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 o...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.展开更多
Objective： The indication of adjuvant chemotherapy recommendation（ACR） in breast cancer patients with intermediate recurrence score（RS） is controversial. This study investigated the relationship between routine c...Objective： The indication of adjuvant chemotherapy recommendation（ACR） in breast cancer patients with intermediate recurrence score（RS） is controversial. This study investigated the relationship between routine clinicopathological indicators and ACR, and established a nomogram for predicting the probability of ACR in this subset of patients.Methods： Data for a total of 504 consecutive patients with intermediate RS from January 2014 to December2016 were retrospectively reviewed. A nomogram was constructed using a multivariate logistic regression model based on data from a training set（378 cases） and validated in an independent validation set（126 cases）. A Youdenderived cut-off value was assigned to the nomogram for accuracy evaluation.Results： The multivariate logistic regression analysis identified that age, histological grade, tumor size, lymph node（LN） status, molecular subtype, and RS were independent predictors of ACR. A nomogram based on these predictors performed well. The P value of the Hosmer-Lemeshow test for the prediction model was 0.286. The area under the curve（AUC） values were 0.905 [95% confidence interval（95% CI）： 0.876–0.934] and 0.883（95%CI： 0.824–0.942） in the training and validation sets, respectively. The accuracies of the nomogram for ACR were84.4% in the training set and 82.1% in the validation set.Conclusions： We developed a nomogram to predict the probability of ACR in breast cancer patients with intermediate RS. This model may aid the individual risk assessment and guide treatment decisions in clinical practice.展开更多
Objective:To explore the prognosis-predictive influence of human epidermal growth factor receptor 2(HER2)-low status in breast cancer patients after neoadjuvant therapy(NAT).Methods:Consecutive patients with invasive ...Objective:To explore the prognosis-predictive influence of human epidermal growth factor receptor 2(HER2)-low status in breast cancer patients after neoadjuvant therapy(NAT).Methods:Consecutive patients with invasive breast cancer who underwent NAT and surgery from January 2009 to December 2020 at multiple centers were included.A modified CPS+EG scoring system that integrates HER2-low status,CPS+EGH_(low)was developed.Multiple scoring systems were compared via receiver operating characteristic curves with the area under curve(AUC),the Akaike information criterion,the C-index,and calibration curves.Results:A total of 2,141 patients were included:1,074,640,and 427 patients in the training,internal validation,and external validation groups,respectively.HER2-low patients had a significantly better breast cancer-specific survival(BCSS,P=0.008)and recurrence-free interval(RFI,P=0.030)compared to HER2-zero patients(P=0.038)but inferior outcomes than HER2-amplified ones(BCSS,P=0.002;RFI,P<0.001).The CPS+EGH_(low)(AUC:0.846,0.817,0.901)could stratify patients according to BCSS in training,internal validation,and external validation group,respectively,overperforming pathological stage(PS)(AUC:0.746,0.779,0.754),CPS+EG(AUC:0.771,0.752,0.748),and Neo-Bioscore(AUC:0.783,0.777,0.786,all P<0.05).Conclusions:HER2-low status showed a significant prognostic value in breast cancer patients after NAT.The CPS+EGH_(low)model significantly outperformed PS,CPS+EG,and Neo-Bioscore in clinical outcome prediction,which may guide further therapy targeting HER2-low.展开更多
Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment failure.Natural killer(NK)cell-mediated antibody-dependent ce...Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment failure.Natural killer(NK)cell-mediated antibody-dependent cell cytotoxicity(ADCC)represents an essential antitumor immune mechanism of trastuzumab.Traditional Chinese medicine(TCM)has been used for centuries to treat diseases because of its capacity to improve immune responses.Xianling Lianxia formula(XLLXF),based on the principle of“strengthening body and eliminating toxin”,exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC.Notably,this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC,as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments.Mechanistically,the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible Src homology 2(SH2)containing protein(CISH)expression,which in turn activates the Janus kinase 1(JAK1)/signal transducer and activator of transcription 5(STAT5)pathway.Collectively,these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.展开更多
