Tumor Biology - Volume 46, issue s1

Authors: Mang, Anika | Zou, Wei | Rolny, Vinzent | Reck, Martin | Cigoianu, Daniel | Schulze, Katja | Holdenrieder, Stefan | Socinski, Mark A. | Shames, David S. | Wehnl, Birgit | Patil, Namrata S.

Article Type: Research Article

Abstract: BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments. OBJECTIVE: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients. METHODS: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation). Patients were stratified into high- and low-risk groups (overall survival [OS] and progression-free survival [PFS] outcomes) based on serum tumor biomarker levels. …RESULTS: The CYFRA 21-1 and CA 125 biomarker combination predicted OS and PFS in patients with SD. Risk of death was ~4-fold higher for the biomarker-stratified high-risk versus low-risk SD patients (hazard ratio [HR] 3.80; 95% confidence interval [CI] 3.02–4.78; p  < 0.0001). OS in patients with the low- and high-risk SD was comparable to that in patients with the CT-defined partial response (PR; HR 1.10; 95% CI 0.898–1.34) and progressive disease (PD) (HR 1.05; 95% CI 0.621–1.77), respectively. The findings were similar with PFS, and consistent across treatment arms. CONCLUSIONS: Biomarker testing shows potential for providing prognostic information to help direct treatment in NSCLC patients with SD. Prospective clinical studies are warranted. ClinicalTrials.gov: NCT02366143 Show more

Keywords: Metastatic, non-small cell lung cancer, stable disease, prognosis, survival, biomarkers

DOI: 10.3233/TUB-230001

Citation: Tumor Biology, vol. 46, no. s1, pp. S177-S190, 2024

Authors: Geiger, Kimberly | Joerger, Markus | Roessler, Max | Hettwer, Karina | Ritter, Christoph | Simon, Kirsten | Uhlig, Steffen | Holdenrieder, Stefan

Article Type: Research Article

Abstract: BACKGROUND: Protein tumor markers are released in high amounts into the blood in advanced non-small cell lung cancer (NSCLC). OBJECTIVE: To investigate the relevance of serum tumor markers (STM) for prognosis, prediction and monitoring of therapy response in NSCLC patients receiving chemotherapy. METHODS: In a biomarker substudy of a prospective, multicentric clinical trial (CEPAC-TDM) on 261 advanced NSCLC patients, CYFRA 21-1, CEA, SCC, NSE, ProGRP, CA125, CA15-3 and HE4 were assessed in serial serum samples and correlated with radiological response after two cycles of chemotherapy and overall (OS) and progression-free survival (PFS). RESULTS: While …pretherapeutic STM levels at staging did not discriminate between progressive and non-progressive patients, CYFRA 21-1, CA125, NSE and SCC at time of staging did, and yielded AUCs of 0.75, 0.70, 0.69 and 0.67 in ROC curves, respectively. High pretherapeutic CA15-3 and CA125 as well as high CYFRA 21-1, SCC, CA125 and CA15-3 levels at staging were prognostic for shorter PFS and OS –also when clinical variables were added to the models. CONCLUSIONS: STM at the time of first radiological staging and pretherapeutic CA15-3, CA125 are predictive for first-line treatment response and highly prognostic in patients with advanced NSCLC. Show more

Keywords: Lung cancer, therapy monitoring, prediction, prognosis, tumor markers

DOI: 10.3233/TUB-230014

Citation: Tumor Biology, vol. 46, no. s1, pp. S191-S206, 2024

Authors: Buma, Alessandra I.G. | Schuurbiers, Milou M.F. | van Rossum, Huub H. | van den Heuvel, Michel M.

Article Type: Review Article

Abstract: The optimal positioning and usage of serum tumor markers (STMs) in advanced non-small cell lung cancer (NSCLC) care is still unclear. This review aimed to provide an overview of the potential use and value of STMs in routine advanced NSCLC care for the prediction of prognosis and treatment response. Radiological imaging and clinical symptoms have shown not to capture a patient’s entire disease status in daily clinical practice. Since STM measurements allow for a rapid, minimally invasive, and safe evaluation of the patient’s tumor status in real time, STMs can be used as companion decision-making support tools before start and …during treatment. To overcome the limited sensitivity and specificity associated with the use of STMs, tests should only be applied in specific subgroups of patients and different test characteristics should be defined per clinical context in order to answer different clinical questions. The same approach can similarly be relevant when developing clinical applications for other (circulating) biomarkers. Future research should focus on the approaches described in this review to achieve STM test implementation in advanced NSCLC care. Show more

