Prognosis Of Advanced Non-small Cell Lung Cancer Research Articles

The Construction of a Nomogram Using the Pan-Immune-Inflammation Value Combined with a PILE Score for Immunotherapy Prediction Prognosis in Advanced NSCLC.

The purpose of this study was to investigate the predictive value of Pan-Immune-Inflammation Value (PIV) combined with the PILE score for immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and to construct a nomogram prediction model to provide reference for clinical work. Patients with advanced NSCLC who received ICIs treatment in Qingdao Municipal Hospital from January 2019 to December 2021 were selected as the study subjects. The chi-square test, Kaplan-Meier survival analysis, and Cox proportional risk regression analysis were used to evaluate the prognosis. The results were visualized by a nomogram, and the performance of the model was judged by indicators such as the area under the subject operating characteristic curve (AUC) and C-index. The patients were divided into high- and low-risk groups by PILE score, and the prognosis of patients in different risk groups was evaluated. Multivariate Cox regression analysis showed that immune-related adverse events (irAEs) were prognostic factors for overall survival (OS) improvement, and ECOG PS score ≥2, bone metastases before treatment, and high PIV expression were independent risk factors for OS. The C index of OS predicted by the nomogram model is 0.750 (95% CI: 0.677-0.823), and the Calibration and ROC curves show that the model has good prediction performance. Compared with the low-risk group, patients in the high-risk group of PILE were associated with a higher inflammatory state and poorer physical condition, which often resulted in a poorer prognosis. PIV can be used as a prognostic indicator for patients with advanced NSCLC treated with ICIs, and a nomogram prediction model can be constructed to evaluate the survival prediction of patients, thus contributing to better clinical decision-making and prognosis assessment.

The Impact of Kinlessness on Survival in Patients With Advanced Non-small Cell Lung Cancer: A Single-Center Retrospective Study.

Objectives Among patients with advanced non-small cell lung cancer (NSCLC), there are those who do not have a spouse, family members, or friends to support them in their cancer treatment and daily life: the kinless patients. Therefore, we designed an exploratory study of kinlessness and the prognosis of advanced NSCLC. Methods We retrospectively analyzed the prognosis of clinical factors and treatment and kinlessness in patients with advanced NSCLC with wild-type or unknown status for epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALK) and who visited our hospital from November 2018 to February 2023. In addition to the survival analysis by kinlessness, a multivariable analysis of survival was performed for all clinical factors. In a secondary analysis, a multivariable analysis of the choice of best supportive care (BSC) was performed for all clinical factors. Results One hundred forty-four patients are included in our cohort. There were 131 patients with kin, with a median survival of 1.34 years (95% CI of 1.01-1.79 years). There were 13 patients has no kin, with a median survival of 0.53 years (95% CI 0.23-0.76 years). The log-rank analysis showed that kinless patients had significantly shorter overall survival than patients who have kin. A Cox regression analysis showed that age, distant metastasis, performance status, and kinlessness were associated with overall survival. Secondary analysis showed that there was no statistical association between kinlessness and the choice of BSC in our cohort. Conclusions Kinless patients had shorter survival than patients who have kin in our single-center, retrospective study of patients with advanced NSCLC with wild-type or unknown status for (EGFR/ALK). Further research to evaluate the clinical impact of kinlessness in the treatment of advanced NSCLC is needed.

Precision Surgery in NSCLC

Non-small cell lung cancer (NSCLC) is still one of the leading causes of death worldwide. This is mostly because the majority of lung cancers are discovered in advanced stages. In the era of conventional chemotherapy, the prognosis of advanced NSCLC was grim. Important results have been reported in thoracic oncology since the discovery of new molecular alterations and of the role of the immune system. The advent of new therapies has radically changed the approach to lung cancer for a subset of patients with advanced NSCLC, and the concept of incurable disease is still changing. In this setting, surgery seems to have developed a role of rescue therapy for some patients. In precision surgery, the decision to perform surgical procedures is tailored to the individual patient; taking into consideration not only clinical stage, but also clinical and molecular features. Multimodality treatments incorporating surgery, immune checkpoint inhibitors, or targeted agents are feasible in high volume centers with good results in terms of pathologic response and patient morbidity. Thanks to a better understanding of tumor biology, precision thoracic surgery will facilitate optimal and individualized patient selection and treatment, with the goal of improving the outcomes of patients affected by NSCLC.

Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade.

Programmed death-1 (PD-1) blockade promotes combination therapy in advanced non-small cell lung cancer (NSCLC), hypofractionated radiotherapy (HFRT) and chemotherapy combined with immunotherapy improves the outcome of prognosis in advanced NSCLC, while effective biomarkers to follow prognostic efficacy are still to be found. We enrolled 44 NSCLC patients with HFRT combined with PD-1 blockade, 13 patients with chemotherapy combined with immunotherapy, additionally collected tissue samples from 8 patients with earlystage NSCLC without therapy, and peripheral whole blood from 16 healthy donors, detected the expression differences of cytokines Interleukin 6 (IL-6), Interleukin 8 (IL-8) and Interleukin 17A (IL-17A) in the peripheral plasma and tissues by flow cytometry, immunofluorescence, and real-time fluorescence quantitative PCR. Cultured peripheral blood mononuclear cell (PBMC) and tumor-infiltrating T cells with recombinant human IL-8 in vitro to observe the changes of immune memory T cell subtypes and apoptosis. Our results show that IL-6, IL-8, and IL-17A are highly expressed in advanced NSCLC, high levels of IL-8 are significantly associated with poor prognosis in advanced NSCLC patients treated with HFRT+PD1 blockade, high circulating IL-8 in NSCLC increased apoptosis of effector memory RA (TemRA; CD45RA+CCR7-) T cell subsets and CD8+ T cell subsets in tissues, resulting in decreased peripheral TemRA and stem cell-like memory T cells (TSCM: CD45RA +CCR7 + CD95 +) in tissue. We suggest that IL-8 can impair immune memory function in NSCLC. It is a useful biomarker to evaluate the efficacy of HFRT+PD1 blockade in advanced NSCLC. Further exploration of easily available plasma biomarkers for personalized treatment of NSCLC is required.

Novel predictors associated with therapeutic effects of immune checkpoint inhibitors on bone metastasis of non-small cell lung cancer.

e21071 Background: In recent years, immune checkpoint inhibitors (ICIs) have brought dramatic therapeutic effects on lung cancer. However, there are few reports regarding the therapeutic effect of ICIs on bone metastasis of non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the therapeutic effects of ICIs on bone metastases of NSCLC and to analyze the predictors associated with ICI's response to them. Methods: This retrospective study analyzed NSCLC with bone metastases who initiated ICI treatment between 2016 and 2019. Clinical data was investigated and used as variables for analyzing the therapeutic effect predictors of ICIs. Blood sampling data were used within 1 week before ICI treatment initiation. The therapeutic effect of ICIs on bone metastases was evaluated by MD Anderson criteria (MDA criteria), and overall survival (OS) after the initiation of ICI treatment was investigated. Based on the evaluation of MDA criteria, univariate analysis was performed between the response group (CR+PR) and non-response group (SD+PD), and variables with p < 0.05 were used for multivariate logistic regression analysis to investigate the predictors associated with the therapeutic effect of ICIs. Results: The 55 patients were included comprising 40 males and 15 females (mean age of 66.3±7.9 years) and the mean follow-up period was 23.2 months. The response rate of ICIs to bone metastasis was 30.9% including 3 cases in CR and 14 cases in PR. The median survival time was 9.3 months, and the 1-year and 2-year survival rates were 40.6% and 19.3%, respectively. The OS was significantly longer in the response group than in the non-response group (p < 0.01). In the blood sampling data, the cutoff value of neutrophil-to-lymphocyte ratio (NLR) determined by receiver operating characteristic (ROC) curve analysis was 2.1. The multivariate analysis based on the variables with p < 0.05 in the univariate analysis revealed significant differences in sex, treatment line of ICIs, and NLR (Table). Conclusions: Treatment with ICIs showed favorable responses to bone metastasis and better prognosis in advanced NSCLC. Moreover, this study revealed that “female, NLR < 2.1, and first-line treatment of ICIs” were independent predictors associated with favorable response to bone metastasis.[Table: see text]

ICI in combination with chemotherapy or anti-angiogenic agents as second-line or beyond treatment for advanced non-small cell lung cancer: A retrospective study.