Multi-gene assays have emerged as crucial tools for risk stratification in early-stage breast cancer.This study aimed to evaluate the prognostic significance of the 21-gene recurrence score(RS)in Chinese patients with...Multi-gene assays have emerged as crucial tools for risk stratification in early-stage breast cancer.This study aimed to evaluate the prognostic significance of the 21-gene recurrence score(RS)in Chinese patients with pN0-l,estrogen receptor-positive(ER+),human epidermal growth factor receptor 2-negative(HER2)breast cancer.Among 800 patients recruited between 2009 and 2016,the median RS was 24(0-69),with 27.4%,46.8%,and 25.9%patients classified into low-,intermediate-,and high-risk groups.Cox regression analysis demonstrated that the high-risk category was associated with significantly higher odds of invasive disease-free survival(IDFS)and distant disease-free survival(DDFS)events compared with the low-risk category(IDFS:HR=2.450,95%Cl 1.017-5.902,P=0.046;DDFS:HR=2.829,95%Cl 1.013-7.901,P=0.047).No significant association between RS category and overall survival(OS)was found(intermediate vs.low:HR=1.244,95%Cl 0.292-5.297,P=0.768;high vs.low:HR=2.933,95%Cl 0.759-11.327,P=0.119).RS,as a continuous variable,was a highly significant predictor for IDFS(HR=1.028,95%Cl 1.010-1.047,P=0.002),DDFS(HR=1.030,95%Cl 1.010-1.051,P=0.003),and OS(HR=1.034,95%Cl 1.007-1.063,P=0.014).Our findings suggested that RS may predict IDFS in Chinese patients with ER+/HER2 breast cancer with NO or N1 disease.展开更多
Single-cell RNA sequencing(scRNA-seq)is a novel technology that allows transcriptomic analyses of individual cells.During the past decade,scRNA-seq sensitivity,accuracy,and efficiency have improved due to innovations ...Single-cell RNA sequencing(scRNA-seq)is a novel technology that allows transcriptomic analyses of individual cells.During the past decade,scRNA-seq sensitivity,accuracy,and efficiency have improved due to innovations including more sensitive,automated,and cost-effective single-cell isolation methods with higher throughput as well as ongoing technological development of scRNA-seq protocols.Among the variety of current approaches with distinct features,researchers can choose the most suitable method to carry out their research.By profiling single cells in a complex population mix,scRNA-seq presents great advantages over traditional sequencing methods in dissecting heterogeneity in cell populations hidden in bulk analysis and exploring rare cell types associated with tumorigenesis and metastasis.scRNA-seq studies in recent years in the field of breast cancer research have clustered breast cancer cell populations with different molecular subtypes to identify distinct populations that may correlate with poor prognosis and drug resistance.The technology has also been used to explain tumor microenvironment heterogeneity by identifying distinct immune cell subsets that may be associated with immunosurveillance and are potential immunotherapy targets.Moreover,scRNA-seq has diverse applications in breast cancer research besides exploring heterogeneity,including the analysis of cell-cell communications,regulatory single-cell states,immune cell distributions,and more.scRNA-seq is also a promising tool that can facilitate individualized therapy due to its ability to define cell subsets with potential treatment targets.Although scRNA-seq studies of therapeutic selection in breast cancer are currently limited,the application of this technology in this field is prospective.Joint efforts and original ideas are needed to better implement scRNA-seq technologies in breast cancer research to pave the way for individualized treatment management.This review provides a brief introduction on the currently available scRNA-seq approaches along with their corresponding strengths and weaknesses and may act as a reference for the selection of suitable methods for research.We also discuss the current applications of scRNA-seq in breast cancer research for tumor heterogeneity analysis,individualized therapy,and the other research directions mentioned above by reviewing corresponding published studies.Finally,we discuss the limitations of current scRNA-seq technologies and technical problems that remain to be overcome.展开更多
