Apatinib reverses alectinib resistance by targeting vascular endothelial growth factor receptor 2 and attenuating the oncogenic signaling pathway in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene-positive lung cancer cell lines.

Overexpression of insulin growth factor 1 receptor (IGF-1R) and its ligand, insulin growth factor 1 (IGF-1), is related to treatment resistance and worse prognosis in many types of tumors. We reported recently that IGF-1R activation by IGF induces resistance to alectinib and stimulates the production of vascular endothelial growth factor, which indicates that IGF induces alectinib resistance and angiogenesis. This study aimed to determine the effect of bigeminal inhibition of anaplastic lymphoma kinase (ALK) and angiogenesis on human insulin growth factor 1 receptor (hIGF-1)-triggered drug resistance in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer. Human lung adenocarcinoma H3122 and H2228 cells were exposed to a combination of insulin growth factor 1 receptor (IGF-1), alectinib, or apatinib. The effects of the combination therapy were examined using cell the Cell Counting Kit-8 assay, the colony-forming assay, the scratch test, and flow cytometry analysis, and the molecular mechanism was assessed by western blot. At nontoxic concentrations, apatinib restored alectinib sensitivity by increasing drug-induced apoptosis and inhibiting viability, migration, and invasion in IGF-triggered drug resistant cells. Moreover, we found that apatinib restored sensitivity to alectinib mainly through suppression of the ALK downstream signaling pathway and antiangiogenesis signaling. Taken together, our results indicate that simultaneous inhibition of ALK and vascular endothelial growth factor R2 by the combination of alectinib with apatinib may be useful for controlling progression of EML4-ALK fusion gene lung cancer by reversing ALK-TKI resistance and inhibiting angiogenesis.

Causal linkage between angiotensin-converting enzyme 2 and risk of lung cancer: a bidirectional two-sample Mendelian randomization study.

Background: Observational studies suggest a connection between ACE2 (angiotensin-converting enzyme 2) and lung cancer. However, it's not apparent if confounding variables are interfering with the link. Therefore, we aimed to define the relationships between ACE2 and the risk of lung cancer. Methods: With the aim of developing genetic tools, we selected SNPs substantially associated with ACE2 using a statistically significant criterion. The relevant SNPs were then taken from the lung cancer GWAS dataset for additional research. After that, we used two-sample Mendelian randomization (MR) to ascertain if ACE2 is causally linked to the risk of developing lung cancer. To investigate the causal links' directions, we also performed a reverse MR analysis. Results: According to our findings, there is strong evidence that ACE2 is linked to a decreased chance of developing lung cancer (odds ratio: 0.94; 95% confidence interval: 0.90-0.98; P = 0.0016). The IVW method, the major MR analysis, was not impacted by heterogeneity in any of the analyses, according to Cochrane's Q test ( P Cochran e ' sQ = 0.207). The MR-Egger intercept (P intercept = 0.622) showed no indication of horizontal pleiotropy in any of the investigations. Outlier SNPs were not detected by the MR-PRESSO global test (P globaltest = 0.191). The leave-one-out analysis was performed, and the results showed a steady outcome. Nonsignificant causal estimates between lung cancer and ACE2 were produced by reverse MR analysis. Conclusion: MR investigation revealed a significant causal link between ACE2 and the risk of getting lung cancer. These findings may have implications for public health measures aimed at reducing the incidence of lung cancer.

Prognostic impact of age in advanced non-small cell lung cancer patients undergoing first-line checkpoint inhibitor immunotherapy and chemotherapy treatment.

