Cancer Biomarkers - Volume 6, issue 3-4

Authors: Holdenrieder, Stefan | Stieber, Petra

Article Type: Editorial

Keywords: Lung cancer, NSCLC, biomarker, serum, diagnosis

DOI: 10.3233/CBM-2009-0123

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 119-121, 2010

Authors: Tufman, Amanda | Huber, Rudolph Maria

Article Type: Research Article

Abstract: Biological markers are urgently needed to improve the early detection, diagnosis and treatment of lung tumours. Over the past several years various promising biomarkers have emerged in the field of lung cancer. The poor prognosis associated with advanced lung cancer has resulted in attempts to develop lung cancer screening programs. The role of imaging and sputum cytology in lung cancer screening is the focus of much discussion, and efforts to find a suitable blood, sputum or exhaled breath biomarker for the detection of early lung cancer are ongoing. Regarding diagnosis, immunohistochemical profiling is a relatively well established adjunct …to microscopic histology as a means of differentiating tumours originating in the lung from metastases from elsewhere. And, in particular in the case of non small cell lung cancer, a precise histological sub-classification of lung tumours is becoming clinically relevant in the choice of anti-tumour therapy, suggesting an increased and defined role for immunohistochemical markers. Molecular changes which correlate with the proposed subclassification of non-small cell lung cancer have also been identified. The treatment of lung cancer is dependant on the stage at the time of diagnosis. In particular, the decision whether or not to operate is dependant on the presence or absence of tumour cells in specific groups of mediastinal lymph nodes. The use of biomarkers can reveal microscopic lymph node metastases which would go unnoticed using conventional histology alone, and can provide early information about the presence of brain metastases. In addition, there is evidence that specific genetic factors predispose tumours to metastasis, which may have a role in the future risk-stratification of patients. Treatment with chemotherapy can be associated with significant toxicity, and is unfortunately not always successful in slowing the progression of lung cancer. The concept of individualized treatment depends on our ability to predict which tumours will respond to which medications. Numerous biomarkers have been suggested to have predictive value in response to chemotherapy, including ERCC-1 for response to cisplatin, beta-tubulin for response to taxanes, and RRM1 for response to gemcitabine. Increasing understanding of the EGFR pathway in NSCLC has led to the development of a class of medications aimed at inhibiting this pathway, including erlotinib, gefitinib and cetuximab. The efficacy of these medications seems to correlate with the presence of mutations in the EGFR gene. It has now been widely accepted that specific activating mutations in EGFR predicts the response of NSCLC to gefitinib and erlotinib. The failure of treatment with EGFR inhibitors also appears to correlate with both specific mutations in EGFR and with mutations in other proteins in the EGFR pathway. The importance of angiogenesis to tumour growth has led to interest in medications which inhibit angiogenesis. The vascular endothelial growth factor (VEGF) and its receptor are of particular interest. Once treatment has been initiated, biomarkers play an important role in patient monitoring. The serum levels of CYFRA-21-1 and CEA, as well serum nucleosome levels, correlate with the tumour's response to therapy. In addition, serum levels of circulating tumour cells, as well as the detection of specific mutations in circulating tumour DNA may be of clinical use in the future. This paper describes the current role of biomarkers in the detection, diagnosis and treatment of lung cancer, and presents data relating to the development of new biomarkers which are emerging as tools in the management of this difficult disease. Show more

Keywords: Lung cancer, non-small cell lung cancer, small-cell lung cancer, treatment, diagnosis, staging, chemotherapy, targeted therapy, screening, tumor marker, biomarker, erlotinib, gefitinib, cisplatin, bevacizumab, EGFR, VEGF, IGFR, gemcitabine, pemetrexed, immunehistochemistry, histology, sputum cytology, proteomics, genomics

