Tumor Biology - Volume 46, issue s1

Authors: Holdenrieder, Stefan | van Rossum, Huub H. | van den Heuvel, Michel

Article Type: Editorial

Abstract: Blood-based diagnostics for lung cancer support the diagnosis, estimation of prognosis, prediction, and monitoring of therapy response in lung cancer patients. The clinical utility of serum tumor markers has considerably increased due to developments in serum protein tumor markers analytics and clinical biomarker studies, the exploration of preanalytical and influencing conditions, the interpretation of biomarker combinations and individual biomarker kinetics, as well as the implementation of biostatistical models. In addition, circulating tumor DNA (ctDNA) and other liquid biopsy markers are playing an increasingly prominent role in the molecular tumor characterization and the monitoring of tumor evolution over time. Thus, modern …lung cancer biomarkers may considerably contribute to an individualized companion diagnostics and provide a sensitive guidance for patients throughout the course of their disease. In this special edition on Tumor Markers in Lung Cancer, experts summarize recent developments in clinical laboratory diagnostics of lung cancer and give an outlook on future challenges and opportunities. Show more

Keywords: Lung cancer, tumor markers, liquid biopsy, diagnosis, prognosis

DOI: 10.3233/TUB-240004

Citation: Tumor Biology, vol. 46, no. s1, pp. S1-S7, 2024

Authors: van Rossum, Huub H. | Holdenrieder, Stefan

Article Type: Editorial

Abstract:  Clinical laboratories are responsible for performing lung cancer tumor marker testing as part of routine clinical care. It is their responsibility to guarantee that the reported tumor marker results are reliable and meet the necessary quality standards for proper clinical use. During the different laboratory phases, pre-analytical, analytical and post-analytical, specific steps and processes can introduce errors and generate incorrect clinical interpretation. This editorial briefly outlines critical laboratory issues related to lung cancer tumor markers, specific for each of these three laboratory phases.

Keywords: Tumor markers, clinical laboratory, clinical chemistry, lung cancer

DOI: 10.3233/TUB-240005

Citation: Tumor Biology, vol. 46, no. s1, pp. S9-S14, 2024

Authors: Canki, Esra | Schuurbiers, Milou MF | Linders, Theodora C. | Korse, Catharina M. | van den Heuvel, Michel M. | van Herwaarden, Antonius E. | van Rossum, Huub H.

Article Type: Research Article

Abstract: BACKGROUND: For lung cancer, circulating tumor markers (TM) are available to guide clinical treatment decisions. To ensure adequate accuracy, pre-analytical instabilities need to be known and addressed in the pre-analytical laboratory protocols. OBJECTIVE: This study investigates the pre-analytical stability of CA125, CEA, CYFRA 21.1, HE4 and NSE for the following pre-analytical variables and procedures; i) whole blood stability, ii) serum freeze-thaw cycles, iii) electric vibration mixing and iv) serum storage at different temperatures. METHODS: Left-over patient samples were used and for every investigated variable six patient samples were used and analysed in duplicate. Acceptance criteria were …based on analytical performance specifications based on biological variation and significant differences with baseline. RESULTS: Whole blood was stable for at least 6 hours for all TM except for NSE. Two freeze-thaw cycles were acceptable for all TM except CYFRA 21.1. Electric vibration mixing was allowed for all TM except for CYFRA 21.1. Serum stability at 4°C was 7 days for CEA, CA125, CYFRA 21.1 and HE4 and 4 hours for NSE. CONCLUSIONS: Critical pre-analytical processing step conditions were identified that, if not taken into account, will result in reporting of erroneous TM results. Show more

Keywords: Pre-analytical stability, tumor marker, CYFRA 21.1, NSE, CEA, HE4, serum, CA125

