Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study.

Background: Immune checkpoint inhibitors (ICIs) have dramatically changed the first-line treatment pattern of non-small cell lung cancer (NSCLC) without driver gene alterations. However, the optimal choice for second-line treatment after initial treatment with ICIs is unclear. This study aimed to clarify the efficacy and safety of ICI rechallenge therapy in locally advanced and advanced NSCLC. Methods: We retrospectively analyzed the histories of 224 patients with locally advanced or advanced NSCLC treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy and/or antiangiogenic therapy in first-line treatment. Progression-free survival 2 (PFS2) was the time from the first defined progress disease (PD) to the second disease progression or death. Efficacy evaluation was performed directly in accordance with RECIST v1.1 criteria. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Survival data were estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test in overall cohort and other subgroups. Results: There were no significant differences in objective response rate (ORR) and median PFS2 (mPFS2) between the ICI rechallenge group and non-rechallenge group (ORR: 10.3% vs. 15.3%, P=0.308; mPFS2: 5.33 vs. 4.40 months, P=0.715). And the ICI rechallenge group showed no new safety signals compared with non-rechallenge group. In ICI rechallenge group, patients resistant to first-line immunotherapy had a lower ORR and shorter PFS2 compared with those who responded to initial ICIs treatment (ORR: 7.0% vs. 17.6%, P=0.038; mPFS2: 3.68 vs. 5.91 months, P=0.014). No significant difference in mPFS2 was observed among different second-line treatment groups (P=0.362). Radiotherapy in second-line treatment and ICI rechallenge therapy were not the main factors affecting PFS2. Conclusions: ICI rechallenge therapy beyond disease progression did not improve clinical outcomes in patients with NSCLC, but no new safety signals emerged. However, patients with favorable response to initial ICIs treatment still showed significant efficacy of subsequent ICI rechallenge therapy.

Systematic annotation of orphan RNAs reveals blood-accessible molecular barcodes of cancer identity and cancer-emergent oncogenic drivers.

From extrachromosomal DNA to neo-peptides, the broad reprogramming of the cancer genome leads to the emergence of molecules that are specific to the cancer state. We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic and comprehensive search to identify, annotate, and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen. Together, our findings establish oncRNAs as an emergent class of cancer-specific non-coding RNAs with potential roles in tumor progression and clinical utility in liquid biopsies and disease monitoring.

Comparison of Efficacy and Safety of First-Line Treatment Options for Unresectable Stage III Non-Small Cell Lung Cancer: A Retrospective Analysis.

Background: Based on PACIFIC trial, durvalumab as consolidation therapy following concurrent chemoradiotherapy (cCRT) has been a new standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). In clinical applications, there are heterogeneous adjustments or novel strategies following specialized discussions in experienced multidisciplinary teams. This study retrospectively compared the efficacy and safety of different first-line treatments for unresectable stage III NSCLC. Methods: We retrospectively analyzed 397 patients who received first-line treatment for unresectable stage III NSCLC. Comparisons and statistical analyses of treatment were made in terms of efficacy and safety. Adverse events and responses were assessed using CTCAE v5.0 and RECIST v1.1. The progression-free survival (PFS) was estimated using the Kaplan-Meier method or the Cox survival regression model and compared using the log-rank test. Results: In wild-type driver genes group, the objective response rate (ORR), disease control rate (DCR), and median PFS (mPFS) were prolonged in the radiotherapy group compared to those in the nonradiotherapy group (ORR: 50.94% vs. 30.06%, p < 0.001; DCR: 98.11% vs. 80.37%, p < 0.001; and mPFS: 21.00 vs. 8.20 months, p < 0.001). The incidence of pneumonia at any grade in the radiotherapy group was higher than that in the nonradiotherapy group (9.43% vs. 2.45%, p = 0.008). In the radiotherapy group, the chemoradiotherapy (CRT) plus immunotherapy subgroup had longer mPFS than the CRT subgroup, with increased toxicity at any grade (24.60 vs. 17.90 months, p = 0.025, and 83.17% vs. 65.52%, p = 0.011). In the nonradiotherapy group, the DCR and mPFS were higher in the chemotherapy plus immunotherapy subgroup than in the chemotherapy subgroup, with increased toxicity at any grade (DCR: 93.67% vs. 67.86%, p < 0.001; mPFS: 13.53 vs. 5.07 months, p < 0.001; and 68.35% vs. 41.67%, p = 0.001). In the mutant driver genes group, the efficacy did not significantly differ among the radiotherapy subgroup, targeted therapy subgroup, and radiotherapy plus targeted therapy subgroup (ORR: p = 0.633; mPFS: p = 0.450). Conclusions: For unresectable stage III NSCLC patients with wild-type driver genes, the combination of radiotherapy and immunotherapy in the initial treatment was essential to significantly improve the efficacy. For patients with mutant driver genes, radiotherapy, targeted therapy, and the combination of radiotherapy and targeted therapy showed similar short-term efficacy.