Background Accurate evaluation of response following chemotherapy treatment is essential for surgical decision making in patients with breast cancer. Modalities that have been used to monitor response to neo-adjuvant ...Background Accurate evaluation of response following chemotherapy treatment is essential for surgical decision making in patients with breast cancer. Modalities that have been used to monitor response to neo-adjuvant chemotherapy （NAC） include physical examination （PE）, ultrasound （US）, and magnetic resonance imaging （MRI）. The purpose of this study was to evaluate the accuracy of PE, US, and MRI in predicting the response to NAC in patients with breast cancer. Methods According to the response evaluation criteria in solid tumors guidelines, the largest unidimensional measurement of the tumor diameter evaluated by PE, US, and MRI before and after NAC was classified into four grades, including clinical complete response, clinical partial response, clinical progressive disease, clinical stable disease, and compared with the final histopathological examination. Results Of the 64 patients who received NAC, the pathologic complete response （pCR） was shown in 13 of 64 patients （20%）. The sensitivity of PE, US, and MRI in predicting the major pathologic response was 73%, 75%, and 80%, respectively, and the specificity was 45%, 50%, and 50% respectively. For predicting a pCR, the sensitivity of PE, US, and MRI was 46%, 46%, and 39%, respectively, and the specificity was 65%, 98%, and 92% respectively. Conclusions Compared with final pathologic findings, all these three clinical and imaging modalities tended to obviously underestimate the pCR rate. A more appropriate, universal, and practical standard by clinical and imaging modalities in predicting the response to neo-adjuvant chemotherapy in vivo is essential.展开更多
Background:Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy.However,the unique features of the immune microenviron...Background:Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy.However,the unique features of the immune microenvironment of triple negative breast cancer(TNBC)compared with other subtypes of breast cancer remain elusive.Therefore,we aimed to depict and compare the immune landscape among TNBC,human epidermal growth factor receptor 2-positive(HER2^(+))breast cancer,and luminal-like breast cancer.Methods:Single-cell RNA sequencing(scRNA-seq)was performed on CD45^(+)immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes.By analyzing the scRNA-seq data,immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC,human HER2^(+)breast cancer,and luminal-like breast cancer.Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment.Results:ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified.A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2^(+)or luminal-like breast cancer,which was characterized by higher proportions of regulatory T cells(Tregs)and exhausted CD8+T cells and accompanied by more abundant plasma cells.Tregs and exhausted CD8+T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores.Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC.Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC.Based on the T cell-B cell crosstalk,a prognostic signaturewas established that could effectively predict the prognosis status for patients with TNBC.Additionally,it was found that TNBC had a higher proportion of cytotoxic natural killer(NK)cells,whereas HER2^(+)or luminal-like breast cancer lost this feature,suggesting thatHER2^(+)or luminal-like breast cancer,but not TNBC,may benefit from NK-based immunotherapy.Conclusions:This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC,which provides better prognostic information and effective therapeutic targets for breast cancer.展开更多
p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor p...p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor prognosis.In a retrospective study on tissue microarrays with 132 TNBC cases,DNMT1 overexpression was associated with p53 mutations(P=0.037)and poor overall survival(OS)(P=0.010).In a prospective DEciTabinE and Carboplatin in TNBC(DETECT)trial(NCT03295552),decitabine with carboplatin produced an objective response rate(ORR)of 42%in 12 patients with stage IV TNBC.Among the 9 trialed patients with available TP53 sequencing results,the 6 patients with p53 mutations had higher ORR(3/6 vs.0/3)and better OS(16.0 vs.4.0 months)than the patients with wild-type p53.In a mechanistic study,isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53.In the DETECT trial,decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line(upregulation by 16-fold)and the most responsive patient with TNBC.Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.展开更多