DOI: 10.3233/TUB-220013

Citation: Tumor Biology, vol. 46, no. s1, pp. S15-S25, 2024

Authors: Qian, Xu | Meng, Qing-He

Article Type: Article Commentary

Abstract: Fundamental studies on biomarkers as well as developed assays for their detection can provide valuable information facilitating clinical decisions. For patients with lung cancer, there are established circulating biomarkers such as serum progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen (CEA), and cytokeratin-19 fragment (CYFRA21-1). There are also molecular biomarkers for targeted therapy such as epidermal growth factor receptor (EGFR) gene, anaplastic lymphoma kinase (ALK) gene, KRAS gene, and BRAF gene. However, there is still an unmet need for biomarkers that can be used for early detection and predict treatment response and survival. In this …review, we describe the lung cancer biomarkers that are currently being used in clinical practice. We also discuss emerging preclinical and clinical studies on new biomarkers such as omics-based biomarkers for their potential clinical use to detect, predict, or monitor subtypes of lung cancer. Additionally, between-method differences in tumor markers warrant further development and improvement of the standardization and harmonization for each assay. Show more

Keywords: Circulating tumor markers, lung cancer diagnostics, small-cell lung carcinoma, non-small cell lung carcinoma, circulating tumor DNA, exosomes

DOI: 10.3233/TUB-230012

Citation: Tumor Biology, vol. 46, no. s1, pp. S27-S33, 2024

Authors: Trapé, Jaume | Fernández-Galán, Esther | Auge, Josep Maria | Carbonell-Prat, Marina | Filella, Xavier | Miró-Cañís, Sílvia | González-Fernández, Carolina

Article Type: Research Article

Abstract: BACKGROUND: Tumor markers (TMs) are a heterogeneous group of molecules used in the diagnosis, prognosis and follow-up of cancer patients. During neoplastic differentiation, cells can either directly synthesize or induce the synthesis of TMs, and the release of these molecules into the bloodstream allows their quantification in biological fluids. Although very small concentrations of TMs are usually present in the serum or plasma of healthy subjects, increased concentrations may also be found in the presence of benign diseases or due to technical interference, producing false positive results. MATERIAL AND METHODS AND RESULTS: Our review analyses the …causes of false positives described between January 1970 to February 2023 for the TMs most frequently used in clinical practice: α-fetoprotein (AFP), β2-microglobulin (β2-M), cancer antigen 15-3 (CA 15-3), cancer antigen CA 19-9 (CA 19-9), cancer antigen CA 72-4 (CA 72-4), cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), chromogranin A (CgA), choriogonadotropin (hCG), cytokeratin 19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), human epididymis protein 4 (HE4), serum HER2 (sHER2), squamous cell carcinoma antigen (SCCA), protein induced by vitamin K absence-II (PIVKA-II), Pro-gastrin-releasing peptide (Pro-GRP), prostate-specific antigen (PSA), Protein S-100 (S-100) and thyroglobulin (Tg). A total of 247 references were included. CONCLUSIONS: A better understanding of pathophysiological processes and other conditions that affect the concentration of TMs might improve the interpretation of results and their clinical application. Show more

Keywords: Tumor markers, false positives, benign disease, absence of neoplasia

DOI: 10.3233/TUB-220023

Citation: Tumor Biology, vol. 46, no. s1, pp. S35-S63, 2024

Authors: van den Broek, Daniel | Groen, Harry J.M.

Article Type: Review Article

Abstract: Lung cancer (LC) is one of the leading causes for cancer-related deaths in the world, accounting for 28% of all cancer deaths in Europe. Screening for lung cancer can enable earlier detection of LC and reduce lung cancer mortality as was demonstrated in several large image-based screening studies such as the NELSON and the NLST. Based on these studies, screening is recommended in the US and in the UK a targeted lung health check program was initiated. In Europe lung cancer screening (LCS) has not been implemented due to limited data on cost-effectiveness in the different health care systems and …questions on for example the selection of high-risk individuals, adherence to screening, management of indeterminate nodules, and risk of overdiagnosis. Liquid biomarkers are considered to have a high potential to address these questions by supporting pre- and post- Low Dose CT (LDCT) risk-assessment thereby improving the overall efficacy of LCS. A wide variety of biomarkers, including cfDNA, miRNA, proteins and inflammatory markers have been studied in the context of LCS. Despite the available data, biomarkers are currently not implemented or evaluated in screening studies or screening programs. As a result, it remains an open question which biomarker will actually improve a LCS program and do this against acceptable costs. In this paper we discuss the current status of different promising biomarkers and the challenges and opportunities of blood-based biomarkers in the context of lung cancer screening. Show more