BACKGROUND: Research on the association between age and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy combined with chemotherapy as first-line setting is limited. The aim of study is to determine the influence of age on the progress-free survival (PFS) and overall survival (OS) in those patients after adjusting for potential confounders. METHODS: A total of 207 advanced NSCLC patients treated with immunotherapy combined with chemotherapy in the first-line treatment in Guangxi Medical University Cancer Hospital from March 10, 2019, to December 31, 2022, was retrospectively analyzed. χ2 (categorical variables) was used to analyze the differences among the different age groups. Cox regression and Kaplan-Meier analyses were used to assess the association between age and clinical outcomes. P values < 0.05 (two-sided) were considered statistically significant. RESULTS: The mean age of the cohort was 58.8 ± 10.3 years. The percentages of patients < 65, 65-69, 70-74, and ≥ 75 years were 66.7 %, 19.3 %, 9.2 % and 4.8 %, respectively. Compared to the aged < 65 years group, the HR for the risk of disease progression for each group are 0.67 (95 %CI = 0.40-1.12, P = 0.125), 0.66 (95 %CI = 0.31, 1.43, P = 0.298), and 2.27 (95 %CI = 0.80, 6.45, P = 0.124), respectively, with no significant differences in the results. And the HR for risk of death for the 65-69 years and 70-74 years groups was 1.16 (95 %CI = 0.64-2.08, P = 0.628) and 0.93 (95 %CI = 0.39-2.23, P = 0.879), respectively. The difference has no statistical significance. Whereas in patients aged ≥ 75, there is an increased risk of death after adjusted confounders with HR = 4.83 (95 %CI = 2.06-11.35). The difference was statistically significant (P < 0.001). Trend test indicates that with advancing age, the patient's risk of death increases (HR = 1.33, 95 % CI = 1.02-1.75, P = 0.034). CONCLUSION: Age may not be the primary factor influencing the efficacy of immunotherapy combined with chemotherapy, but particular attention should be given to the elderly population.

Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer.

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

The benefit and risk of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small-cell lung cancer: a systematic review and single-arm meta-analysis of prospective clinical trials.

Background: Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive anti-tumor activities. However, almost all studies on the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer are non-randomized controlled trials with small sample sizes, which might lead to a lack of effective metrics to assess the effectiveness and safety of the therapeutic regimen. Here, this meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer. Methods: A single-arm meta-analysis was performed, and published literature from PubMed, Web of Science and Embase databases as of January 13, 2023, was systematically retrieved. We used the Cochrane risk of bias tool and methodological index for non-randomized studies (MINORS) Methodological items to evaluate the quality of eligible clinical trials. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. The random effect model is used to calculate the pooled parameters. Results: 19 studies (16 were non-comparative single-arm clinical trials and 3 were randomized controlled trials) were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.4% (95% CI, 16.6-28.1%) and 76.8% (95% CI, 72.6-81.1%), respectively. With regard to survival analysis, the pooled PFS and OS were 5.20 (95% CI, 4.46-5.93) months and 14.09 (95% CI, 13.20-14.97) months, respectively. The pooled grade ≥3 adverse effect (AE) rate was 47.6% (95% CI, 33.1-62.0%). Conclusion: PD-1/PD-L1 inhibitors plus anti-angiogenic agents has promising efficacy and safety as second or later-line treatment in patients with advanced non-small cell lung cancer. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023407559.

Correlation between KRAS mutation subtypes and prognosis in Chinese advanced non-squamous non-small cell lung cancer patients.

PURPOSE: The relationship between mutant KRAS and the risk of disease progression and death in advanced non-squamous non-small cell lung cancer (NSCLC) is still controversial among current studies, and the effects of distinct KRAS mutations on prognosis may be different. This study aimed to further investigate the association between them. PATIENTS AND METHODS: Of the 184 patients eventually included in the study, 108 had KRAS wild type (WT) and 76 had KRAS mutant type (MT). Kaplan-Meier curves were plotted to describe the survival for patients among groups, while log-rank tests were conducted to evaluate the survival differences. The univariate and multivariate Cox regression were performed to identify predictors, and subgroup analysis was used to verify the interaction effect. RESULTS: Similar efficacy of first-line therapy was observed for KRAS MT and WT patients (p = 0.830). The association between KRAS mutation and progression-free survival (PFS) was not significant in univariate analysis (hazard ratio [HR] = 0.94; 95% CI, 0.66-1.35), and no KRAS mutation subtype significantly affected PFS. However, KRAS mutation and KRAS non-G12C were associated with increased risk of death compared to KRAS WT in univariate and multivariate analysis. Univariate and multivariate analysis also confirmed that chemotherapy combined with antiangiogenesis or immunotherapy in the KRAS mutation group was associated with decreased risk of disease progression. However, the overall survival (OS) among KRAS mutant patients received different first-line treatments did not significantly differ. CONCLUSION: KRAS mutations and their subtypes are not independent negative predictors of PFS, while KRAS mutation and KRAS non-G12C were independent prognostic factors for OS. Chemotherapy combined with antiangiogenesis or immunotherapy conferred decreased risk of disease progression to KRAS mutation patients compared to single chemotherapy.

