostic staging system. The Kaplan-Meier method and log-rank test were used to compare the survival differences between different subgroups. SPSS software version 19.0 （IBM Corp., Armonk, NY, USA） was used for the statistical analyses. Results： This study consisted of 796 patients with Luminal B HER-negative breast cancer. The 5-year disease-free survival （DFS） of 769 Stage I-III patients was 89.7%, and the 5-year overall survival （OS） of all 796 patients was 91.7%. Both 5-year DFS and 5-year OS were significantly different in the different anatomic and prognostic stage groups, There were 372 cases （46.7%） assigned to a different group. The prognostic Stage II and III patients restaged from anatomic Stage III had significant differences in 5-year DFS （v2 = 11.319; P = 0.001） and 5-year OS （χ2 = 5.225, P = 0.022）. In addition, cases restaged as prognostic Stage I, II, or III from the anatomic Stage II group had statistically significant differences in 5-year DFS （χ2 = 6.510, P = 0.039） but no significant differences in 5-year OS （χ2 = 5.087, P = 0.079）. However, the restaged prognostic Stage I and II cases from anatomic Stage I had no statistically significant differences in either 5-year DFS （χ2 = 0.440, P = 0.507） or 5-year OS （χ2= 1.530, P = 0.216）. Conclusions： The prognostic staging system proposed in the AJCC 8th edition refines the anatomic stage group in Luminal B HER2-negative breast cancer and will lead to a more personalized approach to breast cancer treatment.展开更多
Background:Endocrine therapy(ET)and ET-based regimens are the preferred first-line treatment options for hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative metastatic breast canc...Background:Endocrine therapy(ET)and ET-based regimens are the preferred first-line treatment options for hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative metastatic breast cancer(HR+/HER2-MBC),while chemotherapy(CT)is commonly used in clinical practice.The aim of this study was to investigate the efficacy and clinical outcome of ET and CT as first-line treatment in Chinese patients with HR+/HER2-MBC.Methods:Patients diagnosed with HR+/HER2-MBC between January 1st,1996 and September 30th,2018 were screened from the Chinese Society of Clinical Oncology Breast Cancer database.The initial and maintenance first-line treatment,progression-free survival(PFS),and overall survival(OS)were analyzed.Results:Among the 1877 included patients,1215(64.7%)received CT and 662(35.3%)received ET as initial first-line treatment.There were no statistically significant differences in PFS and OS between patients receiving ET and CT as initial first-line treatment in the total population(PFS:12.0 vs.11.0 months,P=0.22;OS:54.0 vs.49.0 months,P=0.09)and propensity score matched population.For patients without disease progression after at least 3 months of initial therapy,maintenance ET following initial CT(CT-ET cohort,n=449)and continuous schedule of ET(ET cohort,n=527)had longer PFS than continuous schedule of CT(CT cohort,n=406)in the total population(CT-ET cohort vs.CT cohort:17.0 vs.8.5 months;P<0.01;ET cohort vs.CT cohort:14.0 vs.8.5 months;P<0.01)and propensity score matched population.OS in the three cohorts yielded the same results as PFS.Conclusions:ET was associated with similar clinical outcome to CT as initial first-line treatment.For patients without disease progression after initial CT,switching to maintenance ET showed superiority in clinical outcome over continuous schedule of CT.展开更多
Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological fu...Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological function of OTUB2 in TNBC and uncover the underlying mechanisms.Methods:First,we found that the expression of OTUB2 was upregulated in TNBC by bioinformatics analysis,we then validated its expression in TNBC tissues and cells using immunohistochemistry(IHC)and qPCR and plotted the survival curves by Kaplan-Meier method.Gene set enrichment analysis(GSEA)suggested that OTUB2 may be involved in tumor proliferation and metastasis.Further functional assays,including Cell Counting Kit-8(CCK-8),colony formation,Transwell,and wound healing assays,were performed to assess the effects of OTUB2 overexpression and knockdown on TNBC cell proliferation and migration.Additionally,UbiBrowser 2.0 was used to identify OTUB2 substrate proteins and western blotting was conducted to clarify the molecular mechanisms involved.Results:Our results demonstrated that OTUB2 expression was elevated in TNBC and associated with poor prognosis.Overexpression of OTUB2 enhanced the proliferation and migration of TNBC cells,while its knockdown inhibited these processes.Moreover,OTUB2 stabilized tumor necrosis factor receptor-associated factor 6(TRAF6)by deubiquitinating it,leading to activation of the protein kinase B(AKT)pathway.Conclusions:OTUB2 exerts its promoting effects on the progression of TNBC by activating the TRAF6/AKT pathway.展开更多
