Serum EGF-receptor and HER-2 extracellular domains and prognosis of non-small-cell lung cancer.
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ABSTRACT:
SUBMITTER: Jacot W
PROVIDER: S-EPMC2409859 | biostudies-other | 2004 Aug
REPOSITORIES: biostudies-other
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Project description:BackgroundSerum cholinesterase (ChE) was found to be involved in cancer initiation and progression. However, the survival association between serum ChE and non-small cell lung cancer (NSCLC) has not been extensively discussed. In the present study, we aim to elevate the role of ChE in overall survival (OS) of NSCLC patients.MethodsA total of 961 histologically confirmed NSCLC patients diagnosed between 2013 and 2018 in a provincial cancer hospital in southwestern China were retrospectively selected. Relevant information, such as histological type, clinical stage, chemotherapy, smoking status, body mass index (BMI), important serum indicators (albumin, neutrophil-to-lymphocyte ratio, ChE), date of death of the patients was extracted from the computerized hospital information system. Univariate and multivariate Cox proportional hazards models were used to determine the association between baseline serum ChE measured at the diagnosis and the OS of NSCLC patients.ResultsThe median of baseline ChE (7700 units/liter) was used as a cut-off to dichotomize NSCLC patients. After controlling for possible confounding factors, serum ChE at diagnosis was significantly associated with OS of NSCLC: patients with higher level of ChE were observed a better prognosis (hazard ratio, HR: 0.77, 95% CI: 0.67-0.93, p = 0.006). Subgroup analysis revealed significant ChE-OS association for NSCLC patients: with lower systemic inflammation level (baseline NLR < 2.95, HR: 0.71, 95% CI: 0.56-0.89, p = 0.003), of adenocarcinoma (HR: 0.66, 95% CI: 0.54-0.80, p < 0.001), in advanced stage (HR: 0.77, 95% CI: 0.66-0.92, p < 0.01), and received chemotherapy (HR: 0.75, 95% CI: 0.59-0.96, p < 0.02).ConclusionBaseline ChE may have independent prognostic value for NSCLC patients. Longitudinal studies should be performed to corroborate this finding.
| S-EPMC8783506 | biostudies-literature
Project description:Lung cancer remains the leading cause of cancer-associated mortality worldwide, but with the emergence of oncogene targeted therapies, treatment options have tremendously improved. Owing to their biological relevance, members of the ERBB receptor family, including the EGF receptor (EGFR), HER2, HER3 and HER4, are among the best studied oncogenic drivers. Activating EGFR mutations are frequently observed in non-small cell lung cancer (NSCLC), and small molecule tyrosine kinase inhibitors (TKIs) are the established first line treatment option for patients whose tumors bear "typical/classical" EGFR mutations (exon 19 deletions, L858R point mutations). Additionally, new TKIs are rapidly evolving with better efficacy to overcome primary and secondary treatment resistance (e.g., that due to T790M or C797S resistance mutations). Some atypical EGFR mutations, such as the most frequent exon 20 insertions, exhibit relative resistance to earlier generation TKIs through steric hindrance. In this subgroup, newer TKIs, such as mobocertinib and the bi-specific antibody amivantamab have recently been approved, whereas less frequent atypical EGFR mutations remain understudied. In contrast to EGFR, HER2 has long remained a challenging target, but better structural understanding has led to the development of newer generations of TKIs. The recent FDA approval of the antibody-drug conjugate trastuzumab-deruxtecan for pretreated patients with HER2 mutant NSCLC has been an important therapeutic breakthrough. HER3 and HER4 also exert oncogenic potential, and targeted treatment approaches are being developed, particularly for HER3. Overall, strategies to inhibit the oncogenic function of ERBB receptors in NSCLC are currently evolving at an unprecedented pace; therefore, this review summarizes current treatment standards and discusses the outlook for future developments.
