Single nucleotide polymorphisms of MAGE-A3 gene and its clinical implications in Chinese patients with non-small cell lung cancer(NSCLC)

Background： Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism（SNP） loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors.Methods： Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR m RNA expression were detected by q RT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors.Results： Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC（0.681）/CT（0.319）, CC（0.660）/CG（0.340）, CC（0.681）/CA（0.319）, AA（0.984）/AT（0.016） and GG（1.000）/GA（0.000）, respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mR NA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients.Conclusions： Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR m RNA expression levels and helpful to the selection of patients for epidermal growth factor receptor（EGFR） targeted immunotherapy.

Non-platinum doublets versus single agents in non-small cell lung cancer （NSCLC） patients with elderly age and/or poor performance status： a meta-analysis

Objective： The aim of the study was to compare the efficacies and toxicities of non-platinum doublets （doublets group） with a non-platinum single agent （single-agent group） in previously untreated advanced non-small cell lung cancer （NSCLC） patients with elderly age and/or poor performance status （PS）. Methods： The PubMed database was screened. Subsequently, the hazard ratios （HRs） for overall survival （OS） and progression-free survival （PFS）, relative risks （RRs） for overall response rate （ORR） and one-year survival, and odds ratios （ORs） for the different types of toxicities were pooled using the Review Manager 5.0 package. Results： This study comprised of 1427 patients enrolled in four randomized controlled trials. The pooled HR showed that the doublet group could increase ORR （P = 0.002） with no heterogeneity （P = 0.64）, and might improve OS （P = 0.01 / P = 0.06） with heterogeneity （P 0.001）. There was no significant difference in PFS （P = 0.16） and one-year survival （P = 0.25） between two treatment groups. The doublet group led to more grade 3/4 neutropenia and thrombocytopenia than the single-agent group （P = 0.02 and P = 0.000, respectively）. The incidences of grade 3/4 anemia, vomiting, mucositis, constipation, diarrhea, neurotoxicity, allergy, and fatigue between the two treatment groups were insignificant. Conclusion： Except for neutropenia and thrombocytopenia, the non-platinum doublets could increase ORR, and might improve OS for NSCLC patients with elderly age and/or poor PS without addition of more side effects; however, the doublets showed an increased rate of neutropenia and thrombocytopenia. The addition of doublets may not improve PFS and one-year survival.

Expressions and significance of Survivin,MDR1 and MRP in non-small cell lung cancer (NSCLC)

Objective： To investigate the expressions and significance of Survivin, MDR1 and MRP in non-small cell lung cancer （NSCLC）. Methods： Immunohistochemical staining was used to detect the expressions of Survivin, MDR1 and MRP. The correlation between the results was assessed and the impact of Survivin on prognoses was also examined. Results： Survivin was expressed in 78% tissues from NSCLC patients but not found in tissues from control patients （P 〈 0.05）. The expression of Survivin was related to the tissue differentiation stage and lymph nodes metastasis of lung cancer. The mean survival time was shorter in patients with Survivin-expression than those who not. There was a significant correlation between MDR1 and Survivin （P 〈 0.05）, whereas no close correlation was found between MRP and Survivin. Conclusion： （1） Survivin is of critical importance in the development of NSCLC, thus may provide an novel therapeutic target for lung cancer; （2） MDR1 and MRP present in tissues from lung cancer synergistically with Survivin, which might be involved in turnout resistance.

