Objective:Neoadjuvant therapy(NAT)has been widely implemented as an essential treatment to improve therapeutic efficacy in patients with locally-advanced cancer to reduce tumor burden and prolong survival,particularly...Objective:Neoadjuvant therapy(NAT)has been widely implemented as an essential treatment to improve therapeutic efficacy in patients with locally-advanced cancer to reduce tumor burden and prolong survival,particularly for human epidermal growth receptor 2-positive and triple-negative breast cancer.The role of peripheral immune components in predicting therapeutic responses has received limited attention.Herein we determined the relationship between dynamic changes in peripheral immune indices and therapeutic responses during NAT administration.Methods:Peripheral immune index data were collected from 134 patients before and after NAT.Logistic regression and machine learning algorithms were applied to the feature selection and model construction processes,respectively.Results:Peripheral immune status with a greater number of CD3^(+)T cells before and after NAT,and a greater number of CD8^(+)T cells,fewer CD4^(+)T cells,and fewer NK cells after NAT was significantly related to a pathological complete response(P<0.05).The post-NAT NK cell-to-pre-NAT NK cell ratio was negatively correlated with the response to NAT(HR=0.13,P=0.008).Based on the results of logistic regression,14 reliable features(P<0.05)were selected to construct the machine learning model.The random forest model exhibited the best power to predict efficacy of NAT among 10 machine learning model approaches(AUC=0.733).Conclusions:Statistically significant relationships between several specific immune indices and the efficacy of NAT were revealed.A random forest model based on dynamic changes in peripheral immune indices showed robust performance in predicting NAT efficacy.展开更多
Objective:Neoadjuvant chemotherapy(NAC)is currently used in both early stage and locally advanced breast cancers.The survival benefits of standard vs.non-standard NAC cycles are still unclear.This study aimed to inves...Objective:Neoadjuvant chemotherapy(NAC)is currently used in both early stage and locally advanced breast cancers.The survival benefits of standard vs.non-standard NAC cycles are still unclear.This study aimed to investigate the relationship between NAC cycles and survival based on real world data.Methods:We identified patients diagnosed with invasive primary breast cancers who underwent NAC followed by surgery.Patients who received at least 4 NAC cycles were defined as having received standard cycles,while patients who received less than 4 NAC cycles were defined as having received non-standard cycles.Kaplan-Meier curves and Cox proportional hazard models were used to estimate the disease-free survival(DFS)and overall survival(OS).Results:Of the 1,024 included patients,700 patients received standard NAC cycles and 324 patients received non-standard NAC cycles.The DFS estimates were 87.1%and 81.0%(P=0.007)and the OS estimates were 90.0%and 82.6%(P=0.001)in the standard and non-standard groups,respectively.Using multivariate analyses,patients treated with standard NAC cycles showed significant survival benefits in both DFS[hazard ratio(HR):0.62,95%confidence interval(CI):0.44–0.88]and OS(HR:0.54,95%CI:0.37–0.79).Using stratified analyses,standard NAC cycles were associated with improved DFS(HR:0.59,95%CI:0.36–0.96)and OS(HR:0.49,95%CI:0.28–0.86)in the HER2 positive group.Similar DFS(HR:0.50,95%CI:0.25–0.98)and OS(HR:0.45,95%CI:0.22–0.91)benefits were shown for the triple negative group.Conclusions:Standard NAC cycles were associated with a significant survival benefit,especially in patients with HER2 positive or triple negative breast cancer.展开更多
The optimal chemotherapy backbone and specific population of triple-negative breast cancer(TNBC)patients that benefit from neoadjuvant immunotherapy are not well established.This prospective,single-arm,phaseⅡTREND tr...The optimal chemotherapy backbone and specific population of triple-negative breast cancer(TNBC)patients that benefit from neoadjuvant immunotherapy are not well established.This prospective,single-arm,phaseⅡTREND trial assessed the efficacy and safety of tislelizumab plus nab-paclitaxel and epirubicin/cyclophosphamide-based chemotherapy as a neoadjuvant treatment for TNBC(ChiCTR2000035262).The primary endpoint was pathological complete response(pCR),with the secondary endpoints including safety assessment and objective response rate(ORR).ScRNA-seq,bulk RNA-seq,TCR-seq,cyTOF and WES were performed on pre-treatment and post-treatment samples.Among 53 total enrolled patients,44 completed the combined neoadjuvant therapy,and 30 of 44 patients(68.18%)achieved pCR.Additionally,14 out of 44 patients had a complete response(31.82%),with an ORR of 93.18%.The most commonly observed treatment-related adverse events(TRAEs)were alopecia,nausea and liver injury with 6 cases classified as grade 3 or higher adverse events.Immune response-related pathways,including TNF signaling pathway,T cell receptor signaling pathway,were enriched in pCR group.Pre-treatment model was identified and construct to predict response to immunotherapy.CDKN1A+CD8 T lymphocytes were enriched in pCR group after neoadjuvant immunotherapy.Dynamic change of immune-related pathways at an early stage during the neoadjuvant immunotherapy may be associated with the treatment effcacy.In conclusion,neoadjuvant treatment of tislelizumab with nab-paclitaxel and anthracycline-based chemotherapy showed promising clinical activity and was well-tolerated among TNBC patients,without high incidence of TRAEs.These findings provide evidence supporting neoadjuvant tislelizumab with chemotherapy as an effective rational approach for treating TNBC.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.82203786)the Natural Science Foundation of Liaoning Province of China(Grant No.2022-YGJC-68)Chinese Young Breast Experts Research project(Grant No.CYBER-2021-A02)。
文摘Objective:Neoadjuvant therapy(NAT)has been widely implemented as an essential treatment to improve therapeutic efficacy in patients with locally-advanced cancer to reduce tumor burden and prolong survival,particularly for human epidermal growth receptor 2-positive and triple-negative breast cancer.The role of peripheral immune components in predicting therapeutic responses has received limited attention.Herein we determined the relationship between dynamic changes in peripheral immune indices and therapeutic responses during NAT administration.Methods:Peripheral immune index data were collected from 134 patients before and after NAT.Logistic regression and machine learning algorithms were applied to the feature selection and model construction processes,respectively.Results:Peripheral immune status with a greater number of CD3^(+)T cells before and after NAT,and a greater number of CD8^(+)T cells,fewer CD4^(+)T cells,and fewer NK cells after NAT was significantly related to a pathological complete response(P<0.05).The post-NAT NK cell-to-pre-NAT NK cell ratio was negatively correlated with the response to NAT(HR=0.13,P=0.008).Based on the results of logistic regression,14 reliable features(P<0.05)were selected to construct the machine learning model.The random forest model exhibited the best power to predict efficacy of NAT among 10 machine learning model approaches(AUC=0.733).Conclusions:Statistically significant relationships between several specific immune indices and the efficacy of NAT were revealed.A random forest model based on dynamic changes in peripheral immune indices showed robust performance in predicting NAT efficacy.
