Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HER-2/ neu is an immunogenic protein eliciting both humoral and cellular immune responses in patients with HER-2/ neu-positive ((+)) tumors. Preexisting cytotoxic T lymphocyte (CTL) immunity to HER-2/ neu has so far been mainly evaluated in terms of detection of CTL precursor (CTLp) frequencies to the immunogenic HLA-A2-binding nona-peptide 369-377 (HER-2(9(369))). In the present study, we examined patients with HER-2/ neu(+) breast, ovarian, lung, colorectal, and prostate cancers for preexisting CTL immunity to four recently described HER-2/ neu-derived and HLA-A2-restricted "cytotoxic" peptides and to a novel one spanning amino acids 777-785 also with HLA-A2-binding motif. We utilized enzyme-linked immunosorbent spot (ELISpot) assay, which allows a quantitative and functional assessment of T cells directed against specific peptides after only brief in vitro incubation. CTL reactivity was determined with an interferon gamma (IFN-gamma) ELISpot assay detecting T cells at the single cell level secreting IFN-gamma. CTLp were defined as peptide-specific precursors per 10(6) peripheral blood mononuclear cells (PBMCs). Patients' PBMCs with increased CTLp were also tested against autologous tumor targets and peptide-pulsed dendritic cells (DCs) in cytotoxicity assays. We also studied patients with HER-2/ neu-negative ((-)) tumors and healthy individuals. Of the HER-2/neu(+) patients examined, 31% had increased CTLp to HER-2(9(952)), 19% to HER-2(9(665)), 16% to HER-2(9(689)), and 12.5% HER-2(9(435)), whereas only 2 of 32 patients (6%) responded to HER-2(9(777)). The CTLp recognizing HER-2(9(952)) were extremely high in two patients with breast cancer, one with lung cancer, and one with prostate cancer. None of the HER-2/neu(-) patients or healthy donors exhibited increased CTLp to any of these peptides. Besides IFN-gamma production, preexisting CTL immunity to all five HER-2/ neu peptides was also shown in cytotoxicity assays where patients' PBMCs with increased CTLp specifically lysed autologous tumor targets and autologous peptide-pulsed DCs. Our results demonstrate for the first time that (1) preexisting immunity to peptides HER-2(9(435)), HER-2(9(952)), HER-2(9(689)), HER-2(9(665)), and HER-2(9(777)) is present in patients with HER-2/ neu(+) tumors of distinct histology, (2) HER-2(9(777)) is a naturally processed peptide expressed on the surface of HER-2/ neu(+) tumors, as are the other four peptides, and (3) HER-2/ neu(+) prostate tumor cells can be recognized and lysed by autologous HER-2 peptide-specific CTL. Our findings broaden the potential application of HER-2/ neu-based immunotherapy.
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PMID:Natural CD8+ T-cell responses against MHC class I epitopes of the HER-2/ neu oncoprotein in patients with epithelial tumors. 1368 Jan 93

Major prognostic factors for early-stage non-small-cell lung cancer (NSCLC) are tumor size and nodal status. It has been suggested that HER2/neu overexpression may be related to poor prognosis in NSCLC. We evaluated the significance of HER2/neu overexpression on survival in patients with NSCLC. Data were collected on 239 patients treated surgically for stage I/II NSCLC between 1987 and 1996. None of the patients received adjuvant chemotherapy or radiation. Formalin-fixed, paraffin-embedded tumor tissue samples were stained with p185/HER2 receptor antibody. Results were reported as positive (2+, 3+) or negative (0, 1+) (Group A). A separate analysis considered only 3+ as positive (Group B). HER2/neu overexpression was seen in 18% in Group A (43 of 239) and 6% in Group B (15 of 239). HER2/neu overexpression was highest in bronchoalveolar cell carcinoma and adenocarcinoma. More stage I tumors were positive than stage II in both groups, but this was significant only in Group A (21% vs. 7%, P = 0.02). No difference was seen with age, gender, or grade for either group. In Group A, the relapse rate was 55% for HER2/neu-overexpressing tumors and 31% for HER2/neu-negative tumors (P = 0.003). Median time to relapse in patients with HER2/neu-positive tumors was 2.9 years; it was not reached in patients with HER2/neu-negative tumors. Median survival of patients with HER2/neu-positive tumors was 3.6 years compared to 5 years in patients with HER2/neu-negative tumors (P = 0.66). In Group B, the relapse rate was 60% for HER2/neu-overexpressing tumors and 33% for negative tumors (P = 0.036). Median time to relapse was 3.4 years in HER2/neu positive and had not been reached in negative tumors. There was no difference in 5-year survival rates for both groups (47% for HER2/neu positive and 50% for negative, P = 0.66).
Clin Lung Cancer 2001 Feb
PMID:Effect of HER2/neu expression on survival in non-small-cell lung cancer. 1470 Apr 81