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).

PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Pretreatment Fibrinogen-Albumin Ratio (FAR) Associated with Treatment Response and Survival in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Anti-PD-1 Therapy Plus Platinum-Based Combination Chemotherapy.

PURPOSE: PD-1 inhibitors have been routinely used to treat advanced non-small cell lung cancer (NSCLC) and have significantly improved clinical outcomes. In this study, we aimed to explore the influence of pretreatment fibrinogen-albumin ratio (FAR) on treatment response and survival in advanced NSCLC patients treated with first-line anti-PD-1 therapy plus platinum-based combination chemotherapy. PATIENTS AND METHODS: A total of 91 patients with advanced NSCLC were included in the study. All patients received at least two cycles of systemic first-line anti-PD-1 therapy plus platinum-based combination chemotherapy. Receiver operating characteristics analysis was performed to determine the optimal cutoff values of FAR. Univariate and multivariate analyses were used to identify independent prognostic factors, and the Kaplan-Meier method was used to estimate survival curves. RESULTS: Multivariate logistic regression analysis showed that N stage (N2-3) and high FAR (≥0.175, optimal cutoff value) were independent predictors for objective response rate (P = 0.0002, P = 0.0005, respectively). Multivariate Cox regression analysis of progression-free survival and overall survival showed that high FAR (≥0.145) was independent prognostic factors (P = 0.0061, P = 0.0024, respectively). Progression-free survival and overall survival were significantly shorter in the high FAR (≥0.145) group than those in the low FAR (<0.145) group (P = 0.0024, P = 0.0024, respectively). CONCLUSION: Pretreatment FAR was an independent predictor for treatment response and independent prognostic factors in advanced NSCLC patients treated with first-line anti-PD-1 therapy plus platinum-based combination chemotherapy.

The Association between Pretreatment anemia and Overall Survival in Advanced Non-small Cell lung Cancer: A Retrospective Cohort Study Using Propensity Score Matching.

Background: The purpose of this study was to investigate whether pretreatment anemia was an independent risk factor for survival in patients with advanced non-small cell lung cancer (NSCLC) after adjusting for other covariates. Methods: We used propensity score matching (PSM) to minimize the influence of confounding factors and used χ2 (categorical variables), Student's t-test (normal distribution), or Mann-Whitney U test (skewed distribution) to analyze the differences among the Hb groups. Cox regression and Kaplan-Meier analyses were used to assess the association between anemia and survival. P values < 0.05 (two-sided) were considered statistically significant. Results: The average age of the 758 selected participants was 58.2±11 years, and 210 patients (27.7%) had anemia. In the multivariate analysis, anemia was associated with a poor prognosis in the unmatched cohort (Hazards ratio (HR)=1.3, 95% (confidence interval (CI): 1.1-1.6; p= 0.008), and the matched cohort (HR=1.7, 95% CI: 1.3-2.3; p <0.001), emerging as an independent risk and prognostic factor in advanced NSCLC patients. In the Kaplan-Meier curve, the average survival time of anemic and non-anemic patients was 9.3 months (95% CI: 7.9-11.4 months) vs. 14.1 months (95% CI: 12-16.3 months) (p=0.0073) in the unmatched cohort. After propensity score matching, the average survival time of anemic and non-anemic patients was 10.9 months (95% CI: 8.8-12.9. months) vs. 17.8 months (95% CI: 16.0-23.3 months) (p <0.001). Conclusion: Pretreatment anemia was an independent risk and prognostic factor for survival in patients with advanced NSCLC. Large-scale studies are required to confirm our findings.

