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)

With the advent of new therapeutic modalities, the treatment options for oncologists can vary greatly depending upon the aggressiveness of the patient's cancer. Patients may receive no therapy, adjuvant therapy, aggressive adjuvant therapy (taxane based), monoclonal antibody therapy (e.g. Herceptin) or bone marrow transplantation. It is now mandatory to determine accurate prognostic patient profiles at diagnosis and during therapy to determine who would benefit most from a particular therapeutic regimen or to determine who should be shifted into more aggressive therapy. We now have ultra-sensitive methods of tumor cell detection that can determine the presence of minimal residual cancer (MRC) in marrow, stem cell product (SCP) and lymph node to help create these prognostic profiles. The author has conducted a critical review of the literature regarding the type of testing used to detect MRC, the incidence of MRC in marrow, SCP, and lymph node, and the clinical significance of MRC at diagnosis and during therapy. To date it is now clear that immunohistochemistry is a very useful diagnostic tool with adequate sensitivity to detect MRC. The presence of MRC at diagnosis in marrow and/or lymph node is associated with a poor prognosis for a number of disorders including breast cancer, neuroblastoma, gastrointestinal tumors, and lung cancer. In addition, the presence of MRC during therapy in marrow and/or SCP is associated with a very poor prognosis for patients with breast cancer. The use of testing for MRC in the patient provides prognostic information that may be of use to the oncologist.
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PMID:Clinical relevance of minimal residual cancer in patients with solid malignancies. 1050 48

HER-2/neu is overexpressed in most epithelial malignancies. Lung cancer, prostate cancer, and ovarian cancer are common epithelial tumors in which clinical trials are currently in progress to explore the potential therapeutic role for monoclonal antibodies to HER-2/neu (trastuzumab [Herceptin; Genentech, Inc, South San Francisco, CA]). In preclinical studies with tumor cell lines, trastuzumab was found to have additive and synergistic effects with some chemotherapeutic agents. Clinical trials investigating combination chemotherapy with trastuzumab and a variety of chemotherapeutic agents are already in progress in lung cancer.
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PMID:HER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, and ovarian cancer. 1123 29

HER2 is an erbB/HER type 1 tyrosine kinase receptor that is frequently over-expressed in malignant epithelial tumours. Herceptin, a humanised mouse monoclonal antibody to HER2, is proven therapeutically in the management of metastatic breast cancer, significantly prolonging survival when combined with cytotoxic chemotherapeutic agents. Immunohistochemical studies suggest that non-small-cell lung cancer (NSCLC) tumours may over-express HER2. Our aim was to evaluate HER2 gene amplification and semi-quantitative immuno-expression in NSCLC. A total of 344 NSCLC cases were immunostained for HER2 expression in 2 centres using the HercepTest. Fluorescence in situ hybridisation (FISH) analysis for HER2 gene amplification was performed on most positive cases and a subset of negative cases. Fifteen cases (4.3%) demonstrated 2+ or 3+ membranous HER2 immuno-expression. There was no correlation between immuno-expression and tumour histology or grade. Tumours from higher-stage disease were more often HercepTest-positive (p < 0.001). All 4 HercepTest 3+ cases demonstrated gene amplification. One of the 5 2+ cases tested for gene amplification showed areas of borderline amplification and areas of polyploidy. None of the 19 HercepTest-negative cases demonstrated gene amplification or polyploidy (p < 0.001). Gene amplification was demonstrated in all HercepTest 3+ scoring NSCLC cases. Unlike breast cancer, gene amplification and HER2 protein over-expression assessed by the HercepTest appeared to be uncommon in NSCLC. Herceptin may therefore target only a small proportion of NSCLC tumours and be of limited clinical value in this disease, particularly in the adjuvant setting.
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PMID:Herceptest: HER2 expression and gene amplification in non-small cell lung cancer. 1130 80