Background:Trend analysis in infection-related malignancy of the liver is still limited.We aimed to evaluate the incidence trend in hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(iCCA),combined hepatoce...Background:Trend analysis in infection-related malignancy of the liver is still limited.We aimed to evaluate the incidence trend in hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(iCCA),combined hepatocellular carcinoma and cholangiocarcinoma(cHCC-CCA),and primary hepatic lymphoma(PHL)in the USA during 2000-2019.Method:In this population-level study,cases of HCC,iCCA,cHCC-CCA,and PHL from the Surveillance,Epidemiology,and End Results(SEER)registries during 2000-2019 were included.The average annual percentage change(AAPC)in 2000-2019 was computed to describe the age-adjusted incidence trends for each disease and was stratified by demographic and geographic variables.Results:HCC and iCCA incidence increased from 5.51(per 100,000 persons)to 8.83 and 0.92 to 1.94 during 2000-2019,respectively,whereas cHCC-CCA and PHL incidence plateaued at-0.04 and-0.10,respectively.The AAPCs of HCC,iCCA,cHCC-CCA,and PHL were 2.5%(95%confidence interval[CI],2.2%to 2.8%),3.9%(95%CI,2.1%to 5.7%),0.4%(95%CI,−1.1%to 1.9%),and 0.2%(95%CI,−0.9%to 1.3%),respectively.The HCC incidence patterns differed between age groups,with a decreased trend for young adults(AAPC,−1.1%[95%CI,−2.2%to−0.1%])and the fastest increase trend for elderly people(AAPC,3.2%[95%CI,2.8%-3.5%]).For iCCA,the incidence significantly increased for all age and race/ethnicity subgroups.The incidence trends in cHCC-CCA and PHL plateaued for the general population and all subgroups.Geographic disparities were found for HCC,with the highest proportion in Alaska Natives(91.6%)and the lowest proportion in Iowa(77.5%).Conclusions:Although the incidence of infection-related malignancies of the liver increased in the USA during 2000-2019,a plateaued trend was observed for HCC during 2010-2019,especially for young adults.Racial/ethnic differences and geographic diversity remain.Systematic screening and prevention are highly requested.展开更多
Background Human behaviors and tumors go hand in hand.The wave of globalization has brought about a global homogenization of human behaviors,which further triggers a potential global human behavior-related cancer burd...Background Human behaviors and tumors go hand in hand.The wave of globalization has brought about a global homogenization of human behaviors,which further triggers a potential global human behavior-related cancer burden(HBRCB)convergence.Methods This study systematically evaluated the global,regional,and national metrics of HBRCBs over the last 30 years using data from the Global Burden of Diseases(GBD)2019 results and the WHO Global Health Observatory(GHO)data repository.Results The results showed the global remission and convergence of HBRCB in the last three decades and the foreseeable future(2020–2044).Overall,HBRCBs are decreasing with the global emphasis on positive dietary habits,safe sex,substance addiction withdrawal,and active physical exercise habits.Globally,from 1990 to 2019,with the development of social development index(SDI)level from 0.511 to 0.651,the HBRCBs had been decreasing from 1507.908 to 1145.344 in age-standardized disability-adjusted life years(ASDALY)and from 61.467 to 49.449 in(age-standardized death rates)ASDR per 100,000 population with changes of−24.04%and−19.55%,respectively.Meanwhile,the variance in HBRCBs among countries and territories generally showed a decreasing or flat trend.The variance of HBRCBs among 204 countries and territories in 2019–2044 decreased from 1495.210 to 449.202 in males and from 214.640 to 78.848 in females for ASDR due to all behavior risks,and from 911,211.676 to 317,233.590 in males and from 146,171.660 to 62,926.660 in females for ASDALY.The global HBRCBs was becoming more uniform due to the globalization of human behaviors.Conclusions This study revealed the significance of addressing HBRCBs as a uniform and continuous issue in future global health promotion.It also demonstrated the potential existence of a chain effect in global health,where globalization leads to human behavior homogenization,which in turn results in HBRCB convergence.Properly measuring the commonalities and individualities among different regions and finding a balance when designing and evaluating HBRCB-related global policies in the global convergence trend of HBRCBs will be major concerns in the future.展开更多
基金supported in part by the grants from the National Natural Science Foundation of China (Grant No. 81472462)Medical Guidance Foundation of Shanghai Municipal Science and Technology Commission (Grant No. 15411966400)Technology Innovation Act Plan of Shanghai Municipal Science and Technology Commission (Grant No. 14411950200, 14411950201) and Sanofi
文摘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.