Background:Cyclin-dependent kinase 4/6(CDK4/6)inhibitors have transformed the management of hormone receptor–positive/HER2–negative(HR+/HER2–)advanced breast cancer,yet evidence for elderly or poor-performance pati...Background:Cyclin-dependent kinase 4/6(CDK4/6)inhibitors have transformed the management of hormone receptor–positive/HER2–negative(HR+/HER2–)advanced breast cancer,yet evidence for elderly or poor-performance patients remains limited.This study examined real-world outcomes of palbociclib plus endocrine therapy in Asian patients,with additional subgroup analyses by age and performance status.Methods:We retrospectively analyzed 46 consecutive Asian patients with recurrent or de novo HR+/HER2−breast cancer treated with first-line palbociclib plus ET between April 2021 and March 2025.The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall response rate(ORR),disease control rate(DCR),and safety.Subgroup analyses were performed by age(<70 vs.≥70 years)and performance status(PS;0–1 vs.2–3).Results:The median PFS was 26.6 months(range,1.4–69.5).Stratified by age,median PFS was 26.9 months in patients<70 years and 26.2 months in those≥70 years(p=0.760).By PS,PFS was 26.9 months for PS 0–1 and 17.8 months for PS 2–3(p=0.099).ORR was 60.9%and DCR 93.5%;notably,all PS 2–3 patients achieved disease control.Hematologic toxicities were common,with neutropenia(80.4%)and leukopenia(86.7%)predominating,but grade≥3 anemia was rare(2.2%).Elderly patients experienced anemia more frequently,while overall toxicity remained manageable.Dose reductions occurred in 47.8%without loss of efficacy.Conclusions:In routine Japanese practice,palbociclib plus ET provided prolonged PFS and high disease control consistent with pivotal trials and international real-world evidence.Importantly,elderly patients tolerated treatment well,and selected PS 2–3 patients also derived clinical benefit.These findings indicate that neither age nor PS alone should preclude the use of palbociclib in carefully monitored real-world patients.展开更多
文摘BACKGROUND There is currently no effective targeted therapy for advanced HER2-negative gastric cancer(GC).While immunotherapy combined with chemotherapy is the first-line treatment for GC,patient survival outcomes remain highly hetero-geneous,highlighting the urgent need for reliable predictive biomarkers.The fibrinogen-to-albumin ratio(FAR)integrates both inflammation(elevated fibrinogen levels)and nutritional status(reduced albumin levels).Although FAR has been associated with immunotherapy resistance in various solid tumors,its prognostic value in GC patients receiving immunochemotherapy remains unclear.AIM To assess the predictive value of the FAR in the long-term prognosis of advanced HER2-negative GC patients receiving sintilimab-based immunotherapy combined with chemotherapy.METHODS This retrospective study included 260 patients with unresectable or metastatic HER2-negative GC who received sintilimab plus chemotherapy from 2021 to 2024.Pre-treatment FAR values were calculated,and the optimal cutoff value was determined using receiver operating characteristic curve analysis.The association between the FAR and overall survival(OS)and progression-free survival(PFS)was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models.Independent prognostic factors were identified by multivariate Cox regression analysis based on OS,and a nomogram model was constructed incorporating FAR.The concordance index(C-index)and calibration curves were used to assess the predictive performance and calibration of the model.RESULTS Patients with high FAR(≥0.08)had significantly shorter median PFS[7.80 months(6.40-8.30)vs 10.00 months(9.30-11.20),P<0.001]and OS[14.20 months(12.20-16.60)vs 19.50 months(18.80-22.00),P<0.001]compared to the group with low FAR(<0.08).Moreover,the group with high FAR had a significantly lower objective response rate(10.22%vs 19.51%,P=0.034)and disease control rate(34.31%vs 49.59%,P=0.013).The incidence of adverse events did not significantly differ between the two groups(P>0.05).Multivariate analysis confirmed the FAR as an independent prognostic factor for OS(HR=2.33,95%CI:1.59-3.43,P<0.001).The nomogram model,incorporating FAR,Eastern Cooperative Oncology Group performance status,programmed cell death ligand 1 expression,tumor stage,and body mass index,demonstrated strong predictive accuracy,with an internal validation C-index of 0.73(95%CI:0.66-0.79).The calibration curve showed a high consistency between predicted and actual survival rates.CONCLUSION Patients with low FAR had significantly better prognostic outcomes than those with high FAR when receiving immunochemotherapy.Thus,FAR may serve as a valuable prognostic biomarker for predicting survival outcomes in patients with advanced HER2-negative GC.