e21057 Background: Immune checkpoint inhibitors (ICIs), which are currently used in the standard second-line treatment for non-small cell lung cancer (NSCLC), have largely improved the prognosis of advanced NSCLC. However, patients treated with ICI monotherapy have low response rates; hence, there is an urgent need to expand the population responding to immunotherapy treatment. This study aimed to explore the efficacy and safety of the combination of ICI with chemotherapy or anti-angiogenic therapy compared to ICI monotherapy in patients previously treated for advanced NSCLC. Methods: Data was collected from previously treated patients with NSCLC who further received ICI monotherapy or combination therapy. The distribution of clinical variables was assessed using the chi-square test or Fisher's exact test. The relationship between descriptive variables and survival was described using Kaplan–Meier curves and compared by log-rank test. Cox proportional-hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to confirm survival differences. Results: A total of 145 patients were included in this study, of which 63 were in the ICI monotherapy group, 57 were in the ICI with chemotherapy group, and 25 were in the ICI with anti-angiogenic therapy group. Compared with the ICI monotherapy group, the ICI with chemotherapy group had significantly higher ORR (31.6% vs. 11.1%, P = 0.006), DCR (84.2% vs. 61.9%, P= 0.006), PFS (mPFS: 6.37 vs. 3.47 months, P< 0.0001; HR = 0.42, 95% CI: 0.29–0.63, P< 0.0001), and OS (mOS: 18.60 vs. 8.47 months, P< 0.0001; HR = 0.40, 95% CI: 0.25–0.64, P= 0.0001). In addition, the ICI with anti-angiogenic therapy group also had significantly elevated DCR (88% vs. 61.9%, P= 0.02), PFS (mPFS: 8.17 vs. 3.47 months, P< 0.0001; HR = 0.30, 95% CI: 0.17–0.53, P< 0.0001), and OS (mOS: 19.20 vs. 8.47 months, P= 0.006; HR = 0.44, 95% CI: 0.24–0.80, P= 0.007) compared with the ICI monotherapy group. There was no significant difference between the ICI with chemotherapy group and the ICI with anti-angiogenic therapy group. Meanwhile, the addition of chemotherapy or anti-angiogenics did not increase immune-related adverse events and had a good safety profile. Conclusions: For previously treated patients with advanced NSCLC, treatment with ICI in combination with chemotherapy led to enhanced ORR, DCR, PFS, and OS compared to treatment with ICI monotherapy. Moreover, treatment with ICI combined with anti-angiogenic therapy led to enhanced DCR, PFS, and OS compared to treatment with ICI monotherapy. The combination of immunotherapies is a promising second-line treatment option for some of the patients in this study, and the findings of this study necessitate the need for further exploration.

Neuropilin-1 is a valuable biomarker for predicting response of advanced non-small cell lung cancer patients to hypofractionated radiotherapy and PD-1 blockade

Programmed death-1 (PD-1) blockade promoted the combination therapy of advanced non-small cell lung cancer (NSCLC), induces changes in peripheral memory T cell subsets. Neuropilin-1 (NRP1) is a new T cell memory checkpoint, its association with the clinical prognosis of NSCLC is less reported. Here, we detected the expression of NRP1 and the depletion-associated factor thymocyte selection-associated HMG box protein (TOX) in peripheral T cell subsets with responders treated with hypofractionated radiotherapy (HFRT) combined with PD-1 blockade and chemoimmunotherapy, aimed to explore their association with the prognosis of advanced NSCLC. NRP1 and TOX expression was localized on tissue-infiltrating T cells by immunofluorescence assay in nine patients who had undergone surgery. Flow cytometry was used to detect the expression of NRP1 and TOX in peripheral circulating T cells in patients with advanced NSCLC before and after HFRT combined with PD-1 blockade (HFRT+PD-1) and chemoimmunotherapy in thirty-nine patients. NSCLC patients showed an increase in NRP1 and TOX in peripheral T cells as compared to that in healthy controls. The expression of NRP1 and TOX in CD8+ T cells was higher in tumor tissues than in uninvolved tissues. Patients who responded to HFRT+PD-1 blockade showed a reduction in NRP1+CD8+, TOX+CD4+, and TOX+CD8+ levels, chemoimmunotherapy responders showed decreased expression of NRP1 in the CD4+ T cell subpopulation.In conclusion, lower expression levels of NRP1 and TOX in peripheral circulating CD8+ T cells were associated with a better prognosis for advanced NSCLC patients treated with HFRT+PD-1 blockade.