Effects of insurance status on long-term survival among non-small cell lung cancer(NSCLC) patients in Beijing,China: A population-based study

Objective: To evaluate the effects of health insurance status on long-term cancer-specific survival of non-small cell lung cancer(NSCLC) in Beijing, China, using a population-based cancer registry data.Methods: Information on NSCLC patients diagnosed in 2008 was derived from the Beijing Cancer Registry.The medical records of 1,134 cases were sampled and re-surveyed to obtain information on potential risk factors.Poorly-insured status was defined as Uninsured and New Rural Cooperative Medical Insurance Scheme(NRCMS),while well-insured included Urban Employees Basic Medical Insurance(UEBMI) and Free Medical Care(FMC).To estimate survival outcomes, individuals were followed-up until December 31, 2018. Cancer-specific survival probabilities at 5 and 10 years after diagnosis were estimated using the Kaplan-Meier method. Log-rank test was used to compare long-term survival with different characteristics. Multivariable Cox proportional hazard regression model was used to examine the relative effect of insurance status on cancer-specific mortality.Results: Well-insured NSCLC patients have longer cancer-specific survival than poorly-insured individuals[hazard ratio(HR)=0.81;95% confidence interval(95% CI): 0.67-0.97), even after adjusting for age, gender, cancer stage, smoking status, family history and residential area. Older age and rural residence were associated with a higher risk of cancer-specific mortality(HR=1.03;95% CI: 1.02-1.03 and HR=1.25;95% CI: 1.07-1.46,respectively). Smoking individuals had a 41% higher long-term cancer-specific mortality risk than non-smoking ones(HR=1.41;95% CI: 1.20-1.66).Conclusions: NSCLC patients with good insurance status had better survival rates than those with poor insurance. An association was significant even after 10 years. Large population-based studies are needed to validate that high reimbursement insurance status can lead to the improvement of long-term cancer prognosis in China.

Clinical Biomarkers and Prognosis in Taiwan Residents Patients with Non-Small Cell Lung Cancer (NSCLC)

Introduction: Lung cancer is the leading cause of cancer death worldwide with poor survival rates. However, the prognostic factors for survival of patients with lung cancer are not well-established. In this study, we examined the impact of routine laboratory biomarkers and traditional factors on survival of patients with non-small cell lung cancer (NSCLC). Method: Secondary data analysis was conducted from a retrospective study of 404 patients with newly diag-nosed lung cancer in 2005-2007 in Taiwan. There were eight routine laboratory biomarkers and eight traditional factors investigated in the analyses. Cox proportional hazards model was used to assess the hazard ratios for the association between risk factors and patient overall survival. The Kaplan-Meier method was used to compare survival curves for each prognostic indicator. Results: High WBC counts (HR = 1.798, 95%CI: 1.225 - 2.639), low Hgb level (HR = 1.437, 95%CI: 1.085 - 1.903), and low serum albumin level (HR = 2.049, 95%CI: 1.376 - 3.052) were significant laboratory prognostic biomarkers for poor NSCLC survival. Additionally we confirmed the traditional prognostic factors for poor overall survival among NSCLC patients, including older age, comorbidity conditions, advanced cancer stage, and non-surgical treatment. Conclusions: This study identified three available laboratory biomarkers, high WBC counts, low Hgb level, and low serum albumin level, to be significant prognostic factors for poorer overall survival in NSCLC patients. Further prognostic evaluation studies are warranted to compare different ethnic groups on the prognostic values of these clinical parameters in NSCLC survival outcomes. These identified prognostic biomarkers should be included in early risk screening of hospitalized lung cancer patient population.

Treatment of Non-Small Cell Lung Cancer (NSCLC) Using CT in Combination with a PET Examination to Minimize the Clinical Target Volume of the Mediastinum