Comparison of Efficacy and Safety of Second-Line Treatment Options for Advanced Small-Cell Lung Cancer: A Retrospective Analysis.

OBJECTIVE: As monotherapy such as topotecan has reached a plateau of effectiveness, new second-line treatments based on experience have been used in clinical application. This study compared the efficacy and safety of different second-line treatments for advanced small-cell lung cancer (SCLC). METHODS: A total of 380 patients with advanced SCLC were screened selectively in the retrospective study. Adverse events and patient responses were assessed using Common Terminology Criteria for Adverse Events v5.0 and Response Evaluation Criteria for Solid Tumors v1.1. The progression-free survival (PFS) was estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test. RESULTS: In the platinum-resistant group, disease control rate (DCR) and median PFS (mPFS) were prolonged in the combination group versus single-agent group (DCR: 49.24% vs 24.39%, P = .004; mPFS: 3.73 vs 1.90 months, P < .001). Grade 3/4 toxicity was similar between the 2 groups (P = .683). The mPFS did not differ among single-agent groups (P = .380). No significant difference was observed in mPFS of different combination therapy groups (P = .170). In terms of platinum-based chemotherapy, the DCR and mPFS were prolonged in irinotecan-platinum group versus taxol-platinum group (DCR: 56.14% vs 9.09%, P = .004; mPFS: 3.87 vs 1.93 months, P = .012). Grade 3/4 toxicity was similar between the 2 groups (P = .614). The mPFS was prolonged in the chemotherapy plus immunotherapy group versus single-agent chemotherapy group (P = .003). In the platinum-sensitive group, the mPFS did not differ between the combination group and single-agent group (P = .200). The mPFS did not differ among different single-agent groups (P = .260) or combination groups (P = .150). There was no difference in mPFS among different platinum-based chemotherapy groups (P = .830). CONCLUSIONS: For patients with platinum-resistant SCLC, combination therapy has shown better efficacy and acceptable toxicity profile than monotherapy. Among combination therapies, irinotecan-platinum has shown better efficacy than taxol-platinum. For patients with platinum-sensitive SCLC, the efficacy of different single-agent or combination therapies was similar.

A novel transcriptomic signature associated with lymphovascular invasion predicts clinical outcomes, tumor microenvironment, and therapeutic response in lung adenocarcinoma.

PURPOSE: Since TNM staging has limitations for predicting post-operative outcomes and relapse, more effective prediction tools need to be researched and developed. Lymphovascular invasion, LVI, as a histopathological feature, has been widely shown to have a correlation with poor prognosis and early recurrence of lung adenocarcinoma (LUAD). However, LVI assessment is limited by subjective bias, and therefore its efficacy in practical clinical application needs further clarification. The aim of this study was to formulate a new signature based on LVI-related genes to predict prognosis and recurrence in patients with lung adenocarcinoma. METHODS: Clinicopathological information, gene sequencing data and whole slide images (WSIs) of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA) databases. LVI statue were evaluated by professional pathologists, and then the differentially expressed genes (LVI DEGs) associated with LVI were screened. The least absolute shrinkage and selection operator (LASSO) and Step Cox regression models were used to construct LVI-associated risk scores (LVRS), including PAQR4, ARGHEF6, CKS1B, CFTR and SEC14L4. The validity of the LVRS score was evaluated on multiple external datasets and our JSSZL cohort dataset. Using LVRS scores and clinical information, nomogram were constructed for use by clinicians. In addition, we further explored the relationship between LVRS score and clinicopathological features, immune infiltration, tumor mutational load, and immunotherapy response, and confirmed the expression of key genes in LVRS score in lung adenocarcinoma tissues using qRT-PCR and immunohistochemistry (IHC) techniques. RESULTS: Based on the LVRS, patients could be classified into high-LVRS and low-LVRS groups. It was found that OS and PFS were significantly worse in the high-LVRS group than in the low-LVRS group (p < 0.001). By ROC curve analysis, it could be found that the nomogram combining LVRS and clinical information could accurately predict the prognosis of LUAD patients with the area under the curve of 1,3,5-year survival rate could reach 0.754, 0.741 and 0.735. The results of univariate and multivariate analysis showed that LVRS was an independent prognostic factor. At the same time, there were significant differences in the mutation profiles and immune microenvironment between the high-LVRS and low-LVRS groups, with the high-LVRS group having a significantly higher mutation rate than the low-LVRS group and exhibiting immunological "cold" features. By the experimental results, higher expression levels of PAQR4 and CKS1B were found in LUAD tissues, while lower expression levels of ARGHEF6, CFTR and SEC14L4 were observed. CONCLUSIONS: The LVRS established in this study serves as a valid tool to predict the prognosis and recurrence status of lung adenocarcinoma patients and has a predictive effect on the response to postoperative treatment. The establishment of LVRS may offer some theoretical support to clinical treatment strategies for patients with lung adenocarcinoma following surgical intervention.