Research Progress of Antibody-drug Conjugates in Advanced Non-small Cell Lung Cancer

肺癌是全球发病率和死亡率最高的恶性肿瘤之一，非小细胞肺癌（non-small cell lung cancer, NSCLC）是肺癌重要的病理类型之一，且晚期患者预后较差，内科治疗仍是其主要治疗手段。抗体偶联药物（antibody-drug conjugates, ADCs）是一类非常有潜力的新型抗肿瘤药物，由单克隆抗体和小分子细胞毒药物通过连接子偶联而成，在肺癌等实体瘤中应用前景广阔。本文对现阶段ADCs在晚期NSCLC中的作用机制和研究进展进行综述。

Presence of allele frequency heterogeneity defined by ctDNA profiling predicts unfavorable overall survival of NSCLC.

The generation of subclonal (low-frequency) mutations is driven by tumor mutations and the relationship between the heterogeneity of tumor mutation abundance and non-small cell lung cancer (NSCLC) remains unknown. We investigate the role of allele frequency heterogeneity (AFH) defined by circulating tumor DNA (ctDNA) profiling in predicting prognosis in advanced NSCLC patients. Publicly available data set of POPLAR (N=211) and OAK (N=642) trials were used for analyzing. A low ratio of allele frequency (AF) of a mutation to the maximum-somatic-allele-frequency (MSAF) was used to define the presence of AFH. The prognostic value of AF/MSAF ratio that was below a defined cutoff point in overall survival (OS) was evaluated using Cox-proportional hazards regression; and the structural break point was determined by LOESS regression and Chow test. The derived AFH was also explored in an independent cohort (N=259) of advanced NSCLC receiving first-line EGFR-TKIs from the First Affiliated Hospital of Guangzhou Medical University. In the POPLAR and OAK cohort, low AF/MSAF ratio was found to be significantly associated with unfavorable OS in univariate and multivariate analysis. The structural break point analysis demonstrated that AF/MSAF <10% could yield the optimal value to stratify patients with poor OS, which was applied for defining the presence of AFH. The presence of AFH significantly correlated with unfavorable OS in advanced NSCLC regardless of treatment arms (overall: HR 1.52, immunotherapy: HR 1.81, chemotherapy: HR 1.32, all P<0.05). In the exploratory EGFR-TKIs cohort, the presence of AFH was also significantly associated with shorter OS (HR 1.72, P=0.039). Our results demonstrate that the presence of AFH predict unfavorable prognosis in advanced NSCLC despite which drug the patients used. The presence of AFH defined by ctDNA might provide an easily-accessible biomarker for risk stratification in the current clinical practice.

Abstract 4212: PD-L1 expression, EGFR and KRAS mutations in unresectable stage III non-small cell lung cancer (NSCLC) patients