文摘Objective:Breast cancer(BC)with chest wall metastasis(CWM)usually shows rich neovascularization.This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2(HER2)-negative advanced BC involving CWM.Methods:This trial involved four centers in China and was conducted from September 2016 to March 2020.Patients received apatinib 500 mg/d[either alone or with endocrine therapy if hormone receptor-positive(HR+)]until disease progression or unacceptable toxicity.Progression-free survival(PFS)was the primary endpoint.Results:We evaluated 26 patients for efficacy.The median PFS(mPFS)and median overall survival(mOS)were4.9[range:2.0-28.5;95%confidence interval(95%CI):2.1-8.3]months and 18(range:3-55;95%CI:12.9-23.1)months,respectively.The objective response rate(ORR)was 42.3%(11/26),and the disease-control rate was76.9%(20/26).In the subgroup analysis,HR+patients compared with HR-negative patients had significantly improved mPFS of 7.0(95%CI:2.2-11.8)months vs.2.3(95%CI:1.2-3.4)months,respectively(P=0.001);and mPFS in patients without or with chest wall radiotherapy was 6.4(95%CI:1.6-19.5)months vs.3.0(95%CI:1.3-4.6)months,respectively(P=0.041).In the multivariate analysis,HR+status was the only independent predictive factor for favorable PFS(P=0.014).Conclusions:Apatinib was highly effective for BC patients with CWM,especially when combined with endocrine therapy.PFS improved significantly in patients with HR+status who did not receive chest wall radiotherapy.However,adverse events were serious and should be carefully monitored from the beginning of apatinib treatment.
文摘Objective: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption. Adding ZOL to neoadjuvant chemotherapy has been shown to have potential anticancer benefits in women with HER2-negative breast cancer. The objective of the present study was to investigate ZOL’s cost-effectiveness from the perspective of health care payers in Japan. Methods: A Markov model was developed to evaluate the costs and effectiveness associated with ZOL + chemotherapy (CTZ) and chemotherapy (CT) alone over a 10-year time horizon. Monthly transition probabilities were estimated according to JONIE1 (Japan Organization of Neoadjuvant Innovative Expert) Study data and an extrapolated Weibull model. Health outcomes were measured in quality-adjusted life years (QALYs). Costs were calculated using year-2018 Japanese yen (JPY) (1.00 US dollars (USD) = 110.4 JPY). Model robustness was addressed through one-way and probabilistic sensitivity analysis. The costs and QALYs were discounted at a rate of 2% per year. Results: In the base case, the use of CTZ was associated with a gain of 3.94 QALYs. The incremental cost per QALY of the CTZ gain was 681,056.1 JPY (6168.99 USD) per QALY. Conclusion: It is convincing that neoadjuvant CTZ for patients with breast cancer would be expected to have statistically significant clinical efficacy. Addition of ZOL to CT might be a cost-effective option compared with CT alone.
基金Supported by Ricerca Sanitaria LILT 2015Beneficentia Foundation Stiftung,No.BEN2016/16 grants
文摘Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and it is usually treated with anti-oestrogen drugs. However, the majority of hormone receptor positive metastatic BC patients develop resistance to anti-oestrogen treatments.The need for more down-stream therapies brought to the development of therapeutic strategies inhibiting the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) pathway. Inhibitors of the mTOR have been tested in different clinical trials; everolimus has been Food and Drug Administration approved for the treatment of oestrogen receptor positive/human epidermal growth factor receptor 2 negative BC patients in combination with exemestane in patients who have progressed to anastrozole or letrozole after the encouraging results coming from BOLERO-2 trial. Similar results were obtained by the TAMRAD investigatory study testing tamoxifen in combination with everolimus in advanced BC. This editorial focuses on the results from BOLERO-2, BOLERO 4 and BOLERO-6, which tested the clinical importance of mTOR inhibition. We comment also on the role of phosphatidylinositol 3-kinase-mTOR inhibition as reported in the BELLE-2 and BELLE-3 trials and the future directions for the inhibition of this tumour metabolic axis.