OBJECTIVE To decrease radiation injury of the esophagus and lungs by utilizing a CT scan in combination with PET tumor imaging in order to minimize the clinical target area of locally advanced non-small cell lung can-cer, without preventive radiation on the lymphatic drainage area. METHODS Of 76 patients with locally advanced non-small cell lung cancer (NSCLC), 32 received a PET examination before radiotherapy. Preventive radiation was not conducted in the mediastinum area without lymphatic metastasis, which was confirmed by CT and PET. For the other 44 patients, preventive radiation was performed in the lymphatic drainage area. PET examinations showed that the clinical target volume of the patients was decreased on average to about one third. The radiation therapy for patients of the two groups was the same, i.e. the dose for accelerated fractionated irradiation was 3 Gy/time and 5 time/week. The preventive dose was 42 to 45 Gy/time, 14 to 15 time/week, with 3-week treatment, and the therapeu- tic dose was 60 to 63 Gy/time, 20 to 21 time/week, with a period of 4 to 5 weeks. RESULTS The rate of missed lymph nodes beyond the irradiation field was 6.3% and 4.5% respectively in the group with and without PET exami- nation (P = 0.831). The incidence of acute radioactive esophagitis was 15.6 % and 45.5% in the two groups respectively (P = 0.006). The incidence of acute radiation pneumonia and long-term pulmonary fibrosis in the two groups was 6.3% and 9.1%, and 68.8% and 75.0%, respectively (P = 0.982 and P = 0.547). CONCLUSION The recurrence rate in the lymph nodes beyond the tar-get area was not increased after minimizing the clinical target volume (CTV), whereas radioactive injury to the lungs and esophageal injury was reduced, and especially with a significant decrease in the rate of acute radioactive esophagitis. The method of CT in combination with PET for minimizing the mediastinal CTV is superior to the conventional preventive radiation of the mediastinum.

Impact of Cardiac Dose on Overall Survival in Lung Stereotactic Body Radiotherapy (SBRT) Compared to Conventionally Fractionated Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

Purpose: To examine possible association between heart irradiation and Overall Survival (OS) in lung SBRT patients and to compare observed associations with cardiac toxicity models previously derived in LA-NSCLC patient studies. Materials and Methods: 197 Patients treated with lung SBRT at Mayo Clinic Arizona were selected for this IRB-approved study. Multivariate Cox model with Akaike Information Criterion (AIC) was used to select patient specific covariates associated with OS. Heart dosimetry was represented by VD indices, which is a percentage of volume exposed to dose D or greater. Multivariate Cox models with patient specific covariates and single VD index per model was used to find a range of doses which were predictive for OS. A digital subdivision of the heart was further used to determine the spatial distribution of doses which were predictive for OS. A coarse subdivision divided heart into 4 segments, while the fine subdivision divided heart into 64 segments. Knowledge constrained Fused Lasso operator was used to derive a more complete model which correlated heart dosimetry with OS. Results of statistical analysis were compared to predictions of a model of cardiac toxicity in LA-NSCLC patients. Results: Higher age (p < 0.001), higher stage (p < 0.001) and squamous cell histology (p = 0.001) were associated with reduced OS. Whole heart DVH analysis did not reveal associations between heart irradiation and reduced OS. Coarse subdivision of the heart into four segments revealed that the irradiation of two inferior segments of the heart with low doses was associated with reduced OS, V2Gy in the right-inferior segment (HR = 1.012/1%, p = 0.02), and V1Gy in the left-inferior segment (HR = 1.01/1%, p = 0.04). Maximum dose in the right-inferior segment of the heart was also associated with reduced OS (HR = 1.02/Gy, p = 0.02). Fine subdivision of the heart into 64 segments revealed that approximately 25% of heart volume in the inferior part of the heart (15/64 segments), when irradiated to doses in the 1 Gy - 5 Gy range, were predictive for reduced OS (HR = 1.01/1%, p = 0.01). A previously derived model of cardiac toxicity in LA-NSCLC patients did not predict a reduction of OS due to heart irradiation in lung SBRT patients, because of relatively low doses to the heart in most lung SBRT patients. Conclusions: Doses lower than 5 Gy in the inferior segments of the heart may be associated with reduced overall survival in patients treated for lung lesions with SBRT. Stage and histology of the disease, as well as patients’ age, were also associated with overall survival. Comparisons of cardiac toxicity patterns in LA-NSCLC patients and lung SBRT patients suggest different etiology of cardiac toxicity in the two groups.