The Effect of PD-1 Inhibitor Combined with Chemotherapy on the Level of Peripheral Blood T Lymphocytes among Patients with Non-Small-Cell Lung Cancer and Its Relationship with Prognosis.

Objective: To explore the effect of combined treatment of PD-1 inhibitor and chemotherapy on the level of peripheral blood T lymphocytes in non-small-cell lung cancer (NSCLC) patients and its relationship with prognosis. Methods: Retrospective analysis was conducted on 150 NSCLC patients treated in Guangxi Medical University Affiliated Tumor Hospital from June 2018 to September 2020, including 77 patients treated with PD-1 inhibitor combined with chemotherapy as the observation group (OG) and 73 patients with chemotherapy alone as the control group (CG). Therapeutic efficacy, immune function indexes, serum tumor markers, incidence of adverse reactions during hospitalization, 1-year survival rate, and life quality after 6 months of treatment were observed and compared between two groups. Results: Compared to the CG, the therapeutic effect of OG was evidently better. Six months after treatment, levels of CD4+/CD8+, NK cells, and CD4 + in two groups were elevated markedly, and indexes of OG were notably and comparatively higher than those in the other group. After treatment, OG was observed with a marked decline regarding levels of CYFRA21-1, CEA, and CA125 compared to those in the CG; and there was no notable difference in terms of adverse reaction occurrence between two groups, but the 1-year survival rate and 6-month life quality in OG over ranked those in CG. Conclusion: For NSCLC patients, the PD-1 inhibitor given on the basis of chemotherapy can further improve the clinical efficacy and improve immune function and long-term survival rate of patients on the premise of ensuring the safety of treatment, which is worth promoting in clinical practice.

PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer: A real-world retrospective cohort study.

Background: The aim of this study was to assessment the efficacy and safety of Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer. Methods: In this study, pre-treatment clinical and laboratory indicators from 73 patients with advanced non-small cell lung cancer were retrieved for retrospective analysis. According to the therapy regimes they received, the patients were separated into groups, PD-1/PD-L1 inhibitors plus chemotherapy group (PC group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents' group (PA group), PD-1/PD-L1 inhibitors plus anti-angiogenic agents plus chemotherapy group (PAC group). Cox's proportional hazards regression model and Kaplan-Meier (KM) curves were used to assess the connection between treatment regimens and progression free survival (PFS) and overall survival (OS). In addition, the association of treatment regimens with the risk of disease progression and death was evaluated by subgroup analysis. Results: The average age of the enrolled patients was 58.2 ± 10.2 years and 75.3% were male. Multivariate analyses showed that patients in PA group (Disease progression: HR 0.4, P=0.005. Death: HR 0.4, P=0.024) and PAC group (Disease progression: HR 0.3, P=0.012. Death: HR 0.3, P=0.045) had a statistically significant lower hazard ratio (HR) for disease progression and death compared to patients in PC group. Kaplan-Meier analysis showed that patients in PA group (mPFS:7.5 vs.3.5, P=0.00052. mOS:33.1 vs.21.8, P=0.093) and PAC group (mPFS:5.1 vs.3.5, P=0.075. mOS:37.3 vs.21.8, P=0.14) had a longer PFS and OS compared to patients in PC group. In all the pre-defined subgroups, patients in PA and PAC groups showed a decreasing trend in the risk of disease progression and death in most subgroups. The patients in PA group (DCR:96.3% vs.58.3%, P=0.001) and PAC group (DCR:100% vs.58.3%, P=0.019) had a better disease control rate (DCR) than patients in PC group. Conclusion: PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy were superior to PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment in patients with advanced non-small cell lung cancer.

Plasmatic Levels of HSP90α at Diagnosis: A Novel Prognostic Indicator of Clinical Outcome in Advanced Lung Cancer Patients Treated With PD-1/PD-L1 Inhibitors Plus Chemotherapy.