基金Supported by the Spanish Ministerio de Educatión, Ciencia y Tecnología, SAF 2003-08522
文摘AIM： To address the role of CD209 in celiac disease （CD） patients. Non-human leukocyte antigen （HLA） genetic factors in CD predisposition are poorly understood, and environmental factors like infectious pathogens may play a role. CD209 is a dendritic and macrophage surface molecule involved in pathogen recognition and immune activation. Recently, a functional variant in the promoter of the CD209 gene （-336A/G） has been shown to affect the transcriptional CD209 activity in vitro and it has been associated with a higher susceptibility to/or severity of infection. METHODS： The study population was composed of two case-control cohorts of 103 and 386 CD patients and 312 y 419 healthy controls as well as a panel of 257 celiac families. Genotyping for the -336A/G CD209 promoter polymorphism was performed using a TaqMan 5＇ allelic discrimination assay. HLA-DQ was determined by hybridization with allele specific probes. RESULTS： Initially, the case-control and familial studies did not find any association of the -336 A/G CD209 genetic variant with CD susceptibility. However, the stratification by HLA-DQ2 did reveal a significant association of CD209 promoter polymorphism in the HLA-DQ2 （-） group （carrier A vs GG in DQ2 （-） vs DQ2 （＋） patients （P = 0.026, OR = 3.71）. CONCLUSION： The -336G CD209 allele seems to be involved in CD susceptibility in HLA-DQ2 （-） patients. Our results might suggest a possible role of pathogens in the onset of a minor group of CD patients.
基金supported by grants from the National Key Research and Development Project of China(Grant No.2020YFA0112304)the National Natural Science Foundation of China(Grant Nos.81922048,82072922,91959207,and 92159301)+3 种基金the Program of Shanghai Academic/Technology Research Leader(Grant No.20XD1421100)the Shanghai Key Laboratory of Breast Cancer(Grant No.12DZ2260100)the Clinical Research Plan of SHDC(Grant Nos.SHDC2020CR4002 and SHDC2020CR5005)the SHDC Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals(Grant No.SHDC12021103).
文摘Objective:Mammographic calcifications are a common feature of breast cancer,but their molecular characteristics and treatment implications in hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2−)breast cancer remain unclear.Methods:We retrospectively collected mammography records of an HR+/HER2−breast cancer cohort(n=316)with matched clinicopathological,genomic,transcriptomic,and metabolomic data.On the basis of mammographic images,we grouped tumors by calcification status into calcification-negative tumors,tumors with probably benign calcifications,tumors with calcification of lowmoderate suspicion for maligancy and tumors with calcification of high suspicion for maligancy.We then explored the molecular characteristics associated with each calcification status across multiple dimensions.Results:Among the different statuses,tumors with probably benign calcifications exhibited elevated hormone receptor immunohistochemical staining scores,estrogen receptor(ER)pathway activation,lipid metabolism,and sensitivity to endocrine therapy.Tumors with calcifications of high suspicion for malignancy had relatively larger tumor sizes,elevated lymph node metastasis incidence,Ki-67 staining scores,genomic instability,cell cycle pathway activation,and may benefit from cyclin-dependent kinase 4 and 6(CDK4/6)inhibitors.Conclusions:Our research established links between tumor calcifications and molecular features,thus proposing potential precision treatment strategies for HR+/HER2−breast cancer.