Keywords: Serum tumor markers, follow-up, prognosis, non-small cell lung cancer, biomarker

DOI: 10.3233/TUB-220034

Citation: Tumor Biology, vol. 46, no. s1, pp. S207-S217, 2024

Authors: Muley, Thomas | Herth, Felix J. | Heussel, Claus Peter | Kriegsmann, Mark | Thomas, Michael | Meister, Michael | Schneider, Marc A. | Wehnl, Birgit | Mang, Anika | Holdenrieder, Stefan

Article Type: Research Article

Abstract: BACKGROUND: Despite successful response to first line therapy, patients with small-cell lung cancer (SCLC) often suffer from early relapses and disease progression. OBJECTIVE: To investigate the relevance of serum tumor markers for estimation of prognosis at several time points during the course of disease. METHODS: In a prospective, single-center study, serial assessments of progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1) and carcino-embryogenic antigen (CEA) were performed during and after chemotherapy in 232 SCLC patients, and correlated with therapy response and overall survival (OS). RESULTS: ProGRP, NSE and CYFRA 21-1 levels decreased …quickly after the first chemotherapy cycle and correlated well with the radiological response. Either as single markers or in combination they provided valuable prognostic information regarding OS at all timepoints investigated: prior to first-line therapy, after two treatment cycles in patients with successful response to first-line therapy, and prior to the start of second-line therapy. Furthermore, they were useful for continuous monitoring during and after therapy and often indicated progressive disease several months ahead of radiological changes. CONCLUSIONS: The results indicate the great potential of ProGRP, NSE and CYFRA 21-1 for estimating prognosis and monitoring of SCLC patients throughout the course of the disease. Show more

Keywords: SCLC, prognosis, chemotherapy, ProGRP, NSE, CYFRA 21-1

DOI: 10.3233/TUB-230016

Citation: Tumor Biology, vol. 46, no. s1, pp. S219-S232, 2024

Authors: van den Heuvel, Michel | Holdenrieder, Stefan | Schuurbiers, Milou | Cigoianu, Daniel | Trulson, Inga | van Rossum, Huub | Lang, David

Article Type: Review Article

Abstract: BACKGROUND: The value of serum tumor markers (STMs) in the current therapeutic landscape of lung cancer is unclear. OBJECTIVE: This scoping review gathered evidence of the predictive, prognostic, and monitoring value of STMs for patients with advanced lung cancer receiving immunotherapy (IT) or targeted therapy (TT). METHODS: Literature searches were conducted (cut-off: May 2022) using PubMed and Cochrane CENTRAL databases. Medical professionals advised on the search strategies. RESULTS: Study heterogeneity limited the evidence and inferences from the 36 publications reviewed. While increased baseline levels of serum cytokeratin 19 fragment antigen (CYFRA21-1) and carcinoembryonic antigen …(CEA) may predict IT response, results for TT were less clear. For monitoring IT-treated patients, STM panels (including CYFRA21-1, CEA, and neuron-specific enolase) may surpass the power of single analyses to predict non-response. CYFRA21-1 measurement could aid in monitoring TT-treated patients, but the value of CEA in this context requires further investigation. Overall, baseline and dynamic changes in individual or combined STM levels have potential utility to predict treatment outcome and for monitoring of patients with advanced lung cancer. CONCLUSIONS: In advanced lung cancer, STMs provide additional relevant clinical information by predicting treatment outcome, but further standardization and validation is warranted. Show more

Keywords: STMs, non-small cell lung cancer, small cell lung cancer, immunotherapy, targeted therapy

DOI: 10.3233/TUB-220039

Citation: Tumor Biology, vol. 46, no. s1, pp. S233-S268, 2024

Authors: van Delft, Frederik A. | Schuurbiers, Milou M.F. | Muller, Mirte | Burgers, Sjaak A. | van Rossum, Huub H. | IJzerman, Maarten J. | van den Heuvel, Michel M. | Koffijberg, Hendrik