Abstract Background: Anti-PD-L1 therapy may improve prognosis in advanced NSCLC. We examined the relation of PD-L1 expression, KRAS and EGFR mutations, with survival in unresectable stage III NSCLC patients. Methods: We obtained data on unresectable stage III NSCLC patients (defined via TNM AJCC staging and without surgery up to 120 days after diagnosis) diagnosed 2001-2012. We retrieved medical data from Danish population-based registries and paraffin-embedded tumor tissue from pathology archives. We assessed PD-L1 expression using the Ventana IHC (SP263) validated assay. We genotyped KRAS and EGFR using PCR-based kits. Follow-up began at NSCLC diagnosis and continued to death, emigration, or 31/12/2014. We used Cox regression to compute hazard ratios (HRs) and associated 95% confidence intervals (95%CI) for PD-L1, EGFR, and KRAS. Results: Among 305 patients, 183 (60%) were men, 167 (55%) were aged &amp;gt;65 years at diagnosis and none used immunotherapy; 148 (49%) had adenocarcinoma, 117 (38%) squamous histology, 96 (31.5%) had PD-L1 positive tumors (&amp;gt;=25%), 6 (2%) had EGFR mutations, and 69 (23%) had KRAS mutations. Among PD-L1 positive tumors, 55% had stage IIIA, 45% IIIB disease; 1% had EGFR and 34% had KRAS mutations. Among PD-L1 negative tumors, 54% had stage IIIA and 46% IIIB; 3% had EGFR and 16% had KRAS mutations. Median survival was similar in patients with KRAS wild-type and KRAS mutations (Hazards ratio (HR)=1.07; 95% CI=0.76-1.51). Patients with an EGFR mutation had a lower non-statistically significant risk of death (HR=0.75; 95% CI=0.28-2.06). Tumor cell positivity for PD-L1 (&amp;gt;=25% versus &amp;lt;25%) yielded an HR=0.80 (95%CI=0.60-1.07). Immune cell positivity for PD-L1 &amp;gt;=1% and &amp;gt;=25% yielded HRs of 0.50 (95%CI=0.39-0.66) and 0.45 (95%CI=0.30-0.67), respectively. Tumor infiltration by immune cells with PD-L1 measured as a continuous variable yielded an HR=0.96 (95%CI=0.93-0.99). Conclusion: Our findings suggest that PD-L1 expression and EGFR mutations, but not KRAS mutations, are associated with survival in this real-world Danish study of unresectable Stage III NSCLC patients. Citation Format: Deirdre Cronin-Fenton, Tapashi Dalvi, Elizabeth Hedgeman, Mette Norgaard, Lars Pedersen, Hanh Hansen, Jon Fryzek, Jill Walker, Anders Mellemgaard, Torben Rasmussen, Norah Shire, James Riggas, Danielle Potter, Stephen Hamilton-Dutoit, Henrik Sørensen. PD-L1 expression, EGFR and KRAS mutations in unresectable stage III non-small cell lung cancer (NSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4212.

Predictive value of microRNA-10b expression in peripheral blood mononuclear cells in evaluating short- and long-term efficacy of chemotherapy for patients with advanced non-small-cell lung cancer.

The expression profile in peripheral blood mononuclear cells (PBMCs) from advanced non-small-cell lung cancer (NSCLC) patients and the role of microRNAs (miRs) in NSCLC remain unclear. Herein, the present study aims to investigate predictive value of miR-10b expression in PBMCs in evaluating short- and long-term efficacy of chemotherapy for NSCLC patients. A total of 194 advanced NSCLC patients were selected as the NSCLC group and 199 healthy individuals were recruited as a control group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to determine the miR-10b expression in PBMCs. The patients with advanced NSCLC were treated with chemotherapy, and the relationship between miR-10b expression in PBMCs and the clinicopathological characteristics, clinical response to chemotherapy and prognosis were analyzed. The values of miR-10b in diagnosis and prediction of clinical response to chemotherapy before chemotherapy were detected by receiver operating characteristic (ROC) curve analysis, the clinical response to chemotherapy by logistic regression analysis, and the risk factors of prognosis in NSCLC patients by Cox regression analysis. Compared with the control group, miR-10b in PBMCs was highly expressed in the NSCLC group. The area under the curve (AUC) of miR-10b expression in the diagnosis of NSCLC was 0.967, with sensitivity and specificity of 85.10% and 99.5%, respectively. MiR-10b expression was related to lymph node metastasis (LNM), distant metastasis, pathological types and differentiation. The AUC of miR-10b expression in the prognosis of advanced NSCLC was 0.793, with sensitivity and specificity of 75.20% and 76.62%, respectively. Logistic regression analysis showed that clinical response to chemotherapy was significantly influenced by miR-10b expression, distant metastasis and LNM. Cox regression analysis showed that the high miR-10b expression, smoking, LNM and distant metastasis were risk factors of prognosis for advanced NSCLC patients. The present study offers intriguing new perspectives based on evidence that miR-10b expression in PBMCs has predictive value for the tumor response to chemotherapy and prognosis for advanced NSCLC patients.