文摘The purpose of this study was to investigate the efficacy and safety of chidamide combined with paclitaxel liposome in the treatment of advanced HER-2-negative breast cancer.First,41 patients with advanced HER-2-negative breast cancer who had received two chemotherapy regimens from May 2017 to November 2017 were randomly selected to receive chidamide combined with paclitaxel liposome treatment(observation group,n=20)or placebo combined with paclitaxel liposome treatment(control group,n=21).The treatment scheme of the observation group was oral chidamide 30mg twice a week for 2 months.In addition,on day 1,the patients were given paclitaxel liposome orally and intravenously administered with 175 mg/m2 for 1 cycle for 21 days and 3 cycles of chemotherapy.The treatment scheme of the control group was oral placebo 30 mg twice a week for 2 months.In addition,the method of paclitaxel liposome administration was the same as the observation group.The response rate(RR),disease control rate(DCR),and progression-free survival(PFS)were compared between the two groups.The results showed that all the 41 patients could be evaluated.In the observation group,CR5,PR7,SD5 and PD3 were obtained.RR was 60.0%and DCR was 85.0%.In the control group,CR3,PR3,SD5 and PD10 were obtained.RR was 28.6%and DCR was 52.4%.RR and DCR in the observation group were better than those in the control group,and the difference was statistically significant(P<0.05).The median PFS of the observation group was 5.2 months,longer than that of the control group(3.1 months,P<0.05).The main adverse reactions in the two groups were gastrointestinal reactions and bone marrow suppression,with grade 1~2 as the main ones.The incidence of leukopenia,thrombocytopenia and nausea and vomiting in the observation group was higher than that in the control group(P<0.05).Therefore,the chidamide combined with paclitaxel liposome is effective in the treatment of advanced HER-2-negative breast cancer,and the adverse reactions can be tolerated.
基金supported by the Jilin Province Health Science and Technology Ability Improvement Project(2023JL057).
文摘Objective:Triple-negative breast cancer(TNBC)is highly aggressive and lacks an effective targeted therapy.This study aimed to elucidate the functions and possible mechanisms of action of zinc finger miz-type containing 2(ZMIZ2)and minichromosome maintenance complex component 3(MCM3)in TNBC progression.Methods:The relationship between ZMIZ2 expression and clinical characteristics of TNBC was investigated.In vitro and in vivo experiments were performed to investigate the role of ZMIZ2 dysregulation in TNBC cell malignant behaviors.The regulatory relationship between ZMIZ2 and MCM3 was also explored.Transcriptome sequencing was performed to elucidate possible mechanisms underlying the ZMIZ2/MCM3 axis in TNBC.Results:High ZMIZ2 expression levels were associated with the malignant degree of TNBC.ZMIZ2 overexpression promoted TNBC cell proliferation,migration,and invasion;inhibited apoptosis;and induced G1 phase cell cycle arrest,whereas knockdown of ZMIZ2 had the opposite effect.ZMIZ2 directly targeted and positively regulated MCM3 expression.MCM3 knockdown reversed the effect of ZMIZ2 overexpression on TNBC tumor growth both in vitro and in vivo.High MCM3 expression levels were linked to the degree of malignancy and poor prognosis in TNBC.The differentially expressed genes associated with the ZMIZ2/MCM3 axis were significantly enriched in multiple pathways,such as the mitogen-activated protein kinase(MAPK),mechanistic target of rapamycin(mTOR),Wnt,and Ras signaling pathways,as verified by The Cancer Genome Atlas data.Conclusions:ZMIZ2 and MCM3 were highly expressed in TNBC.ZMIZ2 promoted the development by positively regulating MCM3 expression.Key pathways,such as the Ras/MAPK,phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mTOR,and Wnt signaling pathways,may be key downstreammechanisms.