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Project description:The aim of the study was a search for diagnostic and/or prognostic biomarkers in patients with non-small cell lung cancer (NSCLC) patients, based on circulating microRNAs (miRs: miR-23a, miR-361, miR-1228 and miR-let7i) in extracellular vesicles (EVs). Serum EVs were isolated from NSCLC patients (n = 31) and control subjects (n = 21). RNA was isolated from EVs and reverse transcription reaction was performed. Relative levels of miR-23a, miR-361, miR-1228 and miR-let7i were assessed in real-time qPCR using TaqMan probes. Analysis was based on the 2-ΔΔCT method. Statistically significant lower levels of miR-23a and miR-let7i were observed among NSCLC patients vs. control group: miR-23a, 0.054 vs. 0.107; miR-let7i, 0.193 vs. 0.369 (p = 0.003, p = 0.005, respectively). A receiver operating characteristic (ROC) curve analysis demonstrated the diagnostic potential of each individual serum EV-derived miRNA with an area under the curve AUC = 0.744 for miR-23a (p = 0.0003), 0.733 for miR-let7i (p = 0.0007). The decreased level of miR-23a in patients correlated with metastasis to lymph nodes and with AJCC tumor staging system. The results demonstrate that miR-23a and miR-let7i may prove clinically useful as significant, non-invasive markers in NSCLC diagnosis. Additionally, changing profile level of miR-23a that correlates with cancer development may be considered as an NSCLC progression marker.
| S-EPMC7998231 | biostudies-literature
Project description:BackgroundCurrent histopathological classification and TNM staging have limited accuracy in predicting survival and stratifying patients for appropriate treatment. The goal of the study is to determine whether the expression pattern of functionally important regulatory proteins can add additional values for more accurate classification and prognostication of non-small lung cancer (NSCLC).MethodsThe expression of 108 proteins and phosphoproteins in 30 paired NSCLC samples were assessed using Protein Pathway Array (PPA). The differentially expressed proteins were further confirmed using a tissue microarray (TMA) containing 94 NSCLC samples and were correlated with clinical data and survival.ResultsTwelve of 108 proteins (p-CREB(Ser133), p-ERK1/2(Thr202/Tyr204), Cyclin B1, p-PDK1(Ser241), CDK4, CDK2, HSP90, CDC2p34, ?-catenin, EGFR, XIAP and PCNA) were selected to build the predictor to classify normal and tumor samples with 97% accuracy. Five proteins (CDC2p34, HSP90, XIAP, CDK4 and CREB) were confirmed to be differentially expressed between NSCLC (n=94) and benign lung tumor (n=19). Over-expression of CDK4 and HSP90 in tumors correlated with a favorable overall survival in all NSCLC patients and the over-expression of p-CREB(Ser133) and CREB in NSCLC correlated with a favorable survival in smokers and those with squamous cell carcinoma, respectively. Finally, the four proteins (CDK4, HSP90, p-CREB and CREB) were used to calculate the risk score of each individual patient with NSCLC to predict survival.ConclusionIn summary, our data demonstrated a broad disturbance of functionally important regulatory proteins in NSCLC and some of these can be selected as clinically useful biomarkers for diagnosis, classification and prognosis.
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Project description:The current staging system for non-small cell lung cancer (NSCLC) is inadequate for predicting outcome. Risk score, a linear combination of the values for the expression of each gene multiplied by a weighting value which was estimated from univariate Cox proportional hazard regression, can be useful. The aim of this study is to analyze survival-related genes with TaqMan Low-Density Array (TLDA) and risk score to explore gene-signature in lung cancer. A total of 96 NSCLC specimens were collected and randomly assigned to a training (n = 48) or a testing cohort (n = 48). A panel of 219 survival-associated genes from published studies were used to develop a 6-gene risk score. The risk score was used to classify patients into high or low-risk signature and survival analysis was performed. Cox models were used to evaluate independent prognostic factors. A 6-gene signature including ABCC4, ADRBK2, KLHL23, PDS5A, UHRF1 and ZNF551 was identified. The risk score in both training (HR = 3.14, 95% CI: 1.14-8.67, p = 0.03) and testing cohorts (HR = 5.42, 95% CI: 1.56-18.84, p = 0.01) was the independent prognostic factor. In merged public datasets including GSE50081, GSE30219, GSE31210, GSE19188, GSE37745, GSE3141 and GSE31908, the risk score (HR = 1.50, 95% CI: 1.25-1.80, p < 0.0001) was also the independent prognostic factor. The risk score generated from expression of a small number of genes did perform well in predicting overall survival and may be useful in routine clinical practice.
