The Exploration Of Personalized Therapeutic Strategy And Promising Biomarkers For Patients With Triple-negative Breast Cancer

To identify the advantageous therapy as the first-line treatment for patients with triple-negative breast cancer(TNBC).Randomized controlled trials were searched on Medline,Embase,ClinicalTrials.gov,and Cochrane Library between January 2001 and December 2021.The primary endpoint was progression-free survival(PFS)and secondary endpoints were overall survival(OS)and treatment-related adverse events(TRAEs).A Bayesian framework was applied to facilitate indirect comparisons,of which the outcomes were presented using the surface under the cumulative ranking curve(SUCRA)values,synthesized hazard ratio,risk ratio,and 95%credible interval.A total of 3140 patients were identified.Pooled results of PFS revealed that chemotherapy plus AKT inhibitors(AKTi)was likely the most effective therapy among enrolled therapies(SUCRA=91.6%),of which the result remained consistent in comparative analysis for OS.In addition,no significant difference was detected between PD-1/PD-L1 antibodies in the entire patients,whereas the PD-1 inhibitors(PD-1i)regimen was advantageous over PD-L1 inhibitors(PD-Lli)therapy for PD-L1 positive TNBC.Concerning TRAEs,an apparent heterogeneity associated with safety profiles were denoted among enrolled agents.Chemotherapy plus AKTi was the most effective therapy with comparable safety profiles.Chemotherapy plus anti-PD-1 regimen was advantageous over the combination therapy based on PD-L1 blockade.Objective To develop and validate a prediction model for the pathological complete response(pCR)to neoadjuvant chemotherapy(NCT)of triple-negative breast cancer(TNBC).Methods We systematically searched Gene Expression Omnibus,ArrayExpress,and PubMed for the gene expression profiles of operable TNBC accessible to NCT.Molecular heterogeneity was detected with hierarchical clustering method,and the biological profiles of differentially expressed genes were investigated by Gene Ontology,Kyoto Encyclopedia of Genes and Genomes analyses,and Gene Set Enrichment Analysis(GSEA).Next,machinelearning algorithms including random-forest analysis and least absolute shrinkage and selection operator(LASSO)analysis were synchronously performed and,then,the intersected proportion of significant genes was undergone binary logistic regression to fulfill variables selection.The predictive response score(pRS)system was built as the product of the gene expression and coefficient obtained from the logistic analysis.Last,the cohorts were randomly divided in a 7:3 ratio into training cohort and validation cohort for the introduction of a robust model,and a nomogram was constructed with the independent predictors for pCR rate.Results A total of 217 individuals from four cohort datasets(GSE32646,GSE25065,GSE25055,GSE21974)with complete clinicopathological information were included.Based on the microarray data,a six-gene panel(ATP4B,FBXO22,FCN2,RRP8,SMERK2,TET3)was identified.A robust nomogram,adopting pRS and clinical tumor size stage,was established and the performance was successively validated by calibration curves and receiver operating characteristic curves with the area under curve 0.704 and 0.756,respectively.Results of GSEA revealed that the biological processes including apoptosis,hypoxia,mTORC1 signaling and myogenesis,and oncogenic features of EGFR and RAF were in proactivity to attribute to an inferior response.Conclusions This study provided a robust prediction model for pCR rate and revealed potential mechanisms of distinct response to NCT in TNBC,which were promising and warranted to further validate in the perspective.Dermatological toxicity is the most common immune-related adverse events(irAEs)following immune checkpoint inhibitors(ICIs).A better understanding of this side effect enables early recognition,diagnosis and management in clinical practice.We did a systematic review and meta-analysis of literature published on ClinicalTrials.gov,PubMed,Embase,and Cochrane Library to assess the differences in cutaneous irAEs among ICIs,the effect from dosage and combined treatment on the incidence,and the predictive values for prognosis.A total of 46 eligible RCTs involving 28569 patients were included.This study indicates that cutaneous irAEs are dose-independent and agent-specific immune reactions with the highest risk observed in CTLA-4 blockade and might not a surrogate prognostic indicator.Objective:In our phase Ib trial,TQB2450,a novel humanized IgG1 antibody against PD-L1,plus antiangiogenic multikinase inhibitor anlotinib demonstrated promising antitumor activities in women with pretreated relapsed or metastatic triple negative breast cancer(TNBC).In the current report,we conducted thorough explorative analyses of the gene mutational profile and,particularly,genomic biomarkers to predict the treatment response and survival outcomes.Methods:Targeted next generation sequencing(NGS)was undertaken using peripheral blood samples collected prior to the start of treatment and at the time of disease progression.Blood-based tumor mutational burden(bTMB)and maximum somatic allele frequency(MSAF)were determined.Correlation between biomarkers and clinical outcomes including objective response rate(ORR)and progression-free survival(PFS)was analyzed.Results:Totally 31 women received targeted NGS and functional driver mutations in 29 women were analyzed.Twenty-six women(89.7%)each harbored a median of 3 gene mutations(range 0-10).The three most frequent mutations were TP53(72%),MLL3(28%),and PIK3CA(17%).At a bTMB cutoff of 5 Muts/Mb,54.6%(6/11)of the women with low bTMB responded to anlotinib plus TQB2450 versus 6.7%(1/15)of the women with high bTMB(P=0.021).Women with low bTMB had a significantly longer median PFS than women with high bTMB(7.5 vs.4.1 months,P=0.008).At a MSAF cutoff of 13%,50.0%(8/16)of the women with low MSAF showed objective response versus 7.7%(1/13)of the women with high MSAF(P=0.020).Women with a low MSAF had a significantly longer median PFS than women with a high MSAF(7.9 vs.2.6 months,log rank test,P<0.0001).Nine women with both low MSAF and low bTMB(90.0%,9/10)showed objective response to anlotinib plus TQB2450 while only 1 woman(0.05%,1/19)among those with other scenarios of MSAF and bTMB responded to the combination treatment(P=0.00046).They also had a significantly longer median PFS than women with other scenarios of MSAF and bTMB(11.1 months vs.2.9 months,P<0.0001).Conclusion:bTMB and MSAF alone or in combination can effectively identify women with pretreated advanced TNBC who could benefit from TQB2450 plus anlotinib,suggesting a molecularly stratified strategy for combined immune therapy and antiangiogenic therapy.The findings support further study of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of treatment response in women with advanced TNBC.