基金National High Level Hospital Clinical Research Funding,Grant/Award Number:2022-PUMCH-B-038。
文摘Background:The standard adjuvant chemotherapy for early-stage,high-risk breast cancer includes anthracyclines and taxanes.While anthracycline-based regimens have proven effective in human epidermal growth factor receptor 2(HER2)-positive breast cancer,their efficacy may be reduced in HER2-negative patients due to the lack of co-amplification of DNA topoisomerase IIα,the primary target of anthracyclines.This study compared the efficacy and safety of the regimen of docetaxel,anthracycline,and cyclophosphamide(TAC)versus a novel regimen consisting of docetaxel,cyclophosphamide,and capecitabine(TCX),hypothesizing that replacement of anthracycline with capecitabine could offer superior outcomes in this patient population.Methods:In this open-label,randomized controlled trial,204 patients with pT1-3,node-positive or high-risk node-negative,HER2-negative early-stage breast cancer were enrolled between May 2011 and December 2013(ClinicalTrials.gov:NCT01354522).Patients were randomized 2:1 to TAC(n=136)or TCX(n=68),with treatment administered every 21 days for six cycles.The primary endpoints were disease-free survival(DFS)and overall survival(OS);secondary endpoints included distant disease-free survival(DDFS),disease-specific survival(DSS),and adverse event(AE)rates.Results:With a median follow-up of 124.4(range,19.5-147.8)months,TCX did not significantly improve the 10-year DFS rate over TAC(71.5%±5.6%vs.67.6%±4.0%,P=0.477).However,the 10-year OS rate was significantly higher in the TCX group than in the TAC group(91.0%±3.5%vs.77.2%±3.6%,P=0.009).The TCX group also showed trends toward improved 10-year DDFS rate(82.0%±4.7%vs.69.8%±3.9%,P=0.052)and significantly higher 10-year DSS rate(93.9%±3.0%vs.77.8%±3.6%,P=0.002)compared to the TAC group.Grade 3-4 AEs occurred significantly more often in the TAC group than the TCX group(67.7%vs.42.7%,P=0.001).Conclusion:TCX may provide superior long-term survival and a more favorable safety profile compared to TAC for patients with high-risk HER2-negative breast cancer,warranting further investigation in larger cohorts.
文摘BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.
基金supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09711002-011-027)the Chinese Academy of Medical Sciences(CAMS)Inno-vation Fund for Medical Sciences(CIFMS,2021-I2M-1-014 and 2023-12M-2-004).
文摘Background:Bireociclib(XZP-3287)is a novel selective cyclin-dependent kinase 4 and 6(CDK4/6)inhibitor,with a favorable safety profile demonstrated in preclinical and phase I studies.BRIGHT-1 aimed to further explore the efficacy and safety of bireociclib monotherapy in patients with locally advanced,recurrent or metastatic,hormone receptor-positive and human epidermal growth factor receptor 2-negative(HR+/HER2−)breast cancer who had progressed on or after prior chemotherapy and endocrine therapy in advanced settings,without previous exposure to CDK4/6 inhibitors.Methods:In this open-label phase II trial,eligible patients received bireociclib 480 mg twice daily(BID)until disease progression or intolerable toxicities.The primary endpoint was the confirmed objective response rate(ORR)assessed by an independent review committee(IRC).The secondary endpoints included progression-free survival(PFS),investigator-assessed ORR,disease control rate(DCR),clinical benefit rate(CBR),duration of response(DoR),overall survival(OS),safety and the pharmacokinetic properties of bireociclib.Results:A total of 131 patients were enrolled.At data cutoff(July 31,2023),the IRC-assessed ORR was 29.8%(95%confidence interval[CI],22.1%to 38.4%),with a DCR of 73.3%(95%CI,64.8%to 80.6%),CBR of 42.0%(95%CI,33.4%to 50.9%)and a median DoR of 15.2 months(95%CI,9.5 months to not reached).The median PFS was 11.0 months(95%CI,7.3 months to 12.9 months)assessed by the IRC,and the median OS was 29.0 months(95%CI,24.9 months to not reached).The most frequently reported treatment-emergent adverse events(TEAEs)of any grade were diarrhea(93.1%),neutrophil count decreased(87.0%),white blood cell decreased(86.3%),vomiting(78.6%),anemia(72.5%),and platelet count decreased(72.5%).The grade≥3 TEAEs occurred in 109(83.2%)patients.The most common grade≥3 TEAEs were neutrophil count decreased(43.5%),white blood cell decreased(32.8%),hypokalemia(20.6%),and diarrhea(19.1%).Conclusions:Bireociclib monotherapy at 480 mg BID exhibited promising and sustained clinical activity,with no unexpected and acceptable toxicity in patients with recurrent or metastatic HR+/HER2−breast cancer who had progressed on or after previous therapy.Trial registration:Clinicaltrials.gov ID,NCT04539496.
基金supported by the National Natural Science Foundation of China to Jinhua Zhou(Nos.82172609)Jiangsu Social Development Project(Nos.BE2022729).