Keywords: Lung cancer screening, biomarkers

DOI: 10.3233/TUB-230004

Citation: Tumor Biology, vol. 46, no. s1, pp. S65-S80, 2024

Authors: Trulson, Inga | Klawonn, Frank | von Pawel, Joachim | Holdenrieder, Stefan

Article Type: Research Article

Abstract: BACKGROUND: Differential diagnosis of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in hospitalized patients is crucial for appropriate treatment choice. OBJECTIVE: To investigate the relevance of serum tumor markers (STMs) and their combinations for the differentiation of NSCLC and SCLC subtypes. METHODS: Between 2000 and 2003, 10 established STMs were assessed retrospectively in 311 patients with NSCLC, 128 with SCLC prior systemic first-line therapy and 51 controls with benign lung diseases (BLD), by automatized electrochemiluminescence immunoassay technology. Receiver operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic …efficacy of both individual and multiple STMs with corresponding sensitivities at 90% specificity. Standards for Reporting of Diagnostic Accuracy (STARD guidelines) were followed. RESULTS: CYFRA 21-1 (cytokeratin-19 fragment), CEA (carcinoembryonic antigen) and NSE (neuron specific enolase) were significantly higher in all lung cancers vs BLD, reaching AUCs of 0.81 (95% CI 0.76–0.87), 0.78 (0.73–0.84), and 0.88 (0.84–0.93), respectively. By the three marker combination, the discrimination between benign and all malignant cases was improved resulting in an AUC of 0.93 (95% CI 0.90–0.96). In NSCLC vs. BLD, CYFRA 21-1, CEA and NSE were best discriminative STMs, with AUCs of 0.86 (95% CI 0.81–0.91), 0.80 (0.74–0.85), and 0.85 (0.79–0.91). The three marker combination also improved the AUC: 0.92; 95% CI 0.89–0.96). In SCLC vs. BLD, ProGRP (pro-gastrin-releasing peptide) and NSE were best discriminative STMs, with AUCs of 0.89 (95% CI 0.84–0.94) and 0.96 (0.93–0.98), respectively, and slightly improved AUC of 0.97 (95% CI 0.95–0.99) when in combination. Finally, discrimination between SCLC and NSCLC was possible by ProGRP (AUC 0.86; 95% CI 0.81–0.91), NSE (AUC 0.83; 0.78–0.88) and CYFRA 21-1 (AUC 0.69; 0.64–0.75) and by the combination of the 3 STMs (AUC 0.93; 0.91–0.96), with a sensitivity of 88% at 90% specificity. CONCLUSIONS: The results confirm the power of STM combinations for the differential diagnosis of lung cancer from benign lesions and between histological lung cancer subtypes. Show more

Keywords: Tumor markers, lung cancer, differential diagnosis, AUC, sensitivity, specificity, NSCLC, SCLC, histology, CEA, CYFRA 21-1, NSE, ProGRP, SCC, CA 125, CA 19-9, CA 15-3, CA 72-4, S100

DOI: 10.3233/TUB-230021

Citation: Tumor Biology, vol. 46, no. s1, pp. S81-S98, 2024

Authors: Trapé, Jaume | Bérgamo, Silvia | González-Garcia, Laura | González-Fernández, Carolina

Article Type: Review Article

Abstract: From its onset and during its progression, lung cancer may affect various extrapulmonary structures. These include the serous membranes, the pleura and pericardium, and less frequently the central nervous system, with leptomeningeal involvement. In these cases, fluid accumulates in the serous membranes which may contain substances secreted by the tumor. Measuring the concentrations of these substances can provide useful information for elucidating the origin of the fluid accumulation, either in pleural and pericardial effusions or in cerebrospinal fluid. This paper describes the histological types of lung cancer that most frequently affect the serosa and leptomeninges. It also reviews the literature …on tumor markers in different fluids and makes recommendations for their interpretation. Show more