A Prospective Study of the Effect of Different Palliative Radiotherapy Fractionation Schedules on Tumor Response and Toxicity in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Background: The optimal dose of palliative radiotherapy (RT) in symptomatic advanced lung cancer is unclear. Patients and methods: Patients with advanced NSCLC who were indicated for thoracic palliative RT with age up to 65 y and Performance Status (PS) 0 - 2 and no significant cardiac or lung co-morbidities were randomized into two fractionation arms: arm A: 30 Gy/10 over 2 weeks and arm B: 27 Gy/6 over 3 weeks (2 fractions per week) using 2 anterior posterior (AP-PA) fields in both arms. Primary end points were symptomatic and radiological tumor response, respiratory functions assessment. Secondary end point was toxicity. Results: From December 2014 to October 2015, 40 patients were randomized, 20 patients in each arm. There was statistically insignificant higher symptomatic improvement in arm B. Four weeks after treatment, 12 out of 40 patients (30%), 6 patients in each arm, had radiological Partial Response (PR) of the primary thoracic lesion without significant difference between the two arms. There was a tendency for improvement in the post treatment mean Forced Vital Capacity (FVC) and Forced Expiratory Volume in one second (FEV1) in each arm without statistical significance. There were no reported skin reactions or esophagitis in both arms up to 4 weeks after treatment. Eleven out of the 40 patients (27.5%), 6 in arm B and 5 in arm A, had radiological signs of radiation pneumonitis without significant difference between both arms. Conclusion: The two RT fractionation schedules showed equal efficacy in terms of symptoms relief, radiological response of the primary thoracic tumor, respiratory functions and toxicity. Thus the 27 Gy/6 fractionation arm appears preferable compared to 30 Gy/10 arm to minimize the patients’ visits and load on the machines.

Tankyrase 2 as a therapeutic target in non-small cell lung cancer: Implications for apoptosis and migration

This letter addresses Wang and Zhang's investigation into the role of tankyrase 2(TNKS2)as a pivotal driver of malignancy in non-small cell lung cancer(NSCLC)through mechanisms including apoptosis inhibition,enhanced cellular migration,andβ-catenin pathway activation.Their study in NSCLC cell lines demonstrates that TNKS2 overexpression stabilizesβ-catenin,subsequently triggering onco-genic gene expression and facilitating cellular migration-key attributes of meta-static potential.These insights position TNKS2 as a compelling target for therapy and a potential prognostic marker in NSCLC.Nevertheless,translating these in vitro findings to clinical practice requires validation in in vivo models.Addi-tionally,further research should investigate TNKS2 expression in patient samples and assess its implications in therapy resistance and combination treatment strategies.

Exercise rehabilitation on patients with non-small cell lung cancer: A meta-analysis of randomized controlled trials

BACKGROUND Lung cancer is one of the most common and deadly cancers worldwide.As the disease progresses and due to the side effects of treatment,patients’physical activity significantly decreases.AIM To systematically review and conduct a meta-analysis on the effects of exercise rehabilitation on the physical activity of lung cancer patients and determine the best implementation methods to provide clinical guidance.METHODS Literature was searched through multiple electronic databases.A random effects model was used to combine effect sizes through standardized mean difference(SMD).The Cochrane risk of bias tool was used to assess the quality of the lite-rature,sensitivity analysis was used to ensure the robustness of the results,and Egger’s test was used to detect publication bias and asymmetry.RESULTS A total of 11 studies involving 541 patients were included in this study.The phy-sical endurance,muscle function and cardiopulmonary function of non-small cell lung cancer(NSCLC)patients were evaluated.The overall effect size of the six-minute walk test(6MWT)was not statistically significant.However,subgroup analysis found that endurance significantly improved when exercise duration exceeded 0.5 hours(P≤0.05).In terms of muscle function,the overall effect size was SMD=0.619.Subgroup analysis showed that strength training,respiratory training,and cross-training(XT)significantly improved muscle function.Exercise rehabilitation significantly enhanced cardiopulmonary endurance(SMD=0.856,P=0.002),and the effect was better when the single exercise duration was more than 1 hour,age was over 65 years,and the intervention period was more than 3 months.CONCLUSION Exercise rehabilitation effectively improved muscle function in NSCLC patients,especially strength training,respiratory training,and cross-training.Cardiopulmonary function also showed improvement,particularly when exercise duration exceeded 1 hour,age was≥65 years,and the intervention period was more than 3 months.A single exercise duration of more than 0.5 hours can enhance patients’physical endurance.Appropriately increasing exercise duration and selecting suitable exercise forms can effectively improve the physical activity of NSCLC patients.