P3.01-008 Association between Icotinib Efficacy and Circulating Tumor Cell Levels in Advanced Non-Small Cell Lung Cancer

Advanced non-small cell lung cancer (NSCLC) studies indicated a potential association between chemotherapy efficacy and circulating tumor cells (CTC) counts in peripheral blood. The icotinib efficacy and circulating tumor cells (CTC) counts in non-small cell lung cancer remain unknown. The aim is to investigate association between the icotinib efficacy and CTC counts in advanced NSCLC patients. A total of 74 advanced NSCLC patients consented to provide 5ml of peripheral blood before systematic therapy, and divided into two groups (those with high CTC counts and those with low CTC counts) based on the patients′ median CTC counts. All the patients were treated with icotinib, and the icotinib efficacy and prognoses were compared. The treatment efficacies were 46.88% (15/32) and 23.81% (10/42) for the low CTC group and the high CTC group, respectively. The median overall survival was 22.0 months (95%CI: 19.6-28.7 months) for the low CTC group and 18.3 months (95% CI: 15.3-25.4 months) for the high CTC group. The median progression-free survival was 11.6 months (95% CI: 8.7-15.6 months) and 7.2 months (95% CI: 3.4-8.7 months) for the low group and the high CTC group, respectively. The CTC counts can be used as a important biomarker for therapy monitoring the icotinib effect on patients with advanced NSCLC. Efficacy and prognosis of icotinib and CTC counts were considered important, and the CTC counts could be used to predict the efficacy of icotinib and prognosis of advanced NSCLC. The change in CTC count levels can be used as a biomarker for evaluating the prognosis of patients with advanced NSCLC.

Correlation between epidermal growth factor receptor tyrosine kinase inhibitor efficacy and circulating tumor cell levels in patients with advanced non-small cell lung cancer.

ObjectiveThe aim of this study was to investigate the correlation between the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and circulating tumor cell (CTC) levels in patients with advanced non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs in reducing CTC counts in patients with advanced NSCLC was studied.Patients and methodsA total of 66 patients with advanced NSCLC were enrolled and divided into two groups (those with high CTC counts and those with low CTC counts) based on the patients’ median CTC counts. All the patients were treated with an EGFR-TKI, and the treatment efficacy and prognoses were compared.ResultsThe treatment efficacies were 53.3% (16/30) and 27.8% (10/36) for the low CTC group and high CTC group, respectively, and this difference was statistically significant (P<0.05). The median overall survival was 22.8 months (95% confidence interval [CI]: 18.9–26.8 months) for the low CTC group and 18.3 months (95% CI: 2.9–8.2 months) for the high CTC group. The median progression-free survival was 11.5 months (95% CI: 8.1–15 months) and 5.6 months (95% CI: 2.9–8.2 months) for the low and high CTC groups, respectively, and the difference was statistically significant (P<0.05).ConclusionThe CTC count can be used as an index for predicting the EGFR-TKI effect on patients with advanced NSCLC. Efficacy and prognosis of EGFR-TKI treatment and CTC count were considered important, and the CTC count could be used to predict the efficacy of EGFR-TKI treatment and prognosis of advanced NSCLC. The change in CTC expression levels can be used as an index for evaluating the prognosis of patients with advanced NSCLC.

Prognostic implications of survivin and lung resistance protein in advanced non-small cell lung cancer treated with platinum-based chemotherapy

Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC), but the chemotherapy often results in the development of chemoresistance. The present study aimed to explore the prognostic implications of survivin and lung resistance protein (LRP) in advanced NSCLC treated with platinum-based chemotherapy. Tumor samples were collected from 61 hospitalized patients with stage IIIB-IV NSCLC that underwent platinum-based chemotherapy. All patient samples were collected in the Oncology Department of the Third Affiliated Hospital of Guangxi Medical University between January 2006 and January 2011. Cytoplasmic survivin and LRP expression were evaluated using immunohistochemistry. The expression of LRP and survivin reached 77% (47/61) and 76% (45/61), respectively. Positive expression of survivin was associated with a lower median progression-free survival (PFS) time (4 vs. 9 months; P=0.038) and a lower median overall survival (OS) time compared with the absence of survivin expression (9 vs. 16 months; P=0.039). Patients with LRP and survivin expression (n=41) demonstrated a median PFS time of 4 months. However, patients with either LRP or survivin expression (n=10) demonstrated a median PFS time of 8 months, which is similar to the median PFS time of the 10 patients with no expression of LRP and survivin (9 months; P=0.022). Either the expression of survivin or the combined expression of LRP and survivin is associated with a poor prognosis in advanced NSCLC treated with platinum-based chemotherapy.