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Project description:We conducted a population-based study to evaluate whether non-small cell lung cancer (NSCLC) prognosis was worse in HIV-infected compared with HIV-uninfected patients.Using the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare claims, we identified 267 HIV-infected patients and 1428 similar controls with no evidence of HIV diagnosed with NSCLC between 1996 and 2007. We used conditional probability function (CPF) analyses to compare survival by HIV status accounting for an increased risk of non-lung cancer death (competing risks) in HIV-infected patients. We used multivariable CPF regression to evaluate lung cancer prognosis by HIV status adjusted for confounders.Stage at presentation and use of stage-appropriate lung cancer treatment did not differ by HIV status. Median survival was 6 months (95% confidence interval (CI): 5-8 months) among HIV-infected NSCLC patients compared with 20 months (95% CI: 17-23 months) in patients without evidence of HIV. Multivariable CPF regression showed that HIV was associated with a greater risk of lung cancer-specific death after controlling for confounders and competing risks.NSCLC patients with HIV have a poorer prognosis than patients without evidence of HIV. NSCLC may exhibit more aggressive behaviour in the setting of HIV.
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Project description:Non-small cell lung cancer (NSCLC)-associated epidermal growth factor receptor (EGFR) mutants are constitutively active and induce ligand-independent transformation in non-malignant cell lines. We investigated the possibility that the ability of mutant EGFRs to transform cells reflects a constitutive cooperativity with Src using a system in which the overexpression of mutant, but not wild-type, EGFR induced anchorage-independent cell growth. Src was constitutively activated and showed enhanced interaction with mutant EGFRs, suggesting that constitutive EGFR-Src cooperativity may contribute to mutant EGFR-mediated oncogenesis. Indeed, the mutant EGFR-mediated cell transformation was inhibited by Src- as well as EGFR-directed inhibitors. Importantly, a tyrosine to phenylalanine mutation of the major Src phosphorylation site on EGFR, Y845, reduced the constitutive phosphorylation of NSCLC-EGFR mutants, as well as that of STAT3, Akt, Erk and Src, and reduced the mutant EGFR-Src association as well as proliferation, migration and anchorage-independent growth. Reduced anchorage-independent growth and migration were also observed when dominant-negative-Src was expressed in mutant EGFR-expressing cells. Overall, our findings show that mutant EGFR-Src interaction and cooperativity play critical roles in constitutive engagement of the downstream signaling pathways that allow NSCLC-associated EGFR mutants to mediate oncogenesis, and support the rationale to target Src-dependent signaling pathways in mutant EGFR-mediated malignancies.