Article Type: Research Article

Abstract: BACKGROUND: Patients treated with immune checkpoint inhibitors (ICI) are at risk of adverse events (AEs) even though not all patients will benefit. Serum tumor markers (STMs) are known to reflect tumor activity and might therefore be useful to predict response, guide treatment decisions and thereby prevent AEs. OBJECTIVE: This study aims to compare a range of prediction methods to predict non-response using multiple sequentially measured STMs. METHODS: Nine prediction models were compared to predict treatment non-response at 6-months (n  = 412) using bi-weekly CYFRA, CEA, CA-125, NSE, and SCC measurements determined in the first 6-weeks of therapy. …All methods were applied to six different biomarker combinations including two to five STMs. Model performance was assessed based on sensitivity, while model training aimed at 95% specificity to ensure a low false-positive rate. RESULTS: In the validation cohort, boosting provided the highest sensitivity at a fixed specificity across most STM combinations (12.9% –59.4%). Boosting applied to CYFRA and CEA achieved the highest sensitivity on the validation data while maintaining a specificity >95%. CONCLUSIONS: Non-response in NSCLC patients treated with ICIs can be predicted with a specificity >95% by combining multiple sequentially measured STMs in a prediction model. Clinical use is subject to further external validation. Show more

Keywords: NSCLC, immunotherapy, machine learning, artificial intelligence, biomarkers, serum tumor markers, response prediction

DOI: 10.3233/TUB-220022

Citation: Tumor Biology, vol. 46, no. s1, pp. S269-S281, 2024

Authors: Duffy, Michael J.

Article Type: Review Article

Abstract: Circulating tumor DNA (ctDNA), i.e., DNA shed from tumor cells into the bloodstream, is emerging as one of the most useful plasma biomarkers in patients with multiple types of cancer, including patients with non-small cell lung cancer (NSCLC). Indeed, NSCLC was the first malignancy in which measurement of ctDNA was approved for clinical use, i.e., mutational testing of EGFR for predicting response to EGFR tyrosine kinase inhibitors in patients with advanced disease. Although historically the gold standard method for EGFR mutational analysis required tumor tissue, the use of ctDNA is more convenient and safer for patients, results in …a faster turn-around-time for return of results, provides a more complete representation of genetic alteration in heterogeneous tumors and is less costly to perform. Emerging uses of ctDNA in patients with lung or suspected lung cancer include screening for early disease, surveillance following initial treatment and monitoring response to therapy in metastatic disease. For evaluating therapy response, ctDNA appears to be especially useful in patients receiving targeted therapies against driver oncogenes or immunotherapy. Further work should not only validate these emerging findings but also aim to optimize and standardize ctDNA assays. Show more

Keywords: Lung, cancer, ctDNA, liquid biopsy, tumor marker, biomarker

DOI: 10.3233/TUB-220044

Citation: Tumor Biology, vol. 46, no. s1, pp. S283-S295, 2024

Authors: Bronkhorst, Abel J. | Holdenrieder, Stefan

Article Type: Review Article

Abstract: The cumulative pool of cell-free DNA (cfDNA) molecules within bodily fluids represents a highly dense and multidimensional information repository. This “biological mirror” provides real-time insights into the composition, function, and dynamics of the diverse genomes within the body, enabling significant advancements in personalized molecular medicine. However, effective use of this information necessitates meticulous classification of distinct cfDNA subtypes with exceptional precision. While cfDNA molecules originating from different sources exhibit numerous genetic, epigenetic, and physico-chemical variations, they also share common features that complicate analyses. Considerable progress has been achieved in mapping the landscape of cfDNA features, their clinical correlations, and optimizing …extraction procedures, analytical approaches, bioinformatics pipelines, and machine learning algorithms. Nevertheless, preanalytical workflows, despite their profound impact on cfDNA measurements, have not progressed at a corresponding pace. In this perspective article, we emphasize the pivotal role of robust preanalytical procedures in the development and clinical integration of cfDNA assays, highlighting persistent obstacles and emerging challenges. Show more

Keywords: Cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), liquid biopsy, preanalytics

DOI: 10.3233/TUB-230011

Citation: Tumor Biology, vol. 46, no. s1, pp. S297-S308, 2024

Authors: Moes-Sosnowska, Joanna | Szpechcinski, Adam | Chorostowska-Wynimko, Joanna