Role of RRM1 in the Treatment and Prognosis of Advanced Non-small Cell Lung Cancer

肺癌是最常见和死亡率最高的恶性肿瘤之一，75%-80%为非小细胞肺癌（non-small cell lung cancer, NSCLC）。且绝大部分患者就诊时已处晚期，失去了根治性手术或放疗的机会，化疗是主要的治疗手段。但由于肿瘤生物学行为的多样性和对化疗药物的耐药等，使得晚期NSCLC的化疗不容乐观。近年来，分子标志物的个体化化疗在晚期NSCLC的应用，使得这些患者生存期有所延长，生活质量有所提高。针对晚期NSCLC，根据分子标志物选择合适的药物，达到个体化化疗是临床中所要面对和解决的问题。本文就核苷酸还原酶M1（ribonucleotide reductase subunit 1, RRM1）在晚期NSCLC治疗和预后中的作用做一简要综述。由RRM1指导的个体化化疗并不能作为晚期NSCLC的常规决策，还需进一步研究。

Predictive value of plasma D-dimer levels in patients with advanced non-small-cell lung cancer.

PurposeThe relationship between plasma D-dimer level and the prognosis of advanced non-small-cell lung cancer (NSCLC) is not well studied. This study investigated the role of plasma D-dimer as a prognostic factor in advanced NSCLC.MethodsThe plasma D-dimer was measured in 1,931 newly diagnosed advanced NSCLC patients by enzyme-linked immunosorbent assay. Correlations between plasma D-dimer levels and other clinical parameters were analyzed. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis.ResultsPlasma D-dimer concentrations were within the normal range in 1,393 patients (72.1%) and elevated in 538 patients (27.9%). The median overall survival was 11.5 and 8.8 months in the normal and high plasma D-dimer group, respectively (P<0.001). The progression-free survival of first-line chemotherapy was 5.0 months and 4.4 months in the groups with normal and high levels of plasma D-dimer, respectively, (P<0.001). By multivariate analyses, the elevated plasma D-dimer level was found to be an independent prognostic factor for poor survival (hazard ratio =1.245; P<0.001).ConclusionPlasma D-dimer is an independent determinant of poor prognosis in advanced NSCLC.

Association of polymorphisms at HORMAD2 and prognosis in advanced non-small-cell lung cancer patients

BackgroundCancer–testis (CT) genes are predominantly expressed in the testis and are ectopically activated in a wide range of cancers. The expression of CT antigens has been shown to significantly affect the survival of patients with non-small-cell lung cancer (NSCLC). Recently, a genome-wide association study (GWAS) and expression analysis have identified a novel CT gene (HORMAD2) associated with lung cancer risk in Han Chinese people. Thus, the aim of this study is to evaluate the potential prognostic value of HORMAD2 polymorphisms in Han Chinese patients with advanced NSCLC and undergoing first-line platinum-based chemotherapy. Materials and methodsWe selected eight single-nucleotide polymorphisms (SNPs) of HORMAD2 with the potential function of affecting the binding of transcription factors, and we genotyped these SNPs in 303 patients with advanced NSCLC using the MassARRAY platform. All patients were treated with first-line platinum-based chemotherapy but without surgery. Log-rank test and Cox proportional hazard models were used for the survival analyses. ResultsFour SNPs at HORMAD2 (rs9620953, rs8135823, rs5753025 and rs9625921) were significantly associated with the survival of advanced NSCLC patients. Among these, patients with the rs9620953 T allele had a significantly reduced risk of death compared to those with the C allele (additive model: HR, 0.53, 95%CI, 0.32–0.89, P=0.016; dominant model: HR, 0.50, 95%CI, 0.29–0.84, P=0.010). Similarly, the G allele at rs8135823 could decrease the death risk of NSCLC patients compared to the T allele (additive model: HR, 0.63, 95%CI, 0.41–0.95, P=0.028; dominant model: HR, 0.60, 95%CI, 0.39–0.93, P=0.022). Furthermore, both the rs5753025 C allele and the rs9625921 G allele also decreased the death risk in NSCLC in different genetic models (additive model for rs5753025: HR, 0.80, 95%CI, 0.65–0.98, P=0.032; heterozygote model for rs9625921: HR, 0.71, 95%CI, 0.51–0.99, P=0.040). In the joint effect analyses, we found that patients with one, two, and three to eight favorable alleles had a better survival compared with patients carrying no alleles. ConclusionsThese findings indicate that polymorphisms at the CT gene HORMAD2 might be involved in the prognosis of advanced NSCLC in Han Chinese. Further larger and functional studies are needed to confirm the results.