Anlotinib combined with whole-brain radiotherapy in non-small cell lung cancer with multiple brain metastases that progressed or developed after at least one lines of prior treatment.

Background: Intracranial metastasis that failed standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of anlotinib combined with whole-brain radiotherapy (WBRT) for NSCLC with brain metastases (BMs) that progressed or developed after at least one line of prior treatment and compare the outcomes with that of the contemporary institutional control. Methods: NSCLC patients with multiple BMs that progressed or developed after at least one line of prior systematic treatment and treated with WBRT subsequently between 2019 and 2021 were selected retrospectively for analysis. Based on whether concurrent anlotinib had been used in combination with WBRT, the cases were divided into the anlotinib group and control group. The primary endpoints were intracranial progression-free survival (iPFS) and safety. Results: A total of 76 patients met the inclusion criteria of the study. Of the 76 patients, 34 received concurrent WBRT and anlotinib followed by anlotinib maintenance and 42 were treated with WBRT alone or in combination with other systemic agents at the physicians' discretion. The median follow-up for the entire cohort was 21 months. The median iPFS for the anlotinib and control group was 6.7 months (95% CI, 4.6-9.9) and 5.3 months (95% CI, 4.0-6.5), respectively (log-rank P = 0.04). There was no difference in overall survival between the two groups (log-rank P = 0.38). In the anlotinib group, treatment-related adverse events were reported in 15 patients (44.1%), with acute or late grade 3-5 adverse events identified in 14.7% of patients (n = 5). Conclusions: WBRT plus anlotinib, as a convenient chemo-free regimen, may represent an overall safe and effective procedure in advanced NSCLC with multiple BMs that progressed or developed after standard systematic treatment.

A Prognostic Risk Model of a Novel Oxidative Stress-Related Signature Predicts Clinical Prognosis and Demonstrates Immune Relevancy in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is among the most prevalent malignant lung cancers with a poor prognosis due to high invasiveness and lethality despite multiple treatments. Since the lung is an important organ associated with oxidative stress, and it has been confirmed that oxidative stress represents a potential cancer-specific depletion, it is of important significance to investigate and evaluate the clinical value of oxidative stress mechanisms regulating tumor cell apoptosis. Furthermore, there are few studies on the impact of the microenvironment on reaction to immune-checkpoint inhibitors (ICIs) in patients with LUAD. Based on the TCGA-LUAD dataset, which is stratified into a training set as well as a validation set in a ratio of 2 : 1, this investigation constructs and validates a prognostic predictive power of a gene signature model of oxidative stress-related prognostic signatures. To ascertain the differences between the high-risk score group and the low-risk score group in tumor-infiltrating lymphocytes and patients' response to ICI therapy. This oxidative stress-related prognostic gene signature is composed of MAP3K19 and NTSR1 and is an independent prognosis-related factor in the LUAD group. The outcome of patients having a low risk score is better, and the difference was statistically significant, and individuals with a low risk score had a larger number of infiltrating immune cell distribution in the tumor microenvironment, which was closely related to clinical outcome. Our study suggests that the synergistic effect of oxidative stress-related prognostic gene markers-MAP3K19 and NTSR1 has clinical significance in the prognosis identification and immunotherapy of LUAD patients. Thus, the results may help to better intersect the oxidative stress-related mechanisms in clinical value in LUAD but requires prospective validation.

