中国非小细胞肺癌免疫检查点抑制剂治疗专家共识(2019年版)

非小细胞肺癌(non-small cell lung cancer, NSCLC)是肺癌中最常见的病理类型,大多数NSCLC患者在确诊时已属晚期。对于驱动基因突变阴性的患者而言,目前的治疗仍以化疗为主,总体预后较差,改善治疗现状、获得长期生存是晚期NSCLC患者最迫切的需求。近年来,肿瘤免疫治疗发展迅速,免疫检查点抑制剂(immune checkpoint inhibitors, ICIs),尤其是以程序性死亡因子-1(programmed death-1, PD-1)/程序性死亡因子配体-1(programmed deathligand 1, PD-L1)为靶点的ICIs在驱动基因突变阴性的NSCLC治疗中取得了突破性的进展,为患者带来了生存获益,改变了NSCLC的治疗格局,显示出越来越重要的地位。由中国临床肿瘤学会(Chinese society of clinical oncology, CSCO)NSCLC专家委员会牵头,组织该领域的相关专家,在参考国内外文献、系统评价中外临床研究结果、结合专家经验与体会的基础上,达成统一意见并制定本共识,以期指导国内同行更好地应用ICIs治疗NSCLC。

中国非小细胞肺癌免疫检查点抑制剂治疗专家共识(2020年版)

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌最常见的病理类型。晚期NSCLC的系统性抗肿瘤治疗经历了化疗、靶向治疗及免疫治疗的变革,患者总体生存时间不断延长。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs),尤其是程序性死亡分子-1(programmed cell death protein 1,PD-1)/程序性死亡分子配体-1(programmed death-ligand 1,PD-L1)抗体已成为表皮生长因子受体(epidermal growth factor receptor,EGFR)/间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)阴性晚期NSCLC一线及二线的标准治疗和局部晚期NSCLC同步放化疗后标准治疗,并在辅助/新辅助治疗中显示出可喜的结果,改变了NSCLC整体治疗格局。随着越来越多的ICIs在国内获批肺癌适应证,中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)NSCLC专家委员会牵头,组织该领域的专家,结合2019年版专家共识,参考最新国内外文献、临床研究数据及系统评价,在专家共同讨论的基础上,达成统一意见并制定、更新本共识,为国内同行更好地应用ICIs治疗NSCLC提供参考意见。

Prediction of Driver Gene Matching in Lung Cancer NOG/PDX Models Based on Artificial Intelligence

Patient-derived tumor xenografts(PDXs)are a powerful tool for drug discovery and screening in cancer.However,current studies have led to little understanding of genotype mismatches in PDXs,leading to massive economic losses.Here,we established PDX models from 53 lung cancer patients with a genotype matching rate of 79.2%(42/53).Furthermore,17 clinicopathological features were examined and input in stepwise logistic regression(LR)models based on the lowest Akaike information criterion(AIC),least absolute shrinkage and selection operator(LASSO)-LR,support vector machine(SVM)recursive feature elimination(SVM-RFE),extreme gradient boosting(XGBoost),gradient boosting and categorical features(Cat Boost),and the synthetic minority oversampling technique(SMOTE).Finally,the performance of all models was evaluated by the accuracy,area under the receiver operating characteristic curve(AUC),and F1 score in 100 testing groups.Two multivariable LR models revealed that age,number of driver gene mutations,epidermal growth factor receptor(EGFR)gene mutations,type of prior chemotherapy,prior tyrosine kinase inhibitor(TKI)therapy,and the source of the sample were powerful predictors.Moreover,Cat Boost(mean accuracy=0.960;mean AUC=0.939;mean F1 score=0.908)and the eight-feature SVM-RFE(mean accuracy=0.950;mean AUC=0.934;mean F1 score=0.903)showed the best performance among the algorithms.Meanwhile,application of the SMOTE improved the predictive capability of most models,except Cat Boost.Based on the SMOTE,the ensemble classifier of single models achieved the highest accuracy(mean=0.975),AUC(mean=0.949),and F1 score(mean=0.938).In conclusion,we established an optimal predictive model to screen lung cancer patients for non-obese diabetic(NOD)/Shi-scid,interleukin-2 receptor(IL-2R)γ^(null)(NOG)/PDX models and offer a general approach for building predictive models.