文摘Objectives:Our previous research demonstrated that SIC-19,an innovative inhibitor of salt-inducible kinase 2(SIK2),effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase(PARP)inhibitors in ovarian cancer.However,the role of SIC-19 in triplenegative breast cancer(TNBC)and pancreatic cancer(PC)remains poorly defined.This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC.Methods:Cell lines with high SIK2 expression were identified through Western blot analysis.The combination’s impact was evaluated using Cell Counting Kit-8(CCK8),clone formation,and apoptosis assays,as well as in vivo xenograft models.Results:Our findings indicated that the IC50 of SIC-19 was inversely correlated with endogenous SIK2 expression in TNBC and PC cell lines.SIC-19 modulates the homologous recombination repair pathway by suppressing levels of RAD50-pS635,thereby enhancing the sensitivity of TNBC and PC cells,as well as xenografts,to PARP inhibitors.Conclusion:These results underscore the potential of combining PARP inhibitors in combination with SIK2 inhibitors as a novel therapeutic approach to increase PARP inhibition’s effectiveness in treating TNBC and PC.This innovative combination therapy represents a promising approach for overcoming resistance mechanisms and improving the outcomes for patients with these challenging malignancies.
基金the National Natural Science Foundation of China(Nos.22307009,82374155,82073997,82104376)the Sichuan Science and Technology Program(Nos.2023NSFSC1108,2024NSFTD0023)+1 种基金the Postdoctoral Research Project of Sichuan Provincethe Xinglin Scholar Research Promotion Project of Chengdu University of TCM.
文摘Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.
文摘Background： Current understanding of tumor biology suggests that breast cancer is a group of diseases with different intrinsic molecular subtypes. Anatomic staging system alone is insufficient to provide future outcome information. The American Joint Committee on Cancer （AJCC） expert panel updated the 8th edition of the staging manual with prognostic stage groups by incorporating biomarkers into the anatomic stage groups. In this study, we retrospectively analyzed the data from our center in China using the anatomic and prognostic staging system based on the AJCC 8th edition staging manual. Methods： We reviewed the data from January 2008 to December 2014 for cases with Luminal B Human Epidermal Growth Factor Receptor 2 （HER2）-negative breast cancer in our center. All cases were restaged using the AJCC 8th edition anatomic and prognostic staging system. The Kaplan-Meier method and log-rank test were used to compare the survival differences between different subgroups. SPSS software version 19.0 （IBM Corp., Armonk, NY, USA） was used for the statistical analyses. Results： This study consisted of 796 patients with Luminal B HER-negative breast cancer. The 5-year disease-free survival （DFS） of 769 Stage I-III patients was 89.7%, and the 5-year overall survival （OS） of all 796 patients was 91.7%. Both 5-year DFS and 5-year OS were significantly different in the different anatomic and prognostic stage groups, There were 372 cases （46.7%） assigned to a different group. The prognostic Stage II and III patients restaged from anatomic Stage III had significant differences in 5-year DFS （v2 = 11.319; P = 0.001） and 5-year OS （χ2 = 5.225, P = 0.022）. In addition, cases restaged as prognostic Stage I, II, or III from the anatomic Stage II group had statistically significant differences in 5-year DFS （χ2 = 6.510, P = 0.039） but no significant differences in 5-year OS （χ2 = 5.087, P = 0.079）. However, the restaged prognostic Stage I and II cases from anatomic Stage I had no statistically significant differences in either 5-year DFS （χ2 = 0.440, P = 0.507） or 5-year OS （χ2= 1.530, P = 0.216）. Conclusions： The prognostic staging system proposed in the AJCC 8th edition refines the anatomic stage group in Luminal B HER2-negative breast cancer and will lead to a more personalized approach to breast cancer treatment.
