Temporal Change in Treatment Patterns of Metastatic Colorectal Cancer and Its Association with Patient Survival:A Retrospective Cohort Study Based on an Intelligent Big-Data Platform

There is a lack of high-quality,large-scale,real-world evidence from patients with metastatic colorectal cancer(mCRC),especially in China.It remains unclear whether efforts to improve the quality of care for mCRC would improve patient survival outcomes in real-world practice.On the basis of an intelligent bigdata platform,we established a large-scale retrospective cohort of mCRC patients.We investigated the temporal changes in the systemic and local treatment(resection,ablation,or radiation to liver,lung,or extrahepatic and/or extrapulmonary metastases)patterns of mCRC,and whether these changes were associated with improved overall survival(OS)over time.Between July 2012 and December 2018,3403 eligible patients were included in this research.The median OS was 42.8 months(95%confidence interval(CI),40.7–46.6)for the entire cohort,25.6 months(95%CI,24.7–26.9)for those treated with systemic therapy only,and not reached(95%CI,78.6 months–not reached)for those receiving local therapy.The utility rate of local therapy increased continuously from 37.9%in 2012–2014 to 46.9%in 2017–2018.A dramatic increase in the utility rate of either cetuximab or bevacizumab was observed since 2017(39.9%,43.2%,and 60.3%in 2012–2014,2015–2016,and 2017–2018,respectively).Compared with 2012–2014,the OS of the entire population significantly improved in 2015–2016(hazard ratio(HR)=0.87(95%CI,0.78–0.99);P=0.034),but not for patients receiving systemic therapy only(HR=0.99(95%CI,0.86–1.14);P=0.889),whereas an improved OS was found in 2015–2018 for both the entire population(HR=0.75(95%CI,0.70–0.81);P<0.001)and for patients receiving systemic therapy only(HR=0.83(95%CI,0.77–0.91);P<0.001).In summary,the quality of care for mCRC,as indicated by the utility rate of targeted and local therapies,has been continuously improving over time in this study cohort,which is associated with continuously improving survival outcomes for these patients.

TMB相关免疫浸润调控评分(MOTIF)预测免疫治疗响应并指导联合增效

Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune checkpoint inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltration of CD8^(+)T cells.Using bulk ribonucleic acid sequencing(RNA-seq)data from 9311 tumor samples across 30 cancer types,we developed a novel tool called the modulator of TMB-associated immune infiltration(MOTIF),which comprises genes that can determine the extent of CD8^(+)T cell infiltration prompted by a certain TMB level.We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle.By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors,we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8^(+)T cell infiltration.Using pretreatment RNA-seq data from 13 ICI-treated cohorts,we validated the use of MOTIF in predicting CD8^(+)T cell infiltration and ICI efficacy.Among the components of MOTIF,we identified EMC3 as a negative regulator of CD8^(+)T cell infiltration,which was validated via in vivo studies.Additionally,MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8^(+)T cell infiltration and improve ICI efficacy.

胃肠肿瘤免疫治疗的进展、挑战与对策

Cancer immunotherapy,largely based on programmed cell death-1(PD-1)/PD-ligand 1(PD-L1)immune checkpoint blockade,has achieved remarkable advancements over the past decade in the treatment of human cancers[1,2],including a subset of gastrointestinal malignancies[3].

Impact of prior chemotherapy with two different fluoropyrimidines on the efficacy of capecitabine plus irinotecan or FOLFIRI with or without bevacizumab in metastatic colorectal cancer:a post hoc analysis of the AXEPT study

Dear Editor,Recently,the phase III Asian XELIRI(capecitabine plus irinotecan)ProjecT(AXEPT)study demonstrated the non-inferiority of modified capecitabine plus irinotecan(mXELIRI)±bevacizumab(Bev)to fluorouracil plus leucovorin with irinotecan(FOLFIRI)±Bev in terms of overall survival(OS)as a second-line treatment for patients with metastatic colorectal cancer[1,2].In the past decade,oral prodrugs of fluorouracil-containing regimens have shown similar efficacies to intravenous fluorouracilcontaining regimens.

Expert opinions on immunotherapy for patients with colorectal cancer

1 BACKGROUND With the rapid development of immune checkpoint inhibitors(ICIs)over the past decades,they have become a major area of interest in the treatment of colorectal cancer(CRC)[1,2].There are evidence pointing that programmed cell death protein-1(PD-1)blockade,alone or in combination with anti-cytotoxic T-lymphocyte-associated protein 4(anti-CTLA4)therapy,achieved durable responses in patients with mismatch repair-deficient(dMMR)or microsatellite instability-high(MSI-H)metastatic CRC(mCRC)[3–6].However,the optimal diagnostic method for detecting dMMR/MSI-H disease as well as the optimal anti-PD-1-based treatment modality still remains controversial in this patient subset.In addition,for the majority of mCRC cases that are mismatch repair-proficient(pMMR)or microsatellite stable(MSS),the clinical benefits from these agents are generally minimal[3,7],driving extensive research efforts to develop effective combination therapies in this disease subset.Moreover,investigations of anti-PD-1-based treatments have also been initiated in the nonmetastatic settings of CRC,with some encouraging preliminary evidence[8].Medical oncologists and surgeons from the Committee of Colorectal Cancer of the Chinese Society of Clinical Oncology had a panel discussion on immunotherapy for patients with colorectal cancer during a seminar on June 16,2020,in Guangzhou,China.Herein,the expert opinions have been summarized along with relevant clinical evidence(Table 1)to guide real-world treatment decision-making regarding the use of ICIs in patients with CRC.

Elevated peripheral blood neutrophil-to-lymphocyte ratio is associated with an immunosuppressive tumour microenvironment and decreased benefit of PD-1 antibody in advanced gastric cancer

Background Due to its limited efficacy and potential toxicity,anti-PD-1 monoclonal antibody is not suitable for all advanced gastric cancer(AGC)patients and predictive biomarkers identifying patients who can benefit from it are urgently needed.This study aimed to evaluate the predictive and prognostic value of inflammatory markers in the context of the systemic inflammatory status and tumour microenvironment.Methods The study included 58 patients from a prospective study investigating the safety and efficacy of toripalimab in chemorefractory AGC patients.Patient characteristics,treatment outcomes,and haematological parameters were analysed.Immune-cell infiltration and gene expression in tumour tissue were examined using transcriptome sequencing.Results In this cohort,the median follow-up time was 4.5 months,the median progression-free survival was 1.9 months,and the median overall survival(OS)was 4.8 months.The objective response rate was 12.1%and th disease control rate(DCR)was 39.7%.Both the baseline blood neutrophil-to-lymphocyte ratio(bNLR)with a cut-point of 2.7 and the early elevated dynamic change of the bNLR(dNLR)with a cut-point of 1.5 were prognostic factors of survival.Patients in the high bNLR or dNLR group had remarkably poor DCR(25.8%vs 59.1%,P=0.023;15.8%vs 54.6%,P=0.008).In multivariate analysis,bNLR and tumour mutational burden were independent prognostic factors of OS.Tumour RNA-seq analysis revealed enriched neutrophil infiltration and a higher tumour NLR in the bNLR-high group.Corresponding tumour gene-expression profiles were associated with neutrophil recruitment and inflammatory cytokine aggregation.Conclusions Our study demonstrated the potential clinical utility of NLR as a biomarker for patient selection and clinical management in predicting the prognosis of AGC patients as well as response to anti-PD-1 therapy.In addition,high bNLR reflected the imbalance of tumour-tissue-infiltrating neutrophils and lymphocytes,and was associated with an immunosuppressive and pro-tumour microenvironment.