We performed a retrospective analysis of potential prognostic markers in 260 patients with surgically resected stage I and II non small-cell lung cancer (NSCLC) with a minimum 5-year follow-up. Cox proportional hazard models and Wilcoxon tests were employed to analyze the effect of patient characteristics on survival and disease-free survival (DFS). In the univariate analysis, the following were significant predictors of shorter overall survival: N-stage (N1 vs N0) (p<0.001); T-stage (T2 vs T1) (p<0.001); antigen A (loss vs presence) (p<0.01); cough (present vs absent) (p=0.01); bcl-2 expression (positive vs negative) (p=0.03); age (>63.5 vs <63.5) (p=0.03); mucin (positive vs negative) (p<0.03). The following were significant predictors of shorter DFS: N-stage (p<0.001); T-stage (p=0.001); loss of antigen A (p=0.01); mucin expression (p<0.01); cough (p=0.02); Ki-67 expression (p=0.02) and negative bcl-2 expression (p=0.03). Analysis of survival difference for histologic subtype, degree of differentiation, aneuploidy, %S-phase, codon 12 K-ras mutation, and immunohistochemistry staining for Lewisy, p53, Rb, microvessel count, HER2, E-cadherin and neuroendocrine markers did not reach statistical significance. In multivariate analysis, the following predicted for shorter overall survival: N-stage (p<0.01), antigen A (p=0.01), age (p<0.01), and bcl-2 (p=0.05); and for DFS, N-stage (p<0.01), antigen A (p<0.01), Ki-67 (p=0.03), mucin (p=0.04) and T-stage (p=0.05). Of all the clinical-pathological, proliferative, and biological markers studied, only a few carried independent prognostic significance.
Clin Lung Cancer 1999 Aug
PMID:Prognostic markers in resected stage I and II non small-cell lung cancer: an analysis of 260 patients with 5 year follow-up. 1472 52

Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin H synthase, has been implicated in the progression of human lung adenocarcinoma. However, the mechanism underlying COX-2's effect on tumor progression remains largely unknown. Lymphangiogenesis, the formation of new lymphatic vessels, has recently received considerable attention and become a new frontier of tumor metastasis research. Here, we study the interaction between COX-2 and the lymphangiogenic factor, vascular endothelial growth factor (VEGF)-C, in human lung cancer cells and their implication in patient outcomes. We developed an isopropyl-beta-D-thiogalactopyranoside-inducible COX-2 gene expression system in human lung adenocarcinoma CL1.0 cells. We found that VEGF-C gene expression but not VEGF-D was significantly elevated in cells overexpressing COX-2. COX-2-mediated VEGF-C up-regulation was commonly observed in a broad array of non-small cell lung cancer cell lines. The use of pharmacological inhibitors or activators and genetic inhibition by EP receptor-antisense oligonucleotides revealed that prostaglandin EP(1) receptor but not other prostaglandin receptors is involved in COX-2-mediated VEGF-C up-regulation. At the mechanistic level, we found that COX-2 expression or prostaglandin E(2) (PGE(2)) treatment could activate the HER-2/Neu tyrosine kinase receptor through the EP(1) receptor-dependent pathway and that this activation was essential for VEGF-C induction. The transactivation of HER-2/Neu by PGE(2) was inhibited by way of blocking the Src kinase signaling using the specific Src family inhibitor, PP1, or transfection with the mutant dominant negative src plasmid. Src kinase was involved in not only the HER-2/Neu transactivation but also the following VEGF-C up-regulation by PGE(2) treatment. In addition, immunohistochemical staining of 59 lung adenocarcinoma specimens showed that COX-2 level was highly correlated with VEGF-C, lymphatic vessels density, and other clinicopathological parameters. Taken together, our results provided evidence that COX-2 up-regulated VEGF-C and promotes lymphangiogenesis in human lung adenocarcinoma via the EP(1)/Src/HER-2/Neu signaling pathway.
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PMID:Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. 1474 69

HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.
Clin Lung Cancer 2004 Jan
PMID:Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. 1496 75

Research over the past decade has led to an increased understanding of the pathophysiology of lung cancer. The HER2/neu receptor is a member of the ErbB family of signaling-transduction receptors and appears to play a major role in the development of lung cancer as well as many other solid tumors. HER2/neu is overexpressed in 16% to 57% of patients with non-small cell lung cancer (NSCLC) and studies have shown that HER2/neu overexpression imparts a poor prognosis in both resected and advanced NSCLC, as it does in breast cancer. Trastuzumab, a humanized monoclonal antibody that recognizes the HER2/neu protein receptor, has been approved by the US Food and Drug Administration for patients with HER2/neu-positive metastatic breast cancer. In NSCLC preclinical studies, marked synergistic growth inhibition occurred when standard cytotoxic chemotherapy was combined with trastuzumab in HER2/neu-expressing cell lines. In the clinical setting, trastuzumab has proven safe and feasible in combination with cytotoxic chemotherapy in both single-institution and multi-institutional cooperative group studies. Unlike the experience in advanced breast cancer, cardiac toxicity is a marginal concern in this population. However, to date, clinical studies with trastuzumab in patients with NSCLC have not shown a demonstrable advantage for the majority of patients.
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PMID:The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. 1498 84

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.
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PMID:Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. 1503 19

The incidence of lung cancer is increasing throughout the world and is the most common cause of cancer-related death. Early detection followed by surgery has a reasonable, curative potential, but 30-50% of patients experience relapses. The immunohistochemical expressions of HER-2, EGFR and COX-2 were investigated in 53 resected non-small cell lung carcinomas and correlated to microvessel density and clinical data. HER-2, EGFR and COX-2 overexpressions were demonstrated in 15%, 30% and 40% of the tumours, respectively. In adenocarcinomas, HER-2 and COX-2 overexpression were more common, whereas in squamous cell carcinomas, EGFR overexpression was more common. COX-2 expression correlated with HER-2 expression (p = 0.002), and demonstrated a trend towards a correlation with microvessel density (p = 0.10). None of the markers alone had any impact on survival. However, HER-2+/EGFR- tumours proved to have a poor prognosis. In conclusion, adjuvant treatment with HER-2 antagonists might be a future treatment option in resected non-small cell lung cancer patients, especially when HER-2 is overexpressed without a concomitant overexpression of EGFR.
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PMID:HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer. 1506 24

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30-50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15-60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
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PMID:Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. 1507 90

This retrospective study aimed at evaluating the prognostic impact of high serum levels of either the HER-2 extracellular domain (ECD) or the epidermal growth factor receptor (EGFR) ECD measured using two specific ELISAs in 221 patients with non-small-cell lung cancer (NSCLC) receiving conventional therapy and 41 nonmalignant pulmonary diseases patients. It was not possible to discriminate between lung cancer and benign lung disease owing to the lack of sensitivity-specificity relationship of HER-2 and EGFR ECD levels. Neither HER-2 nor EGFR ECD specific levels were associated with a particular prognosis of NSCLC patients receiving conventional therapy.
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PMID:Serum EGF-receptor and HER-2 extracellular domains and prognosis of non-small-cell lung cancer. 1522 69


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