基金supported by research and development project of medical data and artificial intelligence in Chinese PLA General Hospital(Grant No.2019MBD-056)
文摘Background:Endocrine therapy(ET)and ET-based regimens are the preferred first-line treatment options for hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative metastatic breast cancer(HR+/HER2-MBC),while chemotherapy(CT)is commonly used in clinical practice.The aim of this study was to investigate the efficacy and clinical outcome of ET and CT as first-line treatment in Chinese patients with HR+/HER2-MBC.Methods:Patients diagnosed with HR+/HER2-MBC between January 1st,1996 and September 30th,2018 were screened from the Chinese Society of Clinical Oncology Breast Cancer database.The initial and maintenance first-line treatment,progression-free survival(PFS),and overall survival(OS)were analyzed.Results:Among the 1877 included patients,1215(64.7%)received CT and 662(35.3%)received ET as initial first-line treatment.There were no statistically significant differences in PFS and OS between patients receiving ET and CT as initial first-line treatment in the total population(PFS:12.0 vs.11.0 months,P=0.22;OS:54.0 vs.49.0 months,P=0.09)and propensity score matched population.For patients without disease progression after at least 3 months of initial therapy,maintenance ET following initial CT(CT-ET cohort,n=449)and continuous schedule of ET(ET cohort,n=527)had longer PFS than continuous schedule of CT(CT cohort,n=406)in the total population(CT-ET cohort vs.CT cohort:17.0 vs.8.5 months;P<0.01;ET cohort vs.CT cohort:14.0 vs.8.5 months;P<0.01)and propensity score matched population.OS in the three cohorts yielded the same results as PFS.Conclusions:ET was associated with similar clinical outcome to CT as initial first-line treatment.For patients without disease progression after initial CT,switching to maintenance ET showed superiority in clinical outcome over continuous schedule of CT.
基金supported by the National Natural Science Foundation of China(No.82373380,Xinhua Xie).
文摘Objectives:Deubiquitinase OTUB2 plays a critical role in the progression of various tumors.However,its specific role in triple-negative breast cancer(TNBC)remains unclear.This study aims to elucidate the biological function of OTUB2 in TNBC and uncover the underlying mechanisms.Methods:First,we found that the expression of OTUB2 was upregulated in TNBC by bioinformatics analysis,we then validated its expression in TNBC tissues and cells using immunohistochemistry(IHC)and qPCR and plotted the survival curves by Kaplan-Meier method.Gene set enrichment analysis(GSEA)suggested that OTUB2 may be involved in tumor proliferation and metastasis.Further functional assays,including Cell Counting Kit-8(CCK-8),colony formation,Transwell,and wound healing assays,were performed to assess the effects of OTUB2 overexpression and knockdown on TNBC cell proliferation and migration.Additionally,UbiBrowser 2.0 was used to identify OTUB2 substrate proteins and western blotting was conducted to clarify the molecular mechanisms involved.Results:Our results demonstrated that OTUB2 expression was elevated in TNBC and associated with poor prognosis.Overexpression of OTUB2 enhanced the proliferation and migration of TNBC cells,while its knockdown inhibited these processes.Moreover,OTUB2 stabilized tumor necrosis factor receptor-associated factor 6(TRAF6)by deubiquitinating it,leading to activation of the protein kinase B(AKT)pathway.Conclusions:OTUB2 exerts its promoting effects on the progression of TNBC by activating the TRAF6/AKT pathway.
文摘Background:Cyclin-dependent kinase 4/6(CDK4/6)inhibitors have transformed the management of hormone receptor–positive/HER2–negative(HR+/HER2–)advanced breast cancer,yet evidence for elderly or poor-performance patients remains limited.This study examined real-world outcomes of palbociclib plus endocrine therapy in Asian patients,with additional subgroup analyses by age and performance status.Methods:We retrospectively analyzed 46 consecutive Asian patients with recurrent or de novo HR+/HER2−breast cancer treated with first-line palbociclib plus ET between April 2021 and March 2025.The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall response rate(ORR),disease control rate(DCR),and safety.Subgroup analyses were performed by age(<70 vs.≥70 years)and performance status(PS;0–1 vs.2–3).Results:The median PFS was 26.6 months(range,1.4–69.5).Stratified by age,median PFS was 26.9 months in patients<70 years and 26.2 months in those≥70 years(p=0.760).By PS,PFS was 26.9 months for PS 0–1 and 17.8 months for PS 2–3(p=0.099).ORR was 60.9%and DCR 93.5%;notably,all PS 2–3 patients achieved disease control.Hematologic toxicities were common,with neutropenia(80.4%)and leukopenia(86.7%)predominating,but grade≥3 anemia was rare(2.2%).Elderly patients experienced anemia more frequently,while overall toxicity remained manageable.Dose reductions occurred in 47.8%without loss of efficacy.Conclusions:In routine Japanese practice,palbociclib plus ET provided prolonged PFS and high disease control consistent with pivotal trials and international real-world evidence.Importantly,elderly patients tolerated treatment well,and selected PS 2–3 patients also derived clinical benefit.These findings indicate that neither age nor PS alone should preclude the use of palbociclib in carefully monitored real-world patients.