文摘Objective： The indication of adjuvant chemotherapy recommendation（ACR） in breast cancer patients with intermediate recurrence score（RS） is controversial. This study investigated the relationship between routine clinicopathological indicators and ACR, and established a nomogram for predicting the probability of ACR in this subset of patients.Methods： Data for a total of 504 consecutive patients with intermediate RS from January 2014 to December2016 were retrospectively reviewed. A nomogram was constructed using a multivariate logistic regression model based on data from a training set（378 cases） and validated in an independent validation set（126 cases）. A Youdenderived cut-off value was assigned to the nomogram for accuracy evaluation.Results： The multivariate logistic regression analysis identified that age, histological grade, tumor size, lymph node（LN） status, molecular subtype, and RS were independent predictors of ACR. A nomogram based on these predictors performed well. The P value of the Hosmer-Lemeshow test for the prediction model was 0.286. The area under the curve（AUC） values were 0.905 [95% confidence interval（95% CI）： 0.876–0.934] and 0.883（95%CI： 0.824–0.942） in the training and validation sets, respectively. The accuracies of the nomogram for ACR were84.4% in the training set and 82.1% in the validation set.Conclusions： We developed a nomogram to predict the probability of ACR in breast cancer patients with intermediate RS. This model may aid the individual risk assessment and guide treatment decisions in clinical practice.
基金supported by the National Natural Science Foundation of China(No.82072937 and 82072897)Interdisciplinary Program of Shanghai Jiao Tong University(No.YG2024QNB05)。
文摘Objective:To explore the prognosis-predictive influence of human epidermal growth factor receptor 2(HER2)-low status in breast cancer patients after neoadjuvant therapy(NAT).Methods:Consecutive patients with invasive breast cancer who underwent NAT and surgery from January 2009 to December 2020 at multiple centers were included.A modified CPS+EG scoring system that integrates HER2-low status,CPS+EGH_(low)was developed.Multiple scoring systems were compared via receiver operating characteristic curves with the area under curve(AUC),the Akaike information criterion,the C-index,and calibration curves.Results:A total of 2,141 patients were included:1,074,640,and 427 patients in the training,internal validation,and external validation groups,respectively.HER2-low patients had a significantly better breast cancer-specific survival(BCSS,P=0.008)and recurrence-free interval(RFI,P=0.030)compared to HER2-zero patients(P=0.038)but inferior outcomes than HER2-amplified ones(BCSS,P=0.002;RFI,P<0.001).The CPS+EGH_(low)(AUC:0.846,0.817,0.901)could stratify patients according to BCSS in training,internal validation,and external validation group,respectively,overperforming pathological stage(PS)(AUC:0.746,0.779,0.754),CPS+EG(AUC:0.771,0.752,0.748),and Neo-Bioscore(AUC:0.783,0.777,0.786,all P<0.05).Conclusions:HER2-low status showed a significant prognostic value in breast cancer patients after NAT.The CPS+EGH_(low)model significantly outperformed PS,CPS+EG,and Neo-Bioscore in clinical outcome prediction,which may guide further therapy targeting HER2-low.
基金This work was supported by the National Natural Science Foundation of China(Grant No.:81774308)the Multi-center Clinical Research Project for Major Diseases of Shanghai Shenkang Hospital Development Center,China(Grant No.:SHDC2020CR1050B)the High-level University Building Innovation Team,China(Grant No.:601521D).
文摘Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment failure.Natural killer(NK)cell-mediated antibody-dependent cell cytotoxicity(ADCC)represents an essential antitumor immune mechanism of trastuzumab.Traditional Chinese medicine(TCM)has been used for centuries to treat diseases because of its capacity to improve immune responses.Xianling Lianxia formula(XLLXF),based on the principle of“strengthening body and eliminating toxin”,exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC.Notably,this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC,as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments.Mechanistically,the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible Src homology 2(SH2)containing protein(CISH)expression,which in turn activates the Janus kinase 1(JAK1)/signal transducer and activator of transcription 5(STAT5)pathway.Collectively,these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.