Article Type: Research Article

Abstract:  The development of targeted therapies for non-small cell lung cancer (NSCLC), such as the epidermal growth factor receptor (EGFR ), anaplastic lymphoma receptor tyrosine kinase (ALK ), and ROS proto-oncogene 1 (ROS1 ), has improved patients’ prognosis and significantly extended progression-free survival. However, it remains unclear why some patients do not benefit from the treatment as much or have a rapid disease progression. It is considered that, apart from the oncogenic driver gene, molecular alterations in a number of caretaker and gatekeeper genes significantly impact the efficacy of targeted therapies. The tumor protein 53 (TP53 ) gene is one …of the most frequently mutated genes in NSCLC. To date, numerous studies have investigated the influence of various TP53 alterations on patient prognosis and responsiveness to therapies targeting EGFR, ALK, or ROS1. This review focuses on the latest data concerning the role of TP53 alterations as prognostic and/or predictive biomarkers for EGFR, ALK, and ROS1 tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. Since the presence of TP53 mutations in NSCLC has been linked to its decreased responsiveness to EGFR, ALK, and ROS1 targeted therapy in most of the referenced studies, the review also discusses the impact of TP53 mutations on treatment resistance. It seems plausible that assessing the TP53 mutation status could aid in patient stratification for optimal clinical decision-making. However, drawing meaningful conclusions about the clinical value of the TP53 co-mutations in EGFR-, ALK- or ROS1-positive NSCLC is hampered mainly by an insufficient knowledge regarding the functional consequences of the TP53 alterations. The integration of next-generation sequencing into the routine molecular diagnostics of cancer patients will facilitate the detection and identification of targetable genetic alterations along with co-occurring TP53 variants. This advancement holds the potential to accelerate understanding of the biological and clinical role of p53 in targeted therapies for NSCLC. Show more

Keywords: Biomarkers, non-small cell lung cancer, EGFR ALK ROS1, targeted therapy, TP53 mutations

DOI: 10.3233/TUB-230034

Citation: Tumor Biology, vol. 46, no. s1, pp. S309-S325, 2024

Authors: Muller, Mirte | Best, Myron G. | van der Noort, Vincent | Hiltermann, T. Jeroen N. | Niemeijer, Anna-Larissa N. | Post, Edward | Sol, Nik | In ’t Veld, Sjors G.J.G. | Nogarede, Tineke | Visser, Lisanne | Schouten, Robert D. | van den Broek, Daan | Hummelink, Karlijn | Monkhorst, Kim | de Langen, Adrianus J. | Schuuring, Ed | Smit, Egbert F. | Groen, Harry J.M. | Wurdinger, Thomas | van den Heuvel, Michel M.

Article Type: Research Article

Abstract: BACKGROUND: Anti-PD-(L)1 immunotherapy has emerged as a promising treatment approach for non-small cell lung cancer (NSCLC), though the response rates remain low. Pre-treatment response prediction may improve patient allocation for immunotherapy. Blood platelets act as active immune-like cells, thereby constraining T-cell activity, propagating cancer metastasis, and adjusting their spliced mRNA content. OBJECTIVE: We investigated whether platelet RNA profiles before start of nivolumab anti-PD1 immunotherapy may predict treatment responses. METHODS: We performed RNA-sequencing of platelet RNA samples isolated from stage III-IV NSCLC patients before treatment with nivolumab. Treatment response was scored by the RECIST-criteria. Data were analyzed …using a predefined thromboSeq analysis including a particle-swarm-enhanced support vector machine (PSO/SVM) classification algorithm. RESULTS: We collected and processed a 286-samples cohort, separated into a training/evaluation and validation series and subjected those to training of the PSO/SVM-classification algorithm. We observed only low classification accuracy in the 107-samples validation series (area under the curve (AUC) training series: 0.73 (95% -CI: 0.63–0.84, n  = 88 samples), AUC evaluation series: 0.64 (95% -CI: 0.51–0.76, n  = 91 samples), AUC validation series: 0.58 (95% -CI: 0.45–0.70, n  = 107 samples)), employing a five-RNAs biomarker panel. CONCLUSIONS: We concluded that platelet RNA may have minimally discriminative capacity for anti-PD1 nivolumab response prediction, with which the current methodology is insufficient for diagnostic application. Show more

Keywords: Blood platelets, RNA-sequencing, nivolumab, immunotherapy

DOI: 10.3233/TUB-220037

Citation: Tumor Biology, vol. 46, no. s1, pp. S327-S340, 2024