基金This work was supported by the National Natural Science Foundation of China(Grant No.81773083)the Scientific and Technological Innovation Leading Talent Project of Liaoning Province(Grant No.XLYC1802108)the Support Project for Young and Technological Innovation Talents of Shenyang(Grant No.RC190393).
文摘Objective:Neoadjuvant chemotherapy(NAC)is currently used in both early stage and locally advanced breast cancers.The survival benefits of standard vs.non-standard NAC cycles are still unclear.This study aimed to investigate the relationship between NAC cycles and survival based on real world data.Methods:We identified patients diagnosed with invasive primary breast cancers who underwent NAC followed by surgery.Patients who received at least 4 NAC cycles were defined as having received standard cycles,while patients who received less than 4 NAC cycles were defined as having received non-standard cycles.Kaplan-Meier curves and Cox proportional hazard models were used to estimate the disease-free survival(DFS)and overall survival(OS).Results:Of the 1,024 included patients,700 patients received standard NAC cycles and 324 patients received non-standard NAC cycles.The DFS estimates were 87.1%and 81.0%(P=0.007)and the OS estimates were 90.0%and 82.6%(P=0.001)in the standard and non-standard groups,respectively.Using multivariate analyses,patients treated with standard NAC cycles showed significant survival benefits in both DFS[hazard ratio(HR):0.62,95%confidence interval(CI):0.44–0.88]and OS(HR:0.54,95%CI:0.37–0.79).Using stratified analyses,standard NAC cycles were associated with improved DFS(HR:0.59,95%CI:0.36–0.96)and OS(HR:0.49,95%CI:0.28–0.86)in the HER2 positive group.Similar DFS(HR:0.50,95%CI:0.25–0.98)and OS(HR:0.45,95%CI:0.22–0.91)benefits were shown for the triple negative group.Conclusions:Standard NAC cycles were associated with a significant survival benefit,especially in patients with HER2 positive or triple negative breast cancer.
基金supported by the National Natural Science Foundation of China(82203786,82373231)the Natural Science Foundation of Liaoning Province of China(2022-YGJC-68,2023-BS-105)Chinese Young Breast Experts Research Project(CYBER-2021-A02,CYBER-2022-001).
文摘The optimal chemotherapy backbone and specific population of triple-negative breast cancer(TNBC)patients that benefit from neoadjuvant immunotherapy are not well established.This prospective,single-arm,phaseⅡTREND trial assessed the efficacy and safety of tislelizumab plus nab-paclitaxel and epirubicin/cyclophosphamide-based chemotherapy as a neoadjuvant treatment for TNBC(ChiCTR2000035262).The primary endpoint was pathological complete response(pCR),with the secondary endpoints including safety assessment and objective response rate(ORR).ScRNA-seq,bulk RNA-seq,TCR-seq,cyTOF and WES were performed on pre-treatment and post-treatment samples.Among 53 total enrolled patients,44 completed the combined neoadjuvant therapy,and 30 of 44 patients(68.18%)achieved pCR.Additionally,14 out of 44 patients had a complete response(31.82%),with an ORR of 93.18%.The most commonly observed treatment-related adverse events(TRAEs)were alopecia,nausea and liver injury with 6 cases classified as grade 3 or higher adverse events.Immune response-related pathways,including TNF signaling pathway,T cell receptor signaling pathway,were enriched in pCR group.Pre-treatment model was identified and construct to predict response to immunotherapy.CDKN1A+CD8 T lymphocytes were enriched in pCR group after neoadjuvant immunotherapy.Dynamic change of immune-related pathways at an early stage during the neoadjuvant immunotherapy may be associated with the treatment effcacy.In conclusion,neoadjuvant treatment of tislelizumab with nab-paclitaxel and anthracycline-based chemotherapy showed promising clinical activity and was well-tolerated among TNBC patients,without high incidence of TRAEs.These findings provide evidence supporting neoadjuvant tislelizumab with chemotherapy as an effective rational approach for treating TNBC.