基金This work was supported by grants from the Technology Innovation Act Plan of Shanghai Municipal Science and Technology Commission(Nos.14411-950200 and 14411950201)the National Natural Science Foundation of China(No.81772797)the Shanghai Municipal Commission of Health and Family Planning(No.201840323)。
文摘Multi-gene assays have emerged as crucial tools for risk stratification in early-stage breast cancer.This study aimed to evaluate the prognostic significance of the 21-gene recurrence score(RS)in Chinese patients with pN0-l,estrogen receptor-positive(ER+),human epidermal growth factor receptor 2-negative(HER2)breast cancer.Among 800 patients recruited between 2009 and 2016,the median RS was 24(0-69),with 27.4%,46.8%,and 25.9%patients classified into low-,intermediate-,and high-risk groups.Cox regression analysis demonstrated that the high-risk category was associated with significantly higher odds of invasive disease-free survival(IDFS)and distant disease-free survival(DDFS)events compared with the low-risk category(IDFS:HR=2.450,95%Cl 1.017-5.902,P=0.046;DDFS:HR=2.829,95%Cl 1.013-7.901,P=0.047).No significant association between RS category and overall survival(OS)was found(intermediate vs.low:HR=1.244,95%Cl 0.292-5.297,P=0.768;high vs.low:HR=2.933,95%Cl 0.759-11.327,P=0.119).RS,as a continuous variable,was a highly significant predictor for IDFS(HR=1.028,95%Cl 1.010-1.047,P=0.002),DDFS(HR=1.030,95%Cl 1.010-1.051,P=0.003),and OS(HR=1.034,95%Cl 1.007-1.063,P=0.014).Our findings suggested that RS may predict IDFS in Chinese patients with ER+/HER2 breast cancer with NO or N1 disease.
基金The authors received financial support from the National Natural Science Foundation of China(Grant Number:81772797)Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20172007)Ruijin Hospital,Shanghai Jiao Tong University School of Medicine“Guangci Excellent Youth Training Program”(GCQN-2017-A18)。
文摘Single-cell RNA sequencing(scRNA-seq)is a novel technology that allows transcriptomic analyses of individual cells.During the past decade,scRNA-seq sensitivity,accuracy,and efficiency have improved due to innovations including more sensitive,automated,and cost-effective single-cell isolation methods with higher throughput as well as ongoing technological development of scRNA-seq protocols.Among the variety of current approaches with distinct features,researchers can choose the most suitable method to carry out their research.By profiling single cells in a complex population mix,scRNA-seq presents great advantages over traditional sequencing methods in dissecting heterogeneity in cell populations hidden in bulk analysis and exploring rare cell types associated with tumorigenesis and metastasis.scRNA-seq studies in recent years in the field of breast cancer research have clustered breast cancer cell populations with different molecular subtypes to identify distinct populations that may correlate with poor prognosis and drug resistance.The technology has also been used to explain tumor microenvironment heterogeneity by identifying distinct immune cell subsets that may be associated with immunosurveillance and are potential immunotherapy targets.Moreover,scRNA-seq has diverse applications in breast cancer research besides exploring heterogeneity,including the analysis of cell-cell communications,regulatory single-cell states,immune cell distributions,and more.scRNA-seq is also a promising tool that can facilitate individualized therapy due to its ability to define cell subsets with potential treatment targets.Although scRNA-seq studies of therapeutic selection in breast cancer are currently limited,the application of this technology in this field is prospective.Joint efforts and original ideas are needed to better implement scRNA-seq technologies in breast cancer research to pave the way for individualized treatment management.This review provides a brief introduction on the currently available scRNA-seq approaches along with their corresponding strengths and weaknesses and may act as a reference for the selection of suitable methods for research.We also discuss the current applications of scRNA-seq in breast cancer research for tumor heterogeneity analysis,individualized therapy,and the other research directions mentioned above by reviewing corresponding published studies.Finally,we discuss the limitations of current scRNA-seq technologies and technical problems that remain to be overcome.