Physical exercise reverses immuno-cold tumor microenvironment via inhibiting SQLE in non-small cell lung cancer

Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one of the most prominent mechanisms explaining the effects of exercise on cancer[1,2].Physical exercise primarily lowers blood cholesterol and triglycerides,and protects against cardiovascular diseases[3].However,whether physical exercise can modulate cholesterol metabolism in tumor cells is currently unknown.

Analysis and Review of Downregulated Actin Cytoskeletal Proteins in Non-Small Cell Lung Cancer

Actin, a highly conserved protein, plays a dominant role in Non-small cell lung cancer (NSCLC). Late diagnosis and the aggressive nature of NSCLC pose a significant threat. Studying the clinic pathological properties of NSCLC proteins is a potential alternative for developing treatment strategies. Towards this, 35 downregulated actin cytoskeletal proteins on NSCLC prognosis and treatment were studied by examining their protein-protein interactions, gene ontology enrichment terms, and signaling pathways. Using PubMed, various proteins in NSCLC were identified. The protein-protein interactions and functional associations of these proteins were examined using the STRING database. The focal adhesion signaling pathway was selected from all available KEGG and Wiki pathways because of its role in regulating gene expression, facilitating cell movement and reproduction, and significantly impacting NSCLC. The protein-protein interaction network of the 35 downregulated actin cytoskeleton proteins revealed that ACTG1, ACTR2, ACTR3, ANXA2, ARPC4, FLNA, TLN1, CALD1, MYL6, MYH9, MYH10, TPM1, TPM3, TPM4, PFN1, IQGAP1, MSN, and ZXY exhibited the highest number of interactions. Whereas HSPB1, CTNNA1, KRT17, KRT7, FLNB, SEPT2, and TUBA1B displayed medium interactions, while UTRN, TUBA1B, and DUSP23 had relatively fewer interactions. It was discovered that focal adhesions are critical in connecting membrane receptors with the actin cytoskeleton. In addition, protein kinases, phosphatases, and adapter proteins were identified as key signaling molecules in this process, greatly influencing cell shape, motility, and gene expression. Our analysis shows that the focal adhesion pathway plays a crucial role in NSCLC and is essential for developing effective treatment strategies and improving patient outcomes.

Immunological features of EGFR-mutant non-small cell lung cancer and clinical practice:a narrative review

Immune checkpoint inhibitors(ICIs)have significantly improved outcomes for patients with advanced driver-negative non-small cell lung cancer(NSCLC).However,targeted therapy remains the preferred treatment for advanced driver-positive NSCLC,including cases with epidermal growth factor receptor(EGFR)mutations.Con-sidering the variability in EGFR-mutant NSCLC,including expression levels of programmed cell death ligand 1(PD-L1),tumor mutation burden(TMB),and other immunological features,the application of immunotherapy in this group is still a subject of investigation.Therefore,we have summarized and analyzed the immunological characteristics and regulatory mechanisms of different EGFR mutations in NSCLC,as well as the current clinical application of immunotherapy in the EGFR-mutant population,to provide a reference for future research.