Keywords: Lung cancer, tumor markers, effusions, review, recommendations

DOI: 10.3233/TUB-220024

Citation: Tumor Biology, vol. 46, no. s1, pp. S99-S110, 2024

Authors: Trulson, Inga | Holdenrieder, Stefan

Article Type: Research Article

Abstract: BACKGROUND: Therapeutic possibilities for non-small cell lung cancer (NSCLC) have considerably increased during recent decades. OBJECTIVE: To summarize the prognostic relevance of serum tumor markers (STM) for early and late-stage NSCLC patients treated with classical chemotherapies, novel targeted and immune therapies. METHODS: A PubMed database search was conducted for prognostic studies on carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA 21-1), neuron-specific enolase, squamous-cell carcinoma antigen, progastrin-releasing-peptide, CA125, CA 19-9 and CA 15-3 STMs in NSCLC patients published from 2008 until June 2022. RESULTS: Out of 1069 studies, 141 were identified as meeting the inclusion criteria. …A considerable heterogeneity regarding design, patient number, analytical and statistical methods was observed. High pretherapeutic CYFRA 21-1 levels and insufficient decreases indicated unfavorable prognosis in many studies on NSCLC patients treated with chemo-, targeted and immunotherapies or their combinations in early and advanced stages. Similar results were seen for CEA in chemotherapy, however, high pretherapeutic levels were sometimes favorable in targeted therapies. CA125 is a promising prognostic marker in patients treated with immunotherapies. Combinations of STMs further increased the prognostic value over single markers. CONCLUSION: Protein STMs, especially CYFRA 21-1, have prognostic potential in early and advanced stage NSCLC. For future STM investigations, better adherence to comparable study designs, analytical methods, outcome measures and statistical evaluation standards is recommended. Show more

Keywords: Non-small cell lung cancer, serum tumor markers, prognosis, CEA, CYFRA 21-1, NSE, SCCA, ProGRP, CA125, CA 19-9, CA 15-3

DOI: 10.3233/TUB-230009

Citation: Tumor Biology, vol. 46, no. s1, pp. S111-S161, 2024

Authors: Muley, Thomas | Schneider, Mark A. | Meister, Michael | Thomas, Michael | Heußel, Claus Peter | Kriegsmann, Mark | Holdenrieder, Stefan | Wehnl, Birgit | Rolny, Vinzent | Mang, Anika | Gerber, Rebecca | Herth, Felix

Article Type: Research Article

Abstract: BACKGROUND: Serum tumor markers (STM) may complement imaging and provide additional clinical information for patients with non-small cell lung cancer (NSCLC). OBJECTIVE: To determine whether STMs can predict outcomes in patients with stable disease (SD) after initial treatment. METHODS: This single-center, prospective, observational trial enrolled 395 patients with stage III/IV treatment-naïve NSCLC; of which 263 patients were included in this analysis. Computed Tomography (CT) scans were performed and STMs measured before and after initial treatment (two cycles of chemotherapy and/or an immune checkpoint inhibitor or tyrosine kinase inhibitor); analyses were based on CT …and STM measurements obtained at first CT performed after cycle 2 only PFS and OS were analyzed by Kaplan-Meier curves and Cox-proportional hazard models. RESULTS: When patients with SD (n  = 100) were split into high- and low-risk groups based on CYFRA 21-1, CEA and CA 125 measurements using an optimized cut-off, a 4-fold increase risk of progression or death was estimated for high- vs low-risk SD patients (PFS, HR 4.17; OS, 3.99; both p  < 0.0001). Outcomes were similar between patients with high-risk SD or progressive disease (n  = 35) (OS, HR 1.17) and between patients with low-risk SD or partial response (n  = 128) (PFS, HR 0.98; OS, 1.14). CONCLUSIONS: STMs can provide further guidance in patients with indeterminate CT responses by separating them into high- and low-risk groups for future PFS and OS events. Show more

Keywords: NSCLC, biomarkers, CYFRA 21-1, CA 125, CEA, risk prediction

DOI: 10.3233/TUB-220042

Citation: Tumor Biology, vol. 46, no. s1, pp. S163-S175, 2024