The human epidermal growth factor receptor-2 (HER2) is overexpressed/amplified in a range of tumor types including breast, ovarian, bladder, salivary gland, endometrial, pancreatic and non-small-cell lung cancer (NSCLC). HER2 is implicated in disease initiation and progression, associated with poor prognosis, and may also predict the response to chemotherapy and hormonal therapy. Anti-HER2 monoclonal antibodies (MAbs) have been designed to specifically antagonize the function of the HER2 receptor in HER2-positive tumors. Clinical phase II and III trials have demonstrated the efficacy of the humanized anti-HER2 MAb, trastuzumab (Herceptin), both as a single agent and in combination with chemotherapy in HER2-positive, metastatic breast cancer patients. However, the prevalence of HER2 overexpression/amplification in various tumor types raises the possibility of using anti-HER2 MAbs to antagonize the abnormal function of overexpressed HER2 receptors in HER2-positive tumors other than breast. Preliminary in vitro studies indicate that anti-HER2 MAbs suppress the proliferation of ovarian, gastric and NSCLC cell lines that overexpress the HER2 receptor. These results indicate that anti-HER2 MAbs may have important therapeutic significance in patients presenting with these or other human carcinomas. Clinical trials are either planned or underway to assess the therapeutic role of trastuzumab in NSCLC, bladder and ovarian cancer.
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PMID:Targeting HER2 in other tumor types. 1152 27

Overexpression of the Her-2/neu oncogene and receptor protein was reported in approximately 20% of breast cancers and was associated with a poor prognosis. Her-2/neu expression was a predictor for response to trastuzumab, a monoclonal antibody that recognizes the Her-2/neu cell surface receptor. Data regarding the expression of Her-2/neu in lung cancer are far more limited, and there is little information regarding the influence of Her-2/neu expression and response to trastuzumab alone or in combination with chemotherapeutic agents. In this report we evaluated Her-2/neu gene expression by fluorescence in situ hybridization (FISH) and the cell surface expression of the Her-2/neu receptor by immunohistochemistry using the HercepTest and by FACS analysis in 31 lung cancer cell lines with 5 breast cancer cell lines as controls. By FACS, we found Her-2/neu overexpression (mean fluorescence intensity >8) in 2 of the 22 non-small cell lung cancer (NSCLC) cell lines (9%), none of 11 small cell lung cancer (SCLC) cell lines, and 4 of 5 breast cancer cell lines. A positive HercepTest (2+ or 3+) was found in 6 of 19 NSCLC cell lines (26%, 2+; 5%, 3+), 1 of 3 SCLC cell lines (33%), and 4 of 5 breast cancer cell lines (80%). One of 6 NSCLC cell lines examined (17%) had gene amplification with >32 copies of Her-2/neu/cell and had homogeneous staining regions. One NSCLC cell line had a maximum of 14 copies of Her-2/neu/cell, and 3 had modest increases in Her-2/neu gene copy number without gene amplification (maximum 5-8 copies/cell). None of the SCLC cell lines had more than a maximum of 4 copies/cell, whereas the 2 breast cancer cell lines had maximum Her-2/neu copy numbers of 80 and 5, respectively. Aneusomy rather than true amplification was the major cause of increased Her-2/neu expression in most of the NSCLC cell lines. There was a strong correlation when the results of fluorescence-activated cell sorter, HercepTest results, and FISH were compared in pairs. Furthermore, Trastuzumab produced a G(1) cell cycle arrest and growth inhibition only in cell lines expressing Her-2/neu. The IC(50) for growth inhibition was correlated with cell surface Her-2/neu expression. The combination of trastuzumab and chemotherapeutic agents produced more than additive growth inhibition in cell lines expressing Her-2/neu, but the level of additivity was not related to the amount of Her-2/neu expression. These data indicate that trastuzumab alone and in combination with chemotherapeutic agents should be tested in NSCLC patients and that Her-2/neu should be assessed by both immunohistochemistry and FISH methods in these studies to determine which test is the best predictor of outcome.
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PMID:Expression of Her-2/neu in human lung cancer cell lines by immunohistochemistry and fluorescence in situ hybridization and its relationship to in vitro cytotoxicity by trastuzumab and chemotherapeutic agents. 1159 20