Efficacy and Safety of PD-1 Immune Checkpoint Inhibitors in Locally Advanced and Advanced Non-Small-Cell Lung Cancer Patients with Chronic Infection.

BACKGROUND: Immune checkpoint inhibitors have become new research hot spots in the treatment of non-small-cell lung cancer (NSCLC), but the efficacy and safety of immunotherapy for patients with chronic infection are still unclear because existing clinical trials often exclude those patients. MATERIALS AND METHODS: We identified 78 locally advanced or advanced NSCLC patients with chronic infection treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: Objective responses were observed in 19 out of 78 (24.36%) patients, and the disease control rate was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI: 3.71-9.27). PFS was 1.44 months (95% CI: 0.00-4.34) for monotherapy versus 7.34 months (95% CI: 4.50-10.18) for combination therapy (p = 0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, p = 0.001; PFS: 7.67 vs. 5.57 months, p = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs. 4.62, p = 0.027). The incidence of AEs of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 AEs. The incidence of leukopenia in any grade of AEs was the highest (57.69%), followed by anemia (25.64%), elevated alanine aminotransferase or aspartate aminotransferase (24.36%), and fatigue (21.79%). Hepatic transaminase increased in 26.7% (16/60) of HBV-infected patients and remained unchanged in 65.0% (39/60) patients. CONCLUSIONS: The PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on NSCLC patients with chronic infection, but still has the potential to increase the incidence of hepatitis.

Efficacy and safety of bevacizumab biosimilar compared with reference bevacizumab in locally advanced and advanced non-small cell lung cancer patients: A retrospective study.

Background: Bevacizumab has played an important role in the systemic treatment of patients with advanced non-small-cell lung cancer (NSCLC) without gene mutation. In recent years, bevacizumab biosimilar has received marketing approval based on the results of phase III clinical studies. However, more clinical data are needed to verify the efficacy and safety of bevacizumab biosimilar in clinical application. Materials and methods: We identified 946 patients with locally advanced or metastatic NSCLC who were treated with bevacizumab biosimilar or bevacizumab from January 1, 2019 to November 30, 2021. Comparisons and statistical analyses of bevacizumab biosimilar and bevacizumab were made in terms of efficacy and safety. Efficacy evaluation was performed directly in accordance with RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results: The objective response rates (ORRs) were 28.9% in the biosimilar group (n=551) and 30.9% in the reference group (n=395; unstratified ORR risk ratio: 0.934, 95% confidence interval [CI]: 0.677-1.138; unstratified ORR risk difference: -0.020, 95% CI: -0.118-0.035). The estimated median progression-free survival (mPFS) were 6.27 (95% CI: 5.53-7.01) and 4.93 (95% CI: 4.24-5.62) months in the biosimilar and reference groups, respectively (P=0.296). The number of treatment lines, combined treatment regimens and with or without radiotherapy were significant factors affecting the PFS of both groups (P<0.001, P=0.001, P=0.039). Different genetic mutations and dose intensity were not the main factors affecting PFS (P=0.627, P=0.946). The incidences of treatment-emergent adverse events (TEAEs) were 76.41% in the biosimilar group and 71.65% in the reference group (P=0.098). The incidences of grade 3 or higher TEAEs were 22.14% and 19.49% in the biosimilar and reference groups, respectively (P=0.324). Conclusions: Bevacizumab biosimilar is equivalent in efficacy to bevacizumab in patients with locally advanced and advanced NSCLC. It showed acceptable toxicity profile and no new adverse events. Patients who were excluded by clinical trials can also benefit from bevacizumab biosimilar.

A Multicenter Retrospective Study on the Prognosis of Stage III Unresectable Mutant Non-Small Cell Lung Cancer With Tyrosine Kinase Inhibitors Therapy.