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Project description:Background Lung cancer has a high incidence and a 5-year survival rate of less than 15%. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Chemotherapy and immunotherapy are the most frequently used alternative treatments for patients with advanced-stage NSCLC in whom surgery failed. Previous studies have suggested that miR-27a is involved in cancer development and progression. The purpose of this study was to investigate the clinical value of miR-27a in the prognosis of NSCLC patients after chemotherapy. Methods Flow cytometry was used to detect the apoptosis rate of SPC-A1 cells treated with optical cisplatin at different times. Simultaneously, the expression of miR-27a in supernatants and cells was detected. Fifty-two newly diagnosed NSCLC patients were recruited. All patients received gemcitabine and cisplatin as first-line chemotherapy and docetaxel as second-line chemotherapy. At the end of every chemotherapy cycle, a therapeutic evaluation was performed according to the RECIST criteria. The expression of serum miR-27a was detected in each cycle. Results After treatment with 2.5 µg/mL cisplatin, the apoptosis rates of SPC-A1 cells were significantly greater than those of the paired untreated control groups at 12, 24, 48 and 72 h. The expression of miR-27a in supernatants and cells was also consistent with the apoptosis rate and changed a time-dependent manner. The chi-square test showed that an increase in miR-27a after chemotherapy was more common in patients who achieved partial response (PR) than in those who achieved no response (NR) (61.5% vs. 30.8%, P=0.026). Kaplan-Meier survival analysis indicated that patients with decreased miR-27a levels had poorer outcomes than those with increased miR-27a levels (P<0.05). Furthermore, dynamic changes in serum miR-27a with a gradual increasing trend during chemotherapy predicted a good prognosis. Conclusions Collectively, our results suggest that miR-27a is involved in the apoptosis of lung cancer cells and that serum miR-27a levels are related to the prognosis of NSCLC patients. The expression levels of miR-27a in the serum may be an independent predictor for the prognosis of NSCLC.
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Project description:Midkine, a heparin-binding growth factor, has been identified as a promising cancer biomarker. In non-small cell lung cancer (NSCLC), the serum and urine midkine levels have not been intensively investigated. The aim of the present study was to investigate the diagnostic and prognostic potential of serum and urine midkine levels in patients with NSCLC. The serum midkine levels were measured in 153 patients with NSCLC, 23 patients with benign pulmonary disease and 95 healthy controls using ELISA. Urine midkine levels were examined in 20 controls and 45 patients with NSCLC. Midkine expression in tumor tissues from 72 patients with NSCLC who underwent definitive surgical resection without any pre-operative treatments was examined by immunohistochemistry. Serum levels were significantly higher in patients with NSCLC than in healthy controls (657.36±496.58 pg/ml vs. 194.49±122.57 pg/ml, P<0.001). As shown in the ROC curve analysis, the sensitivity and specificity of the cut-off serum midkine concentration of 400 pg/ml for predicting the presence of NSCLC were 71.2% and 88.1%, respectively. Positive correlations between the serum midkine levels and immunohistochemistry staining scores (r=0.315, P=0.007) and between the serum midkine levels and urine midkine levels (r=0.636, P<0.001) were observed using Spearman's bivariate correlations. The serum midkine concentration was identified as an independent prognostic factor by multivariate analysis, and its overexpression yielded a relative risk of death of 2.072 (0.01.
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Project description:The human leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) protein has been shown to be of prognostic value in several types of human cancer, however, the expression profiles of LRIG2 have not been described in non-small cell lung cancer (NSCLC). The present study evaluated the mRNA expression of LRIG2 in tumor specimens obtained from 39 NSCLC patients by SYBR Green quantitative polymerase chain reaction and the protein expression of LRIG2 in formalin-fixed paraffin sections obtained from 116 NSCLC patients by immunohistochemistry. The correlations between LRIG2 expression and clinicopathological data were analyzed. The patient survival data were collected retrospectively and the possible prognostic value of LRIG2 protein expression was investigated. The results showed that the mRNA expression of LRIG2 was decreased in NSCLC cancer tissues, which was associated with histological subtypes and tumor differentiation status. The protein expression of LRIG2 was only observed in the cytoplasm of the tumor tissue, which conformed to the mRNA expression results. Furthermore, the patients with high LRIG2 cytoplasmic expression showed poor survival times, and the five-year survival rate for patients with high LRIG2 expression was 27.8%, compared with 38.8% for patients with low expression (P=0.034), indicating that LRIG2 expression levels may have a potential role in the pathogenesis of NSCLC, and also a significant prognostic value. Further studies are required to fully elucidate the exact function of LRIG2 in NSCLC.
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