Despite intensive treatment efforts, the prognosis for lung cancer is very poor; less than 15% of patients survive 5 years. Trastuzumab, a monoclonal antibody targeting the HER2/neu protein receptor, is effective in the treatment of metastatic breast cancer and may be useful in the treatment of non-small cell lung cancer (NSCLC). Using the HercepTest (Dako; Carpenteria, CA), 25% of NSCLC show 2+ or greater HER2/neu expression, but only 6% to 8% of NSCLC tumors have 3+ overexpression. Positive HER2/neu expression is most often seen in adenocarcinomas compared with squamous cell carcinomas or large cell carcinomas, and is rarely seen in small cell lung cancer. As determined by fluorescence in situ hybridization analysis, the high degree of HER2/neu gene expression and gene amplification seen in breast cancer is lower in NSCLC. Polysomy is the cause of increased HER2/neu expression in most NSCLC. Prospective clinical studies with trastuzumab in lung cancer are ongoing. Future studies in NSCLC need to include immunohistochemistry and fluorescence in situ hybridization analysis to determine the method of choice for evaluating clinically relevant HER2/neu-positive tumors.
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PMID:HER2/neu expression in malignant lung tumors. 1189 14

Although recent advances in therapy have improved the quality of life in patients with extensive stage small cell lung cancer (ESSCLC), prolonged survival is still uncommon. To determine the role of HER-2/neu overexpression and other clinical predictors (symptoms at presentation) of adverse outcome in ESSCLC, we performed a retrospective study on subjects with a biopsy-proven diagnosis of ESSCLC. HER-2/neu overexpression was evaluated using immunohistochemistry (IHC) performed on paraffin-embedded specimens. An IHC score of > or = 2+ was considered positive for overexpression. Between 1991 and 2000, 223 patients with ESSCLC were identified, of whom 193 patients (84 females, 109 males) with a mean age of 68.5 years (range: 42-90 years) had adequate tissue specimens for HER-2/neu testing. The symptoms at initial presentation and proportionate number of patients were: weight loss 61 (31.6%), cough 53 (27.5%), dyspnea 33 (17.1%), mass on chest radiograph 18 (9.3%), chest pain 15 (7.7%), asymptomatic 14 (7.2%) and others (weakness, lymphadenopathy, hoarseness and paraneoplastic syndromes) 29 (15.0%). Of the 193 specimens, 57 (29.5%) revealed HER-2/neu overexpression. The median survival for patients with ESSCLC who were HER-2/neu positive was 8 months (range: 1-25.5 months) while that in the HER-2/neu negative group was 16 months (range: 2-34 months). Interestingly, after adjusting for age, performance status and type of therapy, subset analysis revealed that the survival was significantly lower in HER-2/neu positive individuals (P<0.001; Mann-Whitney U-test). In our study, weight loss and cough were the two most common (59%) presenting complaints in patients with ESSCLC. Also, since HER-2/neu positivity was a marker for poor prognosis in ESSCLC, testing for overexpression may play a role in identifying patients at risk for shortened survival. Further studies would delineate whether HER-2/neu overexpression renders SCLC chemoresistant and thus, adversely affects outcome. There exists a need for randomized controlled trials to assess the role of Herceptin (alone or in combination with standard chemotherapy) in patients with ESSCLC.
Lung Cancer 2002 Jun
PMID:Predictive role of HER-2/neu overexpression and clinical features at initial presentation in patients with extensive stage small cell lung carcinoma. 1200 35