BACKGROUND: For unresectable stage III non-small cell lung cancer (NSCLC), concurrent chemoradiotherapy is nowadays the standard treatment. Patients with advanced NSCLC harboring driver-gene mutations benefit from Tyrosine Kinase Inhibitors (TKIs) Therapy. In a real-world setting, there is room for exploring the benefit of TKIs in stage III unresectable NSCLC patients with mutation. METHODS: A total of 81 patients from the Jinling Hospital and the Jiangsu Cancer Hospital with stage III unresectable mutant NSCLC applied targeted therapy were enrolled in this retrospective study. Patients with first-line application of TKIs were followed up to gain the situation of surgery qualifications, progression-free survival and overall survival, so as to evaluate the survival prognosis, then whether patients benefit and what kind of patients benefit most from TKI monotherapy treatment or its combination are explored. RESULTS: The median progression-free survival of involved 81 patients was 13.87 months (95% confidence interval (CI): 11.66-16.08), and the median survival was 41.47 months (95%CI: 20.11-62.83). The 5-year survival rates were 91.0, 80.3, 56.1, 45.5, and 32.5%, respectively. After first-line TKI therapy, seven patients (8.6%) were reevaluated as eligible for surgery and proceeded to surgery. Although no characteristics were found to be statistical prognostic, younger female non-smokers still tended to have a better prognosis with longer progression free survival and overall survival. CONCLUSIONS: TKIs are a viable option for mutant stage III unresectable NSCLC patients who have achieved good clinical benefit from TKI. Patients who cannot tolerate chemoradiotherapy, especially those with driver gene mutations, can choose targeted therapy for first-line treatment.

Immune checkpoint inhibitors combined with chemotherapy/bevacizumab therapy for patients with advanced lung cancer and heavily treated with EGFR mutation: a retrospective analysis.

BACKGROUND: EGFR-mutated lung cancer poorly responded to anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy. Whether patients with EGFR-mutated lung cancer can benefit from anti-PD-1/PD-L1 therapy combined with other drugs remains controversial. We retrospectively evaluated the safety and efficacy of the PD-1 inhibitor combined with other drugs (chemotherapy and/or bevacizumab) in patients with EGFR-mutated lung cancer, who have progressed on EGFR-TKI treatment to determine the activity of the anti-PD-1/PD-L1 therapy combined with chemotherapy or/and bevacizumab therapy in heavily treated patients with EGFR-mutated lung cancer. METHODS: We identified 56 patients with EGFR-mutated lung cancer treated with PD-1/PD-L1 inhibitors alone or combined with the chemotherapy/bevacizumab therapy. The objective response rates were assessed using RECIST v1.1. Adverse events (AEs) were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Academic Ethics Committee of Jiangsu Cancer Hospital. (NO. 2019 160), and individual consent for this retrospective analysis was waived. RESULTS: Objective responses were observed in 6 of 56 (10.7%) patients, and the disease control rate was 53.6% (30/56). The median progression-free survival (PFS) was 3.33 months with 95% CI of 1.58-5.08 months. No patient achieved a complete response. All six patients that achieved PR were treated with the PD-1 inhibitor combined with chemotherapy or bevacizumab therapy. Three of the six patients who achieved PR were treated with radiotherapy combined with PD-1 inhibitor-based therapy. Patients treated with the PD-1 inhibitor-based therapy as second-line therapy showed relatively longer PFS and higher objective response rates than those treated with PD-1 inhibitor-based therapy as third- or late-line therapy (PFS: 5.50 vs. 3.27 months, P=0.301; objective response rates: 25.0% vs. 6.82%, P=0.071). No additional AE profile was observed. CONCLUSIONS: The PD-1 inhibitor combined with the chemotherapy/bevacizumab therapy showed acceptable toxicity profile and moderate efficacy on heavily treated advanced EGFR-mutated lung cancer after the exhaustion of target therapy.

Knockdown of lncRNA TUC338 inhibits esophageal cancer cells migration and invasion.

BACKGROUND: Long non-coding RNAs (lncRNAs) are firmly identified with the event and improvement of tumors. Therefore, elucidating the functions and mechanisms of related lncRNAs is significant for understanding the occurrence and advancement of tumors. The recently discovered lncRNA TUC338 has been shown to play the role of an oncogene in an assortment of tumors. Be that as it may, the articulation and elements of lncRNA TUC338 in esophageal cancer are as yet hazy. This investigation plans to explain the capacities and related molecular mechanisms of lncRNA TUC338 in esophageal malignancy. METHODS: Firstly, the expression of TUC338 in 50 instances of esophageal disease tissues and nearby tissues was detected by fluorescence reckonable PCR, and correlations with the clinic pathological characteristics of patients was further analyzed. Then, a lentiviral interference vector was designed and transfected into an esophageal cancer cell line, and knockdown was verified by fluorescence quantitative PCR. The effects of TUC338 knockdown on the proliferation, clone formation, and migration and infringement of esophageal malignancy cells were tested utilizing the CCK-8 assay, clone formation experiments, and Transwell experiments. Western blot detected the expression of invasion-related proteins. RESULTS: Fluorescence reckonable PCR exhibit that TUC338 was exceptionally communicated in esophageal cancer tissues, and was significantly related with metastasis and TNM stage in tolerant. Functional experiments showed that in esophageal disease cell lines, knocking down the declaration of TUC338 significantly inhibited cell multiplication, clone development, and intrusion and movement. Further experiments on molecular mechanisms showed that knocking down TUC338 inhibited statement of N-cadherin and vimentin in cells. CONCLUSIONS: TUC338 is exceptionally communicated in esophageal malignancy tissues and can regulate cell proliferation and invasion.