BACKGROUND: The purpose of this study was set to investigate the prognostic role of plasmatic levels of heat shock protein 90 alpha (HSP90α) at diagnosis in advanced lung cancer patients treated with Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus chemotherapy. METHODS: A total of 137 advanced lung cancer patients treated with PD-1/PD-L1 inhibitors plus chemotherapy admitted to the Guangxi Medical University Cancer Hospital were enrolled in this study. Smooth curve fitting was conducted to address the nonlinearity of HSP90α and progression-free survival (PFS) and overall survival (OS). We calculated the inflection point using a recursive algorithm. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to assess the prognostic value of HSP90α for PFS and OS. Subgroup analysis was performed to evaluate the relationship between high HSP90α and disease progression and death risk. RESULTS: The average age of patients was 58.6 ± 9.8 years, and 73.7% of them were men. We divided patients according to their plasmatic levels of HSP90α into low (HSP90α <52.7 ng/ml) group and high (HSP90α ≥52.7 ng/ml) group. Kaplan-Meier analysis showed a shorter PFS and OS for the high group with log-rank P < 0.05. Univariate and multivariate analyses indicated that high HSP90α was associated with an increased risk of disease progression and death after fully adjusting potential confounders with hazard ratio (HR) 1.8 (95% CI = 1.0-3.2) and HR 2.4 (95% CI = 1.1-5.1), respectively (P < 0.05). After stratification by subgroup analysis, the relationship between high HSP90α and the risk of disease progression and death was consistent across all patient subgroups. CONCLUSION: Plasmatic levels of HSP90α at diagnosis can be considered a potential independent prognostic marker of advanced lung cancer patients treated with PD-1/PD-L1 inhibitors plus chemotherapy. A further large-scale prospective validation study is needed to determine whether these results are widely applicable.

Prognostic Value of the Glasgow Prognostic Score on Overall Survival in patients with Advanced Non-Small Cell Lung Cancer.

Background: Findings from previous studies regarding the association between the Glasgow Prognostic Score (GPS) and overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) were limited. This study aimed to investigate the prognostic value of GPS in patients with advanced NSCLC after adjusting for potential confounding factors. Methods: A retrospective cohort study was conducted in 494 patients with advanced NSCLC between 2009 and 2019. Clinicopathological characteristics (including GPS) were analyzed to determine predictors of OS using univariate and multivariate Cox proportional hazards models. Survival curves were estimated using the Kaplan-Meier method. Results: Of the enrolled patients with advanced NSCLC, 66.46% were men and 53.85% were aged <60 years. The percentages of GPS scores of 0, 1, and 2 were 36.44%, 36.03%, and 27.53%, respectively. The median OS of the GPS 0, 1, and 2 groups were 23.27, 14.37, and 10.27 months, respectively (log-rank P <0.0001). A higher GPS was independently associated with an increased risk of death (P for trend = 0.0004) after full adjustment for potential confounders. The risk of death increased by 77% in the GPS 1 group (hazard ratio [HR]=1.77, 95% confidence interval [CI]=1.22-2.57, P=0.0027) and 109% in the GPS 2 group (HR=2.09, 95%CI=1.36-3.22, P=0.0008) compared with the GPS 0 group after adjustment. We did not find significant heterogeneity among the analyzed subgroups apart from sex (P interaction=0.017). Conclusion: High pretreatment GPS is independently associated with worse OS in patients with advanced NSCLC. GPS should be considered in patient counseling and decision-making and needs to be further validated by large-cohort and prospective studies.

Comparison of Different EGFR Gene Mutation Status in Patients with Metastatic Non-Small Lung Cancer After First-Line EGFR-TKIs Therapy and Analyzing Its Relationship with Efficacy and Prognosis.