DOI: 10.3233/CBM-2009-0124

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 123-135, 2010

Authors: Schneider, Joachim

Article Type: Research Article

Abstract: Background: This study evaluates the diagnostic power of a fuzzy classifier and a tumor marker panel for the detection of lung cancers in comparison to pneumoconiosis patients at high-risk of developing lung cancer. Methods: CEA, CYFRA 21-1, NSE, SCC and CRP were measured in newly diagnosed lung cancer patients of different histological types and stages in comparison to patients suffering from silicosis. First a fuzzy classifier was generated with a set of 216 primary lung cancer patients (158 non-small cell lung cancer (NSCLC) and 58 small cell lung cancer (SCLC) patients) and 127 patients suffering from pneumoconiosis (51 …silicosis and 76 asbestosis). Subsequently, the classifier was validated on a second cohort of 38 NSCLC patients, 55 silicosis patients, 32 patients with chronic obstructive airway diseases (COLD) and 28 healthy control subjects. Results: At 95%-specificity, NSCLC patients were detected in 50% at stage I (n= 30), in 64% at stage II (n=22), in 82% at stage III (n=56), in 88% at stage IV (n=50) and SCLC patients with limited disease status (n=21) in 71% and with extensive disease status (n=37) in 89% by use of the fuzzy classifier. Detection rates of single markers were below those. For the best single marker in NSCLC, CYFRA 21-1, sensitivities were 23.3% at stage I, 45.4% at stage II, 71.4% at stage III, 84% at stage IV (n=50), respectively. For the best single marker in SCLC, NSE, sensitivities were 61.9% at stage of limited disease and 81.1% at stage of extensive disease. In the validation set, the fuzzy classifier showed correct negative classification in 49 of the 55 cancer-free silicosis patients (specificity: 89%), in all COLD patients (specificity: 100%) and in all but one healthy subject (specificity: 96%). This confirmed an overall specificity of 93.9%. The sensitivity for lung cancer detection in high risk populations was 73.6%. All large cell carcinomas could be detected. The positive predictive value was 80%. The negative predictive value reached 91.5%. Conclusion: With the fuzzy classifier and a marker panel a reliable diagnostic tool for the detection of lung cancers in a high risk population is available. Show more

Keywords: Lung cancer, silicosis, tumor markers, Fuzzy classifier

DOI: 10.3233/CBM-2009-0125

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 137-148, 2010

Authors: Schneider, Joachim

Article Type: Research Article

Abstract: Lung cancer is still a primary cause of cancer death in the western world. Thus, a comprehensive primary diagnostic program which comprises the measurement of biomarkers released by lung cancers is of great importance in the clinical management of lung cancer patients. This review present data for the early lung cancer detection comparing computed tomography (CT), sputum cytology and a tumor marker panel of CYFRA 21-1, CEA, NSE, ProGRP, and SCC which was included into fuzzy classification. Sensitivities in the CT studies were mainly reported with 100% and in sputum analyses with a maximum of 87.5%. The corresponding specificity …in sputum cytology analysis was 92.7%. By use of CT, all peripheral squamous or adenocarcinomas of the lung were detected, but there was a lack in detection of SCLC or central localised tumors. In addition, CT detected many non-calcified nodules, of which only a fraction is actual lung cancer leading to a considerable amount of false positive results. At 95{\%}-specificity the sensitivity of a tumor marker panel included into fuzzy modelling for the detection of NSCLC was 50% at stage I. Also SCLC patients could be detected in more than 70% in limited disease stage. Detection rates of advanced tumor stages were even higher. The positive predictive value of biological markers was 80% while the negative predictive value reached around 90%. Modern biological marker approaches in combination with CT and sputum cytology analyses may improve the differential diagnosis especially for the early detection of lung cancer in high-risk populations. Show more

Keywords: Lung cancer, tumor markers, Fuzzy classifier, computed tomography, sputum cytology

DOI: 10.3233/CBM-2009-0126

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 149-162, 2010

Authors: Molina, Rafael | Holdenrieder, Stefan | Auge, Jose Maria | Schalhorn, Andreas | Hatz, Rudolph | Stieber, Petra

Article Type: Research Article

Abstract: Differential diagnosis of suspicious lung masses is essential for the selection of the appropriate therapy strategy. While non-small cell lung cancer (NSCLC) in early stages and single lung metastases from other cancers mostly are resected by surgery, late stage NSCLC, small cell lung cancers (SCLC) and multiple lung metastases are treated by systemic chemo- and/or radiotherapeutic approaches. In many patients, biopsies for the histopathological subtyping can not be taken due to multimorbidity and instable clinical conditions of the patient or unfavourable localisation of the tumor. In addition, heterogeneity of lung tumors may imply the presence of different malignant …cell types in one suspicious lesion. As tumor-related biomarkers in blood reflect the biochemical properties of cancer cells, their release or non-release may be helpful to support the clinical decision making. This review summarizes the current knowledge about the potential and the role of serum-based biomarkers for the differential diagnosis of lung cancer which is also mirrored in the new recommendations of the National Academy of Clinical Biochemistry (NACB). Show more

Keywords: Diagnosis, lung cancer, biomarker, serum, cytokeratins, CYFRA 21-1, CEA, NSE, ProGRP

DOI: 10.3233/CBM-2009-0127

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 163-178, 2010

Authors: Holdenrieder, Stefan | Nagel, Dorothea | Stieber, Petra

Article Type: Research Article

Abstract: Prognostic information on the course of cancer disease is highly relevant for the accurate decision of the most effective treatment strategy for an individual patient. In early stage disease, the application of adjuvant chemo- or radiotherapy after surgery depends on the risk of the patient to early suffer from tumor recurrence. In advanced stage disease, risk stratification of the patients influences the choice of more aggressive or mild therapy alternatives. Besides tumor related parameters like tumor stage and individual factors, additional information by biomarkers is needed to better characterize patients prognosis in both situations. Although there are plenty …of studies dealing on the prognostic relevance of diverse biomarkers in non-small cell lung cancer (NSCLC), the results are quite heterogeneous and sometimes conflicting. Reasons for this situation may be found in the design, the performance, the evaluation and the quality of result reporting of the studies. In this review, we focus on the prerequisites of informative prognostic trials, spot on the general shortcomings of studies published so far, and summarize the results of the prognostic studies available for early and advanced stages of NSCLC. Show more