Novel risk scoring system for immune checkpoint inhibitors treatment in non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based immunotherapy has improved the clinical outcome of non-small cell lung cancer (NSCLC). However, current indicators, such as programmed cell death-ligand 1 (PD-L1) expression in tumors or tumor mutational burden (TMB), are not considered ideal biomarkers for prognosis. Thus, there is an urgent requirement for a comprehensive risk scoring system. METHODS: In this study, we enrolled 464 NSCLC patients who received ICIs between March 2017 and January 2020 at four clinical centers. Univariate and multivariate (the logistic and the Cox regression) analyses were conducted to screen clinically relevant variables. Significant parameters (P<0.05) including absolute lymphocyte count (ALC, L), Eastern Cooperative Oncology Group Performance Status (ECOG PS, E) and lung/pleural metastasis (M) were selected for LEM score. Weighted values based on odds ratio and hazard ratio of multiple analyses were assigned to each parameter. LEM score was the sum of weighted values of each variable (Good, 0-1; Intermediate, 2-3; Poor, 4-6). Kaplan-Meier curves were used to evaluate the association between LEM score and progression-free survival (PFS). RESULTS: In total, 258 patients were pooled and stratified into three risk categories based on the LEM score. Objective response rate (ORR) was significantly higher in the good-risk group compared with the poor-risk group [55.9% vs. 7.3%, odds ratio (OR), 0.023; 95% confidence interval (CI), 0.005-0.099; P<0.001]. Patients with good risk [hazard ratio (HR), 0.130; 95% CI, 0.084-0.203; median PFS, 12.5 months; P<0.001] or intermediate risk (HR, 0.330; 95% CI, 0.222-0.490; median PFS, 4.2 months; P<0.001) had longer PFS than those with poor risk (median PFS, 2.1 months). DNA sequencing was performed in 41 patients [no durable benefit (NDB): n=29; durable clinical benefit (DCB): n=12] and epidermal growth factor receptor (EGFR) mutations were enriched in samples of the NDB group vs. the DCB group (11/29 vs. 1/12; Fisher's exact P=0.073; OR, 6.722; 95% CI, 0.760-59.479). Additionally, patients with EGFR mutations had higher LEM scores than those with wild-type EGFR. CONCLUSIONS: In conclusion, the LEM score provided a potential prognostic biomarker for NSCLC patients treated with ICIs.

B7-H4 and HHLA2, members of B7 family, are aberrantly expressed in EGFR mutated lung adenocarcinoma.

BACKGROUND: In order to find new immune targets for lung cancer with different EGFR mutant status, we describe differential expression profiles of checkpoint molecules of the new discovery B7 family member to find new immune targets for lung cancer with different EGFR statuses. METHODS: We performed immunohistochemistry with antibodies of B7-H3, B7-H4, VISTA, B7-H6, HHLA2, IDO-1, PD-L1 and CD8 in lung adenocarcinoma tissues constructed from 372 cases in the discovery cohort and 231 cases in the validation set. The differential expression profiles of these indices in EGFR mutant and wild-type lung adenocarcinoma was described and compared. RESULTS: In the discovery cohort, the median IHC scores of B7-H4 and HHLA2 for the EGFR mutant group were significantly higher than those in the wild-type group (median score [interquartile range], mutant vs. wild type: 3.250 [0-7.000] vs. 5.000 [1.000-7.000], P = 0.045 for B7-H4; 8.000 [6.000-10.500] vs. 7.000 [5.000-8.630] P = 0.003 for HHLA2). Meanwhile, the median IHC scores of IDO-1 and PD-L1 in the wild-type group were significantly higher than those in the mutant group (median score [interquartile range], mutant vs. wild type: 1.000 [0-5.000] vs. 3.000 [0-8.500], P = 0.000 for IDO-1; 0 [0-3.500] vs. 3.000 [0-6.000], P = 0.000 for PD-L1). Results above was confirmed in the discovery cohort. The increased CD8 and decreased HHLA2 expression levels were associated with long disease-free survival in lung adenocarcinoma (P = 0.000 for CD8 expression and P = 0.004 for HHLA2 expression). CONCLUSIONS: B7-H4 and HHLA2 are promising immune targets for lung adenocarcinoma, especially for patients with EGFR mutation.

