| Objective:Neoadjuvant chemotherapy(NACT)is one of standard strategies for locally advanced gastric cancer(LAGC).Platinum plus fluorouracil is the basic regimen for NACT.Docetaxel combined triplet regimen is also frequently used in neoadjuvant setting.Our study is aim to compare the efficacy and safety of the docetaxel/oxaliplatin or cisplatin/S-1(DOS/DCS)triplet regimen with oxaliplatin or cisplatin/S-1(SOX/CS)doublet regimen as NACT in LAGC.Methods:The clinicopathologic data of patients with LAGC who received DOS/DCS or SOX/CS as NACT from February 2013 to December 2017 in National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively collected.Mandard Tumor Regression Grade(TRG)system were used to analysis the surgery sample after NACT.The primary endpoint is severe pathological response(SPR)rate(defined as TRG 1-2).The secondary endpoints are pathological complete response(PCR)rate,pathological response rate(defined as TRG 1-3),recurrence rate(RR)and adverse events.Results:115 patients were enrolled in this study.65(56.5%)patients received SOX/CS doublet regimen and 50(43.5%)patients received DOS/DCS triplet regimen.The SPR in DOS/DCS group was 24.0%,which was numerically higher than that in SOX/CS group as 13.9%,with no statistical difference.The PCR rates of DOS/DCS and SOX/CS were 6.0%and 10.8%,respectively,with no statistical difference(P=0.571).The pathological response rate in DOS/DCS was 70.0%,which was significantly higher than that in SOX/CS group as 46.2%(P=0.011).Patients with SPR achieved significantly lower RR than that with non-SPR,as 4.7%and 56.4%in both group respectively(P=0.000).Compared with non-pathological response,patients with pathological response presented with significantly lower RR(32.3%vs.66.0%,P=0.000).The RRs of DOS/DCS and SOX/CS groups were 44.0%and 49.2%(P=0.577).The common grade 3 to 4 adverse events in DOS/DCS and SOX/CS were leucopenia/neutropenia(8.0%vs.4.6%),thrombocytopenia(6.0%vs.6.2%),nausea(4.0%vs.3.1%),vomit(4.0%vs.3.1%),with no significant differences between groups.Conclusions:Although DOS/DCS does not significantly improve SPR rate compared with SOX/CS,it presents with better pathological response and is well tolerated.Patients with SPR achieve significantly lower RR than patients with non-SPR.DOS/DCS might be a potential option for NACT in LAGC.Objective:Neoadjuvant chemotherapy(NACT)can alter tumor immune microenvironment,while the expression of immune molecules in tumor microenvironment can affect prognosis.In this study,we analysis the changes in tumor infiltrating immune cells and checkpoint molecules following NACT in locally advanced gastric cancer(LAGC),aiming to explore the impact of chemotherapy on tumor microenvironment,and seek the potential predictive and prognostic immune biomarkers.Methods:Paired tumor samples(pre-NACT and post-NACT)of 60 patients were retrospectively identified and analysed by multiplex immunohistochemistry with a panel including CD4,CD8,FOXP3,PD-1,PD-L1,and TIM3.Clinical data of patients were collected.We analysed the changes in expression of immune markers following NACT and the correlation between the changes and clinical characteristics,efficacy and survival.Results:Following NACT,the overall median expression levels of CD4,CD8,PD1,PD-L1 and TIM3 were significantly increased(P=0.008 for PD-L1 and P<0.001 for the other markers),while the median FOXP3 expression level remained stable(P=0.120).Individually,the majority of patients presented increased expression of the markers,while 8.5%,11.9%,16.9%,25.4%,22.0%and 42.2%of patients had decreased expression of CD4,CD8,PD-1,PD-L1,TIM3 and FOXP3,respectively.Changes in expression between baseline and post-NACT of TIM3,PD-1,and PD-L1 showed strongly positive pairwise correlations with each other(P<0.001).Patients with good pathological response presented with relatively low expression of baseline PD-1(P=0.038)and TIM3(P=0.0053).Multivariate analysis demonstrated that upregulation of CD8(HR 0.21,P=0.013)following NACT were beneficial prognostic factors of OS.Continuous variable analysis indicated that relatively high level of baseline PD-L1 was associated with poor survival(HR 1.20,P=0.045).Relatively high upregulation level of CD8(HR 0.73,P=0.028)?PD-1(HR 0.76,P=0.027)and PD-L1(HR 0.67,P=0.038)following NACT were asscociated with prolonged survival.Conclusions:NACT results in elevated expression of PD-1?PD-L1 and TIM3,and infiltration of CD4+,CD8+immune cells in LAGC with changes in expression of PD-1?PD-L1 and TIM3 positively related with each other.Significant upregulation of CD8?PD-1 and PD-L1 following NACT might predict better OS.This may raise the possibility of applying checkpoint inhibitor immunotherapy with chemotherapy or even TIM3?PD-1/PD-L1 dual checkpoint inhibitors in LAGC.Objective:Neoadjuvant chemotherapy(NACT)is one of standard strategies for locally advanced gastric cancer(LAGC).However,about 40-50%patients do not respond to NACT.There are no effective biomarkers to predict the efficacy of NACT.Our study analysis whole transcriptome profile in pre-NACT tumor samples,aiming to explore the relationship between molecular portrait and efficacy,and seek the potential predictive biomarkers of NACT in LAGC.Methods:Pre-NACT tumor samples of 31 LAGC patients were retrospectively identified and analyzed by whole-transcriptome analysis.Clinical data of patients were collected.Mandard tumor regression grade(TRG)was used to evaluate pathological efficacy.Mandard TRG 1-2 was defined as severe pathological response(SPR).Gene set enrichment analysis of differentially expressed genes was conducted.The correlation between differentially expressed genes and efficacy of NACT was analyzed.Results:Among the entire cohort,17(54.8%)patients achieved partial response(PR),14(45.2%)patients achieved stable disease(SD)in terms of clinical efficacy.According to pathological response,SPR and non-SPR(TRG 3-5)were presented in 8(25.8%)and 23(74.2%)patients,respectively.Compared with non-SPR patients,patients with SPR showed significantly increased expression of LRP2?CLDN6?CALB2?COL2A1?ASGR2?THPO?BMS1P8(Padjust<0.05),while TERC showed significantly increased in non-SPR group.Conclusions:There was significant difference in the gene expression profiles between patients with different pathological responses to NACT in LAGC.LRP2?CLDN6?CALB2?COL2A1?ASGR2,THPO?BMS1P8 and TERC might be potential predictive biomarkers for NACT,which need tested by further investigation. |
PDF Full Text Request