Enhanced recovery after surgery in elderly patients with non-small cell lung cancer who underwent video-assisted thoracic surgery

BACKGROUND This study was designed to investigate the clinical outcomes of enhanced recovery after surgery(ERAS)in the perioperative period in elderly patients with nonsmall cell lung cancer(NSCLC).AIM To investigate the potential enhancement of video-assisted thoracic surgery(VATS)in postoperative recovery in elderly patients with NSCLC.METHODS We retrospectively analysed the clinical data of 85 elderly NSCLC patients who underwent ERAS(the ERAS group)and 327 elderly NSCLC patients who received routine care(the control group)after VATS at the Department of Thoracic Surgery of Peking University Shenzhen Hospital between May 2015 and April 2017.After propensity score matching of baseline data,we analysed the postoperative stay,total hospital expenses,postoperative 48-h pain score,and postoperative complication rate for the 2 groups of patients who underwent lobectomy or sublobar resection.RESULTS After propensity score matching,ERAS significantly reduced the postoperative hospital stay(6.96±4.16 vs 8.48±4.18 d,P=0.001)and total hospital expenses(48875.27±18437.5 vs 55497.64±21168.63 CNY,P=0.014)and improved the satisfaction score(79.8±7.55 vs 77.35±7.72,P=0.029)relative to those for routine care.No significant between-group difference was observed in postoperative 48-h pain score(4.68±1.69 vs 5.28±2.1,P=0.090)or postoperative complication rate(21.2%vs 27.1%,P=0.371).Subgroup analysis showed that ERAS significantly reduced the postoperative hospital stay and total hospital expenses and increased the satisfaction score of patients who underwent lobectomy but not of patients who underwent sublobar resection.CONCLUSION ERAS effectively reduced the postoperative hospital stay and total hospital expenses and improved the satisfaction score in the perioperative period for elderly NSCLC patients who underwent lobectomy but not for patients who underwent sublobar resection.

Imbalance of Circulating Follicular Regulatory and Follicular Helper T Cell Subpopulations Is Associated with Disease Progression and Serum CYFRA 21-1 Levels in Patients with Non-small Cell Lung Cancer

Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.

Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation:A multicenter,case-series study in China

Objective:To provide real-world evidence for the application of first-line dacomitinib treatment for epidermal growth factor receptor(EGFR)21L858R mutant non-small cell lung cancer(NSCLC)patients in China and to explore the factors influencing the efficacy and safety.Methods:A longitudinal,consecutive case-series,multicenter study with mixed prospective and retrospective data was conducted.The primary endpoint was progression-free survival(PFS),and the secondary endpoints included duration of treatment(DOT),overall survival(OS),objective response rate(ORR),disease control rate(DCR)and safety.Results:A total of 155 EGFR 21L858R mutant patients treated with first-line dacomitinib were included.The median follow-up time for these patients was 20.4 months.Among 134 patients with evaluable lesions,the ORR was 70.9%and the DCR was 96.3%.The median PFS was 16.3[95%confidence interval(95%CI),13.7−18.9]months.Multivariate Cox regression analysis suggested that the baseline brain metastasis(BM)status[with vs.without BM:hazard ratio(HR),1.331;95%CI,0.720−2.458;P=0.361]and initial doses(45 mg vs.30 mg:HR,0.837;95%CI,0.427−1.641;P=0.604)did not significantly affect the median PFS.The median DOT was 21.0(95%CI,17.5−24.6)months and the median OS was not reached.Genetic tests were performed in 64 patients after progression,among whom 29(45.3%)patients developed the EGFR 20T790M mutation.In addition,among the 46 patients who discontinued dacomitinib treatment after progression,31(67.4%)patients received subsequent third-generation EGFR-tyrosine kinase inhibitors.The most common grade 3−4 adverse events were rash(10.4%),diarrhea(9.1%),stomatitis(7.1%)and paronychia(4.5%).The incidence of grade 3−4 rash was significantly higher in the 45 mg group than that in the 30 mg group(21.9%vs.7.5%,P=0.042).Conclusions:First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population:An integrated genomic and transcriptional analysis

Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully investigated.This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.Methods:A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled.HRD status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered HRD-positive.Genomic,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were analyzed.Results:Of the patients,25.1%(89/355)were HRD-positive.Compared to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(P<0.001),and fewer driver gene mutations(P<0.001).Furthermore,HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes,MET and MYC in epidermal growth factor receptor(EGFR)/anaplastic lymphoma kinase(ALK)mutant NSCLC,and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC.HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity.HRD-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T cells.HRD-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.Conclusions:Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC.Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC.This study highlights potential actionable alterations in HRD-positive NSCLC,suggesting possible combinational therapeutic strategies for these patients.

IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Machine learning based on metabolomics unveils neutrophil extracellular trap-related metabolic signatures in non-small cell lung cancer patients undergoing chemoimmunotherapy

BACKGROUND Non-small cell lung cancer(NSCLC)is the primary form of lung cancer,and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease.However,the emergence of drug resistance significantly limits the effectiveness of these therapeutic strategies.Consequently,it is imperative to devise methods for accurately detecting and evaluating the efficacy of these treatments.AIM To identify the metabolic signatures associated with neutrophil extracellular traps(NETs)and chemoimmunotherapy efficacy in NSCLC patients.METHODS In total,159 NSCLC patients undergoing first-line chemoimmunotherapy were enrolled.We first investigated the characteristics influencing clinical efficacy.Circulating levels of NETs and cytokines were measured by commercial kits.Liquid chromatography tandem mass spectrometry quantified plasma metabolites,and differential metabolites were identified.Least absolute shrinkage and selection operator,support vector machine-recursive feature elimination,and random forest algorithms were employed.By using plasma metabolic profiles and machine learning algorithms,predictive metabolic signatures were established.RESULTS First,the levels of circulating interleukin-8,neutrophil-to-lymphocyte ratio,and NETs were closely related to poor efficacy of first-line chemoimmunotherapy.Patients were classed into a low NET group or a high NET group.A total of 54 differential plasma metabolites were identified.These metabolites were primarily involved in arachidonic acid and purine metabolism.Three key metabolites were identified as crucial variables,including 8,9-epoxyeicosatrienoic acid,L-malate,and bis(monoacylglycerol)phosphate(18:1/16:0).Using metabolomic sequencing data and machine learning methods,key metabolic signatures were screened to predict NET level as well as chemoimmunotherapy efficacy.CONCLUSION The identified metabolic signatures may effectively distinguish NET levels and predict clinical benefit from chemoimmunotherapy in NSCLC patients.

Employing a Backpropagation Neural Network for Predicting Fear of Cancer Recurrence among Non-Small Cell Lung Cancer Patients

Objective:Non-small cell lung cancer(NSCLC)patients often experience significant fear of recurrence.To facilitate precise identification and appropriate management of this fear,this study aimed to compare the efficacy and accuracy of a Backpropagation Neural Network(BPNN)against logistic regression in modeling fear of cancer recurrence prediction.Methods:Data from 596 NSCLC patients,collected between September 2023 and December 2023 at the Cancer Hospital of the Chinese Academy of Medical Sciences,were analyzed.Nine clinically and statistically significant variables,identified via univariate logistic regression,were inputted into both BPNN and logistic regression models developed on a training set(N=427)and validated on an independent set(N=169).Model performances were assessed using Area Under the Receiver Operating Characteristic(ROC)Curve and Decision Curve Analysis(DCA)in both sets.Results:The BPNN model,incorporating nine selected variables,demonstrated superior performance over logistic regression in the training set(AUC=0.842 vs.0.711,p<0.001)and validation set(0.7 vs.0.675,p<0.001).Conclusion:The BPNN model outperforms logistic regression in accurately predicting fear of cancer recurrence in NSCLC patients,offering an advanced approach for fear assessment.