Screening TCGA database for prognostic genes in lower grade glioma microenvironment.

BACKGROUND: To identify prognostic hub genes which associated with tumor microenvironment (TME) in lower grade glioma (LGG) of central nervous system. METHODS: We downloaded LGG patients gene transcriptome profiles of the central nervous system in The Cancer Genome Atlas (TCGA) database. Clinical characteristics and survival data through the Genomic Data Commons (GDC) tool were extracted. We used limma package for normalization processing. Scores of immune, stromal and ESTIMATE were calculated using ESTIMATE algorithm. Then, box plots were applied to explore the association between immune scores, stromal scores, ESTIMATE scores and histological type, tumor grade. Kaplan-Meier (K-M) analysis was utilized to explore the prognostic value of scores. Furthermore, heatmaps and volcano plots were applied for visualizing expression of differential expressed-gene screening and cluster analysis. Venn plots were constructed to screen the intersected differentially expressed genes (DEGs). In addition, enrichment of functions and signaling pathways and Gene Set Enrichment Analysis (GESA) of the DEGs were performed. Then we used protein-protein interaction (PPI) network and Cytoscape software to identify hub genes. We evaluated the prognostic value of hub genes and risk score (RS) calculated based on multivariate cox regression analysis. Finally, relationships of hub genes with the TME of LGG patients were evaluated based on tumor immune estimation resource (TIMER) database. RESULTS: Gene expression profiles and clinical data of 514 LGG samples were extracted and the results revealed that higher scores were significantly related with histological types and higher tumor grade (P<0.0001, respectively). Besides, higher scores were associated with worse survival outcomes in immune scores (P=0.0167), stromal scores (P=0.0035) and ESTIMATE scores (P=0.0190). Then, 785 up-regulated intersected genes and 357 down-regulated intersected genes were revealed. Functional enrichment analysis revealed that intersected genes were associated with immune response, inflammatory response, plasma membrane and receptor activity. After PPI network construction and cytoHubba analysis, 25 tumor immune-related hub genes were identified and enriched pathways were identified by GSEA. Besides, receiver operating characteristic (ROC) curves showed significantly predictive accuracy [area under curve (AUC) =0.771] of RS. Furthermore, significant prognostic values of hub genes were observed, and the relationships between hub genes and LGG TME were demonstrated. CONCLUSIONS: We identified 25 TME-related genes which significantly associated with overall survival in patients with central nervous system LGG from TCGA database.

Inhibition of ZEB1-AS1 confers cisplatin sensitivity in breast cancer by promoting microRNA-129-5p-dependent ZEB1 downregulation.

BACKGROUND: Breast cancer is the leading cause of cancer-related mortality in women worldwide. Long non-coding RNAs (lncRNAs) are of critical importance in tumor drug resistance. Herein, this study aims to determine the roles of lncRNA ZEB1-AS1 in drug resistance of breast cancer involving microRNA-129-5p (miR-129-5p) and ZEB1. METHODS: Microarray-based gene expression profiling of breast cancer was conducted to identify the differentially expressed lncRNAs. ZEB1 expression was measured in adjacent and cancerous tissues. Next, MCF-7 and MDA-MB-231 cells were treated with a series of inhibitor, mimic or siRNA to clarify the roles of lncRNA ZEB1-AS1 and miR-129-5p in drug resistance of breast cancer. Then the target relationship of miR-129-5p with lncRNA ZEB1-AS1 and ZEB1 was verified. The expression patterns of miR-129-5p, lncRNA ZEB1-AS1, Bcl-2, MDR-1, ZEB1 and corresponding proteins were evaluated. Moreover, the apoptosis and drug resistance of MCF-7 cell were detected by CCK-8 and flow cytometry respectively. RESULTS: LncRNA ZEB1-AS1 was observed to be an upregulated lncRNA in breast cancer, and ZEB1 overexpression was noted in breast cancerous tissues. MiR-129-5p was revealed to specifically bind to both ZEB1 and lncRNA ZEB1-AS1. Moreover, the expression levels of ZEB1-AS1, ZEB1, Bcl-2, MDR-1, and corresponding proteins were decreased, but the expression of miR-129-5p was increased with transfection of miR-129-5p mimic and lncRNA ZEB1-AS1 siRNA. Besides, drug resistance to cisplatin was inhibited, and cell apoptosis was promoted in breast cancer after transfection of miR-129-5p mimic, lncRNA ZEB1-AS1 siRNA, and ZEB1 siRNA. CONCLUSION: In conclusion, the study provides evidence that lncRNA ZEB1-AS1 silencing protects against drug resistance in breast cancer by promoting miR-129-5p-dependent ZEB1 downregulation. It may serve as a novel therapeutic target in breast cancer treatment.

EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exosome-mediated inhibition of dendritic cells.

EGFR-mutant lung cancer (LC) patients display a poor response to PD-1/PD-L1 blockade. In the absence of independent genetic validation, whether EGFR mutation distorts host antitumor immunity is unknown. Here, we showed that in the clinic, LC with the E746-A750 deletion mutation (EGFR-19del) displayed a temporal association with the loss of intratumoral CD8+ T cells. In a xenograft model, EGFR-19del-expressing Lewis lung cancer (LLC) tumors had a low T cell density at the early stage of tumor development, along with dendritic cells (DCs) exhibiting variant phenotypes in the tumors and draining lymph nodes (LNs). Importantly, EGFR-19del DCs were observed in the LNs of tumor-bearing mice and LC patients. The proliferative activity of T cells within the LN was significantly dampened. In vitro experiments indicated that the function of DCs was repressed by EGFR-19del LLC cells through exosome uptake in which exosomes derived from the EGFR-19del LLC cells could efficiently transfer active EGFR-19del to the surface of the DCs. Injection of EGFR-19del tumor-derived exosomes promoted LLC tumor progression and induced immunosuppression. The combination of gefitinib and GM-CSF treatment recovered tumor T cell infiltration in EGFR-19del tumors by rescuing the function of DCs and increasing the efficacy of anti-PD-L1 treatment. Together, these results indicated that LC with the EGFR E746-A750 deletion mutation induced anergic DCs to repress antitumor immunity through exosomes.

Comparative Effectiveness of Pemetrexed-platinum Doublet Chemotherapy With or Without Bevacizumab as First-line Therapy for Treatment-naive Patients With Advanced Nonsquamous Non-small-cell Lung Cancer in China.

PURPOSE: Bevacizumab plus platinum-based doublet chemotherapy is recommended by the National Comprehensive Cancer Network as a category 1 regimen and is widely used in patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC). In China, a common first-line chemotherapy for NS-NSCLC is the pemetrexed-platinum doublet regimen (Pem-Pt). However, limited evaluation exists to show the effectiveness of the Pem-Pt + bevacizumab (Bev) regimen in advanced NS-NSCLC. This study describes the treatment patterns, effectiveness, and safety profile of Pem-Pt + Bev in patients with NS-NSCLC in China in clinical practice. METHODS: Data from eligible patients with advanced NS-NSCLC who received Pem-Pt with (136 patients) or without (97 patients) bevacizumab from January 2012 to March 2017 were retrospectively evaluated. The effectiveness outcomes included the assessment of progression-free survival (PFS) and objective response rate (ORR) in the overall population, the percentage of patients with pleural effusion or brain metastasis, as well as the percentage of patients receiving maintenance therapy. Moreover, the intracranial remission rate in patients with brain metastasis was estimated. Finally, the adverse events with the 2 treatments were addressed. FINDINGS: Compared with the Pem-Pt regimen, the Pem-Pt + Bev regimen was associated with a significantly longer median PFS and a higher ORR in the overall population (P = 0.0002). An improvement in ORR was observed in Pem-Pt + Bev-treated patients with brain metastasis (P = 0.0045). Moreover, patients receiving Pem-Pt + Bev and maintenance therapy not only showed a longer median PFS than that in those whose treatment was interrupted after induction but also a longer median PFS than that in patients who received Pem-Pt and maintenance therapy. The safety profile was acceptable in all groups, with no observations of hypertension, proteinuria, severe bleeding (1 case of grade I epistaxis was reported with Pem-Pt + Bev), or any unexpected findings reported. IMPLICATIONS: These results from clinical practice further support the concept that pemetrexed-platinum doublet plus bevacizumab could be an effective and tolerable regimen in patients with advanced NS-NSCLC in China.