文摘Background Accurate evaluation of response following chemotherapy treatment is essential for surgical decision making in patients with breast cancer. Modalities that have been used to monitor response to neo-adjuvant chemotherapy （NAC） include physical examination （PE）, ultrasound （US）, and magnetic resonance imaging （MRI）. The purpose of this study was to evaluate the accuracy of PE, US, and MRI in predicting the response to NAC in patients with breast cancer. Methods According to the response evaluation criteria in solid tumors guidelines, the largest unidimensional measurement of the tumor diameter evaluated by PE, US, and MRI before and after NAC was classified into four grades, including clinical complete response, clinical partial response, clinical progressive disease, clinical stable disease, and compared with the final histopathological examination. Results Of the 64 patients who received NAC, the pathologic complete response （pCR） was shown in 13 of 64 patients （20%）. The sensitivity of PE, US, and MRI in predicting the major pathologic response was 73%, 75%, and 80%, respectively, and the specificity was 45%, 50%, and 50% respectively. For predicting a pCR, the sensitivity of PE, US, and MRI was 46%, 46%, and 39%, respectively, and the specificity was 65%, 98%, and 92% respectively. Conclusions Compared with final pathologic findings, all these three clinical and imaging modalities tended to obviously underestimate the pCR rate. A more appropriate, universal, and practical standard by clinical and imaging modalities in predicting the response to neo-adjuvant chemotherapy in vivo is essential.
基金National Natural Science Foundation of China,Grant/Award Numbers:82072937,82072897,82002773Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant,Grant/Award Number:20172007Science and Technology Commission of Shanghai Municipality Shanghai Sailing Program,Grant/Award Number:21YF1427400。
文摘Background:Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy.However,the unique features of the immune microenvironment of triple negative breast cancer(TNBC)compared with other subtypes of breast cancer remain elusive.Therefore,we aimed to depict and compare the immune landscape among TNBC,human epidermal growth factor receptor 2-positive(HER2^(+))breast cancer,and luminal-like breast cancer.Methods:Single-cell RNA sequencing(scRNA-seq)was performed on CD45^(+)immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes.By analyzing the scRNA-seq data,immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC,human HER2^(+)breast cancer,and luminal-like breast cancer.Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment.Results:ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified.A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2^(+)or luminal-like breast cancer,which was characterized by higher proportions of regulatory T cells(Tregs)and exhausted CD8+T cells and accompanied by more abundant plasma cells.Tregs and exhausted CD8+T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores.Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC.Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC.Based on the T cell-B cell crosstalk,a prognostic signaturewas established that could effectively predict the prognosis status for patients with TNBC.Additionally,it was found that TNBC had a higher proportion of cytotoxic natural killer(NK)cells,whereas HER2^(+)or luminal-like breast cancer lost this feature,suggesting thatHER2^(+)or luminal-like breast cancer,but not TNBC,may benefit from NK-based immunotherapy.Conclusions:This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC,which provides better prognostic information and effective therapeutic targets for breast cancer.
基金supported by the National Natural Science Foundation of China(No.82130075 to Min Lu,No.82073292 to Min Lu,No.81772797 to Xiaosong Chen,No.82072937 to Xiaosong Chen,No.82072897 to Kunwei Shen,No.82002773 to Zheng Wang,No.81900157 to Ying Liang)SJTU Transmed Awards Research(to Min Lu),Shanghai Municipal Education Commission-Gaofeng Clinical Medicine(No.828318 to Min Lu and No.20172007 to Xiaosong Chen)+4 种基金Shanghai Excellent Youth Academic Leader(No.20XD1422700 to Min Lu)Program of Shanghai Science and Technology Committee(No.21S11900100 to Min Lu)Dawn Program of Shanghai Education Commission(No.21SG18 to Min Lu)Samuel Waxman Cancer Research Foundation(to Min Lu)Foundation of National Facility for Translational Medicine(Shanghai)(No.NRCTM(SH)-2021-08).
文摘p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor prognosis.In a retrospective study on tissue microarrays with 132 TNBC cases,DNMT1 overexpression was associated with p53 mutations(P=0.037)and poor overall survival(OS)(P=0.010).In a prospective DEciTabinE and Carboplatin in TNBC(DETECT)trial(NCT03295552),decitabine with carboplatin produced an objective response rate(ORR)of 42%in 12 patients with stage IV TNBC.Among the 9 trialed patients with available TP53 sequencing results,the 6 patients with p53 mutations had higher ORR(3/6 vs.0/3)and better OS(16.0 vs.4.0 months)than the patients with wild-type p53.In a mechanistic study,isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53.In the DETECT trial,decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line(upregulation by 16-fold)and the most responsive patient with TNBC.Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.