PURPOSE: The purpose of this study is to compare the different EGFR mutation status in patients with metastatic non-small cell lung cancer (NSCLC) after first-line EGFR-TKIs therapy and analyze its relationship with efficacy and prognosis. PATIENTS AND METHODS: This study retrospectively analyzed the data of patients with metastatic NSCLC harboring EGFR mutation in the Affiliated Tumor Hospital of Guangxi Medical University from June 2016 to December 2020. Samples were collected before treatment and at the time of disease progression after first-line EGFR-TKIs therapy. Amplification refractory mutation system (ARMS) PCR and next-generation sequencing (NGS) were used to detect EGFR mutation. ORR, DCR, and PFS of different EGFR mutation groups were compared. RESULTS: The EGFR mutation rate of re-biopsy was 60.23%. The inconsistency rate of EGFR mutations in the same and different simple types was 72.22% (26/36) and 92.31% (48/52), respectively. Alterations in terms of EGFR mutations were divided into four groups: Group A: EGFR-sensitive mutation negative and T790M negative (39.77%); Group B: EGFR-sensitive mutation positive and T790M negative (18.19%); Group C: EGFR-sensitive mutation negative and T790M positive (36.36%); Group D: EGFR-sensitive mutation positive and T790M positive (5.68%). The differences between the four groups in ORR and DCR were not statistically significant (P>0.05). The median PFS of all patients was 10.65 months. PFS of Group A, B, C, and D was 12.26, 7.96, 10.55, and 13.81 months, respectively, with statistical significance (Log rank P = 0.014). CONCLUSION: EGFR mutation status in metastatic NSCLC patients receiving the first- and second-generation TKIs after disease progression show diversity. Monitoring the EGFR mutation changes is of great importance for subsequent clinical decision-making and exploring the underlying mechanisms of acquired resistance.

The predictive value of pretreatment haemoglobin-to-red cell distribution width ratio for overall survival of patients with advanced non-small cell lung cancer: a propensity score matching analysis.

OBJECTIVE: To investigate the prognostic value of pretreatment haemoglobin-to-red cell distribution width radio (HRR) in predicting overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: This retrospective study analysed patients with advanced NSCLC. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were conducted to evaluate the predictive value of HRR for OS. A propensity matching analysis was used to reduce the impact of other confounding factors on the results. RESULTS: A total of 448 patients were enrolled in the study. The median HRR was 0.984, which was used as the cut-off value. Regardless of matching or not, a lower HRR was correlated with an unfavourable risk of death. After propensity matching, univariate and multivariate analysis showed that HRR was an independent factor for the prognosis of NSCLC (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.17, 2.04; HR 1.57, 95% CI, 1.17, 2.10; respectively). Kaplan-Meier analysis showed that low HRR was associated with shortened OS. The relationship between HRR and the risk of death was consistent across all patient subgroups after stratification by subgroup analysis. CONCLUSIONS: These findings showed that a lower pretreatment HRR could be a potentially valuable prognostic factor in patients with advanced NSCLC.

Predictive value of pretreatment albumin-to-alkaline phosphatase ratio for overall survival for patients with advanced non-small cell lung cancer.

OBJECTIVES: To investigate the relation between AAPR and OS in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective cohort study was conducted with 808 patients with advanced NSCLC who were treated in Guangxi Medical University Affiliated Tumor Hospital in China from 5 March 2009 to 31 August 2018. The target-independent and dependent variables were AAPR measured in patients before anticancer treatment and overall survival (OS), respectively. Covariates involved in this study included age, gender, ECOG status, smoking history, clinical stages, pathological type, driver mutation (EGFR or ALK), metastasis or not (bone, lung, liver, brain, malignant plural effusion, and other organs), number of organ metastasis(≤3, >3), first-line regiment and number of treatment lines (≤3, >3). RESULTS: The mean age of the selected patients was 58.3 ± 10.9 years and 68.6% were male. We divided patients according to their AAPR into low (AAPR < 0.34, n = 266), medium (AAPR = 0.34-0.47, n = 259), and high (AAPR > 0.47, n = 283) tertile groups. Medium and high AAPR were associated with a decreased risk of death after fully adjusted Cox proportional hazard model(s) with hazards ratio (HR) 0.77 (95%CI = 0.58-1.03) and HR 0.59 (95%CI = 0.45-0.78), respectively (P for trend <.05). The median OS of low, medium, and high AAPR was 9.3, 11.8, and 16.9 months, respectively (P value <.0001). No optimal cutoff value of AAPR for prognosing OS was identified by smooth curve fitting. The HR and the 95% confidence intervals of the left and right sides of the inflection point 0.6 as cutoff value were 0.28 (95%CI = 0.14-0.57) and 0.77 (95%CI = 0.34-1.73), respectively (P value = .127). By subgroup analysis, similar results were consistently observed across nearly all the subgroups. CONCLUSION: Our study implied that pretreatment AAPR can be used as an independent prognostic factor in patients with advanced NSCLC. This ratio should be applied for risk stratification and clinical decision-making in those patients.

