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

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

A nomogram to predict adjuvant chemotherapy recommendation in breast cancer patients with intermediate recurrence score

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.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer:a clinical and translational study

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.

Single-cell atlas reveals a distinct immune profile fostered by T cell-B cell crosstalk in triple negative breast cancer

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.

Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy

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.

Prognostic value of the 21-gene recurrence score in ER-positive,HER2-negative,node-positive breast cancer was similar in nodenegative diseases:a single-center study of 800 patients

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.