文摘Background:Trend analysis in infection-related malignancy of the liver is still limited.We aimed to evaluate the incidence trend in hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(iCCA),combined hepatocellular carcinoma and cholangiocarcinoma(cHCC-CCA),and primary hepatic lymphoma(PHL)in the USA during 2000-2019.Method:In this population-level study,cases of HCC,iCCA,cHCC-CCA,and PHL from the Surveillance,Epidemiology,and End Results(SEER)registries during 2000-2019 were included.The average annual percentage change(AAPC)in 2000-2019 was computed to describe the age-adjusted incidence trends for each disease and was stratified by demographic and geographic variables.Results:HCC and iCCA incidence increased from 5.51(per 100,000 persons)to 8.83 and 0.92 to 1.94 during 2000-2019,respectively,whereas cHCC-CCA and PHL incidence plateaued at-0.04 and-0.10,respectively.The AAPCs of HCC,iCCA,cHCC-CCA,and PHL were 2.5%(95%confidence interval[CI],2.2%to 2.8%),3.9%(95%CI,2.1%to 5.7%),0.4%(95%CI,−1.1%to 1.9%),and 0.2%(95%CI,−0.9%to 1.3%),respectively.The HCC incidence patterns differed between age groups,with a decreased trend for young adults(AAPC,−1.1%[95%CI,−2.2%to−0.1%])and the fastest increase trend for elderly people(AAPC,3.2%[95%CI,2.8%-3.5%]).For iCCA,the incidence significantly increased for all age and race/ethnicity subgroups.The incidence trends in cHCC-CCA and PHL plateaued for the general population and all subgroups.Geographic disparities were found for HCC,with the highest proportion in Alaska Natives(91.6%)and the lowest proportion in Iowa(77.5%).Conclusions:Although the incidence of infection-related malignancies of the liver increased in the USA during 2000-2019,a plateaued trend was observed for HCC during 2010-2019,especially for young adults.Racial/ethnic differences and geographic diversity remain.Systematic screening and prevention are highly requested.
基金supported by the Development Center for Medical Science and Technology National Health Commission of the People's Republic of China(WA2021RW27).
文摘Background Human behaviors and tumors go hand in hand.The wave of globalization has brought about a global homogenization of human behaviors,which further triggers a potential global human behavior-related cancer burden(HBRCB)convergence.Methods This study systematically evaluated the global,regional,and national metrics of HBRCBs over the last 30 years using data from the Global Burden of Diseases(GBD)2019 results and the WHO Global Health Observatory(GHO)data repository.Results The results showed the global remission and convergence of HBRCB in the last three decades and the foreseeable future(2020–2044).Overall,HBRCBs are decreasing with the global emphasis on positive dietary habits,safe sex,substance addiction withdrawal,and active physical exercise habits.Globally,from 1990 to 2019,with the development of social development index(SDI)level from 0.511 to 0.651,the HBRCBs had been decreasing from 1507.908 to 1145.344 in age-standardized disability-adjusted life years(ASDALY)and from 61.467 to 49.449 in(age-standardized death rates)ASDR per 100,000 population with changes of−24.04%and−19.55%,respectively.Meanwhile,the variance in HBRCBs among countries and territories generally showed a decreasing or flat trend.The variance of HBRCBs among 204 countries and territories in 2019–2044 decreased from 1495.210 to 449.202 in males and from 214.640 to 78.848 in females for ASDR due to all behavior risks,and from 911,211.676 to 317,233.590 in males and from 146,171.660 to 62,926.660 in females for ASDALY.The global HBRCBs was becoming more uniform due to the globalization of human behaviors.Conclusions This study revealed the significance of addressing HBRCBs as a uniform and continuous issue in future global health promotion.It also demonstrated the potential existence of a chain effect in global health,where globalization leads to human behavior homogenization,which in turn results in HBRCB convergence.Properly measuring the commonalities and individualities among different regions and finding a balance when designing and evaluating HBRCB-related global policies in the global convergence trend of HBRCBs will be major concerns in the future.