Notch 3 Protein, not its Gene Polymorphism, is Associated with the Chemotherapy Response and Prognosis of Advanced NSCLC Patients

Aim: To study the relation of NOTCH3 and its gene polymorphisms with the chemotherapy response and the prognosis of patients with Non-small cell lung cancer (NSCLC). Methods: A total of 594 patients with advanced stage of NSCLC (IIIA, IIIB and IV) NSCLC were enrolled. All patients received Platinum-based chemotherapy. The NOTCH3 expression in tumors and its gene polymorphisms were determined. In vitro, several NSCLC cell lines received the NOTCH3 over-expression vector and small interfering RNA (siRNA) to study the role of NOTCH3 in regulation the cellular biological behaviors. Results: The genotype and the allele frequencies of NOTCH3 gene polymorphisms at 605C>T and 1735T>C were not significantly different between good responders and poor responders to chemotherapy. However, high NOTCH3 expression in tumor represented a significantly higher possibility of being resistant to chemotherapy. Also, patients with high NOTCH3 expression had a poorer prognosis than those with low NOTCH3 expression. In vitro studies showed that NOTCH3 inhibition dramatically suppressed the proliferation, migration, invasiveness abilities and prompted apoptosis in NSCLC cells. Conclusion: NOTCH3 regulates the cellular behavior, including, proliferation, marker to predict the chemotherapy response and prognosis of advanced NSCLC. marker to predict the chemotherapy response and prognosis of advanced NSCLC.

OPN Polymorphism Is Related to the Chemotherapy Response and Prognosis in Advanced NSCLC.

Background. Osteopontin (OPN) is associated with prognosis of patients with non-small-cell lung cancer (NSCLC). However, little is known about the association between OPN gene polymorphism and the chemotherapy response in NSCLC patients. Methods. A total of 497 patients with inoperable advanced stage of NSCLC (stages III B and IV NSCLC) were enrolled. All patients had received platinum-based chemotherapy. OPN gene polymorphisms at 156 GG/G, 443 C/T, and −66T/G were determined. Results. The genotypes and allele frequency of −443C>T were significantly different between the responders and nonresponders. Responders had a markedly higher frequency of −443TT genotype than responders (40.71% versus 19.09%, P < 0.001). With CC as reference, the TT genotype carriers had a higher chance to be well responders (adjusted OR = 4.43, 95% CI: 2.60–7.53, adjusted P < 0.001). The median overall survival time for patients with −443CC, −443CT, and −443TT genotype carriers was significantly different. Multivariate Cox proportional hazards regression models showed that OPN −443C>T gene polymorphisms were closely correlated to poor NSCLC prognosis. Conclusion. OPN −443C>T gene polymorphism may be used as a molecular marker to predict the treatment response to chemotherapy in advanced NSCLC patients.

BMP-4 genetic variants and protein expression are associated with platinum-based chemotherapy response and prognosis in NSCLC.

To explore the role of genetic polymorphisms of bone morphogenic proteins 4 (BMP-4) in the response to platinum-based chemotherapy and the clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC), 938 patients with stage III (A+B) or IV NSCLC were enrolled in this study. We found that the variant genotypes of 6007C > T polymorphisms significantly associated with the chemotherapy response. The 6007CC genotype carriers had a higher chance to be responder to chemotherapy (adjusted odd ratio = 2.77; 95% CI: 1.83–4.18; adjusted < 0.001). The 6007C > T polymorphisms and BMP-4 expression also affect the prognosis of NSCLC. Patients with high BMP-4 expression had a significantly higher chance to be resistant to chemotherapy than those with low BMP-4 expression (OR = 2.81; 95% CI: 1.23–6.44; P = 0.01). The hazard ratio (HR) for 6007TT was 2.37 times higher than 6007CC (P = 0.003). In summary, the 6007C > T polymorphism of BMP-4 gene and BMP-4 tissue expression may be used as potential predictor for the chemotherapy response and prognosis of advanced NSCLC.