Pyroptosis:A promising target for lung cancer therapy

Pyroptosis is a type of programed cell death that differs from apoptosis,ferroptosis,or necrosis.Numerous studies have reported that it plays a critical role in tumorigenesis and modification of the tumor microenvironment in multiple tumors.In this review,we briefly describe the canonical,non-canonical,and alternative mechanisms of pyroptotic cell death.We also summarize the potential roles of pyroptosis in oncogenesis,tumor development,and lung cancer treatment,including chemotherapy,radiotherapy,targeted therapy,and immunotherapy.Pyrop-tosis has double-edged effects on the modulation of the tumor environment and lung cancer treatment.Further exploration of pyroptosis-based drugs could provide novel therapeutic strategies for lung cancer.

Alterations of DNA damage response pathway:Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

Changing profile of lung cancer clinical characteristics in China:Over 8-year population-based study

Background:Although examinations and therapies for bronchial lung cancer,also called lung cancer(LC),have become more effective and precise,the morbidity and mortality of LC remain high worldwide.Describing the changing profile of LC characteristics over time is indispensable.This study aimed to understand the changes in real-world settings of LC and its characteristics in China.Methods:In this study,119,785 patients were enrolled from 2012 to 2020 in the Shanghai Pulmonary Hospital.The patients’medical records were extracted from the hospital’s database.Demographic characteristics,general clinicopathological information,and blood coagulation indices at the initial diagnoses were analyzed using the Kruskal-Wallis,Nemenyi,chi-squared,and Bonferroni tests.Changes in demographic characteristics during the 8-year study period,namely dynamic changes among different stages and different pathological types,were evaluated.Results:The percentages of female(from 38.50%[323/839]in 2012 to 48.29%[5112/10,585]in 2020)and non-smoking LC(from 69.34%[475/685]to 80.48%[8055/10,009])patients increased significantly during the study period,with a trend toward a younger age at diagnosis(from 3.58%[30/839]to 8.99%[952/10,585]).Over the study period,the proportion and absolute number of lung adenocarcinoma cases increased(from 67.97%[433/637]to 76.31%[6606/8657])while the proportion of lung squamous cell carcinoma decreased(from 21.19%[135/637]to 12.08%[1046/8657]).Comprehensive driver gene mutation examination became more common,and epidermal growth factor receptor(EGFR)mutation occurred more frequently in female vs.male(62.03%[12793/20625]vs.29.90%[8207/27,447])and non-smoking vs.smoking(53.54%[17,203/32,134]vs.23.73%[3322/13,997])patients(both P<0.001).The distribution of the common driver genes differed among different stages of LC.EGFR mutation was detected most frequently at each stage,and other driver gene alterations were more common in advanced stages(P<0.001).The combination of chemotherapy,targeted ther-apy,and immunotherapy,as a comprehensive management regimen,gradually became predominant over the study period(P<0.001).A hypercoagulable state was shown in advanced-stage LC patients and patients with the anaplastic lymphoma kinase fusion,indicated by significantly elevated levels of d-dimer,fibrinogen,and fibrinogen degradation products.Conclusions:This study comprehensively depicted the changing characteristics of Chinese LC patients over an 8-year period to provide preliminary insights into LC treatment.Trial registration:ClinicalTrials.gov,NCT05423236.

Update on lymphocyte-activation gene 3 (LAG-3) in cancers: from biological properties to clinical applications

Immunotherapy that targets checkpoints, especially programmed cell death protein 1 and programmed cell death ligand 1, has revolutionized cancer therapy regimens. The overall response rate to mono-immunotherapy, however, is limited, emphasizing the need to potentiate the efficacy of these regimens. The functions of immune cells are modulated by multiple stimulatory and inhibitory molecules, including lymphocyte activation gene 3 (LAG-3). LAG-3 is co-expressed together with other inhibitory checkpoints and plays key roles in immune suppression. Increasing evidence, particularly in the last 5 years, has shown the potential of LAG-3 blockade in anti-tumor immunity. This review provides an update on the biological properties and clinical applications of LAG-3 in cancers.