A Retrospective Cohort Study on Pretreated Neutrophil-to-Lymphocyte Ratio and Prognosis of Small Cell Lung Cancer: Evidence of Effect Modification by Chemotherapy Regimen.

PURPOSE: Neutrophil-to-lymphocyte ratio (NLR) has been suggested as an independent risk factor for progression-free survival (PFS) and overall survival (OS) in small cell lung cancer (SCLC). However, it is still unknown whether there is a linear relationship between the NLR and the risk of death in SCLC. The objective of this study is to provide further results. PATIENTS AND METHODS: A retrospective cohort study was performed among a total of 251 participants with SCLC. Smooth curve fitting and piecewise Cox regression model were used to determine the linear relationship between NLR and mortality risk. A multivariable Cox regression model was used to estimate the effects of NLR on OS. Interaction and stratified analyses were conducted according to covariates. RESULTS: The analysis indicated no significant nonlinear relationship or threshold effect between NLR and hazard of death. Multivariate analysis revealed that every unit increase in NLR was associated with a 10% increase in mortality risk. High NLR (>3.5) at baseline was associated with poor OS (hazard ratio [HR]=1.97, P=0.009). The difference in median OS duration between the high and low NLR groups was statistically significant (9.1 months vs 14.6 months, P=0.0067). Furthermore, interaction analysis identified the chemotherapy regimen to play an interactive role in the association between NLR and hazard of death. CONCLUSION: NLR was identified as an independent risk factor for OS in SCLC and the linear correlation was observed between them. Administration of etoposide plus cisplatin (EP) regimen in patients with low NLR resulted in better long-term outcome than that of etoposide plus carboplatin (EC) regimen, while administration of the EC regimen conferred longer OS than that of the EP regimen in patients with high NLR.

Prognostic Value of Pretreatment Albumin-to-Alkaline Phosphatase Ratio in Extensive-Disease Small-Cell Lung Cancer: A Retrospective Cohort Study.

PURPOSE: Evidence regarding the relationship between albumin-to-alkaline phosphatase ratio (AAPR) and overall survival (OS) in extensive-disease small-cell lung cancer (ED-SCLC) patients is limited. This study aimed to investigate whether AAPR was independently related to OS in ED-SCLC patients after adjusting for potential covariates. PATIENTS AND METHODS: This was a retrospective cohort study of 224 patients with ED-SCLC. The target independent and dependent variables were pretreatment AAPR and OS, respectively. Covariates included age; sex; Eastern Cooperative Oncology performance status score; smoking history; existence of metastasis to organs such as the bone, lung, liver, brain, malignant plural effusion and others; sum of organ metastasis (≤3, >3), evaluation of first-line treatment; and sum of treatment lines (<2, ≥2). Student's t test or chi-squared test was used to analyze the associations between AAPR and clinical characteristics. Kaplan-Meier survival analysis and Cox's proportional hazards regression model were used to assess the prognostic value of AAPR for OS. RESULTS: The average patient age was 60.51±8.73 years, and 87.95% were men. A non-linear relationship between AAPR and OS was detected, with an inflection point of 0.35. The hazard ratios (HRs) of the left (AAPR <0.35) and right sides (AAPR ≥0.35) of inflection point were 0.04 (95% CI=0.00-0.70, p=0.0268) and 0.52 (95% CI=0.16-1.64, p=0.2659), respectively. Kaplan-Meier analysis showed a median OS of 9.73 months (95% CI=8.6-12.33) for AAPR <0.35 and 13.7 months (95% CI=11.43-16.37) for AAPR ≥0.35 (log-rank p<0.0001). The Cox proportional hazards model showed that AAPR <0.35 increased the risk of death after adjusting for potential confounders (HR=1.65, 95% CI=1.11-2.46). In subgroup analysis, the trends of HRs were increased across all subgroups with AAPR <0.35 after stratification. CONCLUSION: Pretreatment AAPR might be served as an independent prognostic indicator in ED-SCLC patients. Our findings should be further validated in large-scale and prospective clinical trials.