Keywords: Prognosis, lung cancer, biomarker, serum, cytokeratins, CYFRA 21-1, CEA

DOI: 10.3233/CBM-2009-0128

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 179-190, 2010

Authors: Barak, Vivian | Holdenrieder, Stefan | Nisman, Benjamin | Stieber, Petra

Article Type: Research Article

Abstract: As the release and amount of circulating biomarkers show considerable variations between individuals, single value determinations are often difficult to be interpreted on their diagnostic or prognostic significance on the individual level. However, changes of the biomarker levels in a specific person during the disease course are quite informative for the estimation of the efficacy of therapy or the early detection of recurrent disease because they consider only intraindividual variations. If methods for marker determination are maintained, preanalytical and analytical standard prerequistits are respected, thresholds for each marker have to be defined which exceeds the normal, intraindividual biological variation. Then …continuous biomarker increases may be indicative for disease activity in terms of inefficient therapy response or tumor recurrence while decreasing values often are associated with activity reduction of cancer disease. Here, we review the current knowledge on biomarker kinetics in patients with non-small cell lung cancer (NSCLC) and discuss the conditions and pitfalls of their relevance for the estimation efficacy of therapy and the early detection of recurrent disease. Further, we suggest a scenario to reveal the power of the defined biomarker use in future and to include those markers into the individual management of NSCLC patients. Show more

Keywords: Therapy monitoring, lung cancer, biomarker, serum, cytokeratins, CYFRA 21-1, CEA

DOI: 10.3233/CBM-2009-0129

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 191-196, 2010

Authors: Holdenrieder, Stefan | Stieber, Petra

Article Type: Research Article

Abstract: The dysregulation of proliferating and apoptotic processes is a common feature in cancerogenesis. Thus, apoptotic products released into blood circulation are suggested as promising markers for the early cancer detection. However though sensitive assays are available, the lack of organ- and tumor-specificity limits the usefulness of most apoptotic parameters for screening purposes. However, they seem to be valuable for the prognosis and the prediction of response to systemic chemo- or radiotherapy in cancer disease. Here, the relevance of diverse circulating apoptotic markers is reviewed for the clinical management of patients with lung cancer. Among those promising markers are ligands …and receptors of the FAS-system, members of the intracellular caspase cascade, cleaved apoptosis substrates such as cytokeratines, nucleosomal DNA, and apoptosis modulators like survivin. The review discusses their role for diagnosis, prognosis and therapy monitoring of lung cancer disease. Show more

Keywords: Cell death, apoptosis, cancer, tumor, diagnosis, prognosis, serum, plasma, sFas, CD95, cytokeratins, CYFRA 21-1, TPA, TPS, M30, caspases, DNA, nucleosomes

DOI: 10.3233/CBM-2009-0130

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 197-210, 2010

Authors: Fleischhacker, Michael | Schmidt, Bernd

Article Type: Research Article

Abstract: Recent results indicate that not only intact circulating tumor cells but also extracellular, free-circulating nucleic acids containing tumor-associated genetic alterations can be detected in peripheral blood of cancer patients. The development of sensitive and specific methods for the detection of miniscule quantities of DNA or RNA has made it possible to isolate and characterize these tumor-associated alterations in cell-free circulating nucleic acids. So far almost all genetic alterations found in a tumor were also found in free-circulating nucleic acids, i.e. point mutations (like in p53, K-ras, myc, EGFR, etc.), microsatellite alterations, epigenetic alterations like hypermethylation of CpG islands in promotor …regions and the overexpression of tumor-associated genes at the mRNA and the microRNA level. In this review we discuss the potential use of the detection and characterization of tumor-associated alterations in free-circulating nucleic acids for the differentiation between patients with benign lung diseases and lung cancer patients. In addition, we highlight some technical points considering the pre-analytical probe handling and assay standardization, as well as the biology behind free-circulating nucleic acids. Show more

DOI: 10.3233/CBM-2009-0131

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 211-219, 2010

Authors: Stieber, Petra | Holdenrieder, Stefan

Article Type: Research Article

Keywords: Lung cancer, biomarker, serum, cytokeratins, CYFRA 21-1, CEA, NSE, ProGRP, guidelines, recommendations

DOI: 10.3233/CBM-2009-0132

Citation: Cancer Biomarkers, vol. 6, no. 3-4, pp. 221-224, 2010