Overexpression of the HER2/neu oncogene and receptor protein has been reported in 20%-30% of patients with breast cancer and is associated with a poor prognosis. HER2/neu expression in breast cancer patients assessed by fluorescence in situ hybridization or immunohistochemistry is a predictor for response to trastuzumab, a humanized monoclonal antibody against the HER2/neu cell-surface protein. Data regarding HER2/neu expression in lung cancer are more limited, and there is little information regarding HER2/neu expression and response to trastuzumab alone or in combination with chemotherapeutic agents. Gemcitabine is an active agent against non-small-cell lung cancer (NSCLC) and has demonstrated activity in breast cancer as well. In vitro modified tetrazolium salt growth assays were performed to determine whether the combination of trastuzumab/gemcitabine produced synergistic or additive effects on breast and lung cancer cell lines. The effects of trastuzumab alone, gemcitabine alone, and the trastuzumab/gemcitabine combination was evaluated on 4 NSCLC cell lines, 1 small-cell lung cancer (SCLC) cell line, and 2 breast cancer cell lines. HER2/neu surface protein expression was assessed by fluorescence flow cytometry and immunohistochemistry. Fluorescence in situ hybridization analysis was used to study gene expression. Trastuzumab treatment alone resulted in growth inhibition in all cell lines expressing HER2/neu and the inhibitive effect correlated with the level of cell surface HER2/neu protein expression. Treatment with gemcitabine alone resulted in growth inhibition in both breast and NSCLC cell lines. A synergistic growth inhibition effect was seen with the trastuzumab/ gemcitabine combination as indicated by combination index values < 1. The degree of synergy observed did not directly correlate with the level of surface protein expression, as synergy was seen even in cancer cell lines expressing low levels of HER2/neu. No treatment effect was seen in the SCLC cell line, which did not express HER2/neu. These preclinical studies indicate a need to study the clinical synergistic effects of the gemcitabine/trastuzumab combination in breast cancer and NSCLC patients whose tumors overexpress HER2/ neu.
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PMID:Preclinical studies of gemcitabine and trastuzumab in breast and lung cancer cell lines. 1205 39

The overexpression of HER2, a transmembrane glycoprotein tyrosine kinase, has been implicated in mitogenesis, cell survival, invasion and angiogenesis. Preclinical evidence suggests that HER2 overexpression contributes to tumor progression in non-small cell lung cancer (NSCLC) and retrospective clinical correlative studies show that it is probably associated with poor clinical outcome. Trastuzumab (Herceptin, Genentech Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody that targets HER2 and is currently approved for use in the treatment of patients with HER2-overexpressing metastatic breast cancer. Two primary mechanisms proposed for the activity of trastuzumab are downregulation of HER2 and induction of antibody-dependent cell-mediated cytotoxicity. Evidence from preclinical studies of trastuzumab in NSCLC and other cell lines, the presence of HER2 overexpression in NSCLC clinical specimens and the clinical benefit derived from trastuzumab in phase II and III metastatic breast cancer trials have led to the development of clinical trials of trastuzumab in NSCLC. Phase II studies of trastuzumab in patients with stage IIIB or IV NSCLC are being conducted to test the efficacy of trastuzumab as a single agent or in combination with chemotherapy. Preliminary results show combinations of chemotherapy plus trastuzumab are well tolerated, with encouraging response rates of 21-40%. A randomized phase II trial of chemotherapy with or without trastuzumab showed promise in a small subgroup of patients with 3+ HER2 overexpression by immunohistochemistry or HER2 DNA amplification by fluorescence in situ hybridization. Taken together, these data indicate that trastuzumab warrants further investigation in a clinical study in selected patients with NSCLC.
Lung Cancer 2002 Jul
PMID:Non-small cell lung cancer clinical trials with trastuzumab: their foundation and preliminary results. 1205 63

Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes, topoisomerase inhibitors, vinorelbine (Navelbine), and gemcitabine (Gemzar), platinum-based combination therapy has appeared to reach a threshold of therapeutic effectiveness. A paradigm shift in approach to non-small-cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development. Such new agents include antibody epithelial growth factor receptor (EGFR) inhibitors (eg, the monoclonal antibodies trastuzumab [Herceptin] and cetuximab [IMC-C225, Erbitux]) and EGFR tyrosine kinase inhibitors (eg, ZD1839 [Iressa] and OSI-774), angiogenesis inhibitors (eg, matrix metalloproteinase inhibitors), vascular endothelial growth factor (VEGF) inhibitors (eg, monoclonal antibody to VEGF ligand and small-molecule tyrosine kinase), and signal transduction inhibitors (eg, ISIS-3521, an antisense oligonucleotide to protein kinase C-alpha). A number of these agents have entered advanced-phase clinical investigation. It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment, including maintenance therapy. It is even possible that these new biologic therapies will be used together as rational combinations (based on pathologic diagnosis) for advanced non-small-cell lung cancer.
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PMID:Targeted therapy in non-small-cell lung cancer. 1237 97


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