Pretreatment plasma d-dimer levels as an independent prognostic factor for overall survival among patients with advanced non-small-cell lung cancer.

OBJECTIVE: To evaluate the prognostic accuracy of d-dimer levels for advanced non-small-cell lung cancer (NSCLC). METHODS: This retrospective cohort study included 651 patients initially diagnosed with advanced NSCLC. Patients with d-dimer levels ≥0.5 mg/L were included in the high d-dimer group, whereas patients with lower levels were included in the normal group. Cumulative survival was estimated using Kaplan-Meier curves and compared using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model. RESULTS: The median plasma d-dimer level in the study cohort was 0.61 ± 0.49 mg/L. d-dimer levels were elevated in 60.98% of patients, and 80.1% of such patients had adenocarcinoma. Univariate and multivariate analyses identified d-dimer content as an independent factor for the prognosis of NSCLC (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.19-1.98). Kaplan-Meier analysis revealed that high plasma d-dimer levels were associated with shorter overall survival (HR = 1.48, 95% CI = 1.19-1.84). In addition, the receipt of <2 lines of treatment was associated with a higher risk of death than the receipt of >2 lines. CONCLUSION: The present results imply that pretreatment plasma d-dimer levels could represent a prognostic factor for advanced NSCLC.

Predictive value of tumor genetic alteration profiling for chemotherapy and EGFR-TKI treatment in advanced NSCLC.

Previous studies have suggested that a variety of tumor driver genetic alterations affected the treatment efficacy of chemotherapy and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). The present study aimed to investigate the association between the tumor genetic alteration landscape and the treatment outcome of first-line chemotherapy and EGFR-TKIs in advanced NSCLC. A total of 94 patients with advanced NSCLC were recruited. All patients received first-line chemotherapy and/or EGFR-TKIs (either first- or second-generation EGFR-TKI, or third-generation EGFR-TKI) alone or sequentially. Prior to chemotherapy and/or EGFR-TKI treatment, plasma, effusion and/or tumor tissues from the included patients were subjected to next-generation sequencing, targeting 59 genes. The results indicated that the positive genetic alteration status prior to first-line chemotherapy was associated with prolonged progression-free survival (PFS) time compared with the negative status [9.1 vs. 4.0 months; hazard ratio (HR)=6.68; 95% CI, 2.25-19.82; P=0.001). Furthermore, patients with EGFR activating mutation harboring concomitant alterations exhibited a shorter PFS (11.1 vs. 7.4 months; HR=2.14; 95% CI, 1.03-4.44; P=0.04) and overall survival (OS) time [not reached (NR) vs. 32.8 months; HR=4.30; 95% CI, 1.41-13.16; P=0.01] than those without concomitant alterations, with first- and second-generation EGFR-TKI treatment. Similarly, patients with T79M mutation harboring concomitant alterations exhibited a shorter PFS (15.6 vs. 3.6 months; HR=9.48; 95% CI, 2.29-39.28; P=0.002) and OS time (NR vs. 32.8 months; HR=4.85; 95% CI, 1.16-20.29; P=0.03) with osimertinib treatment. Taken together, the results demonstrated that positive genetic alteration status predicted greater efficacy of first-line chemotherapy, while concomitant genetic alterations were associated with poor treatment outcome for first- or second-generation EGFR-TKI and third-generation EGFR-TKI treatment.