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Cancers
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Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC)
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Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 18131

Special Issue Editor

Dr. Alfredo Tartarone

E-Mail Website
Guest Editor
Department of Onco-Hematology, Division of Medical Oncology, Centro di Riferimento Oncologico della Basilicata, IRCCS, via Padre Pio 1, 85028 Rionero in Vulture, Italy
Interests: non-small-cell lung cancer; small-cell lung cancer; chemotherapy; immunotherapy; targeted therapies

Special Issue Information

Dear Colleagues,

Lung cancer, of which non-small cell lung cancer (NSCLC) represents about 80% of all cases, is the second most common cancer diagnosed in the general population and one of the leading causes of cancer-related death worldwide. As is well known, despite the advances in treatment of NSCLC, the outcomes of patients with advanced disease are still disappointing.

However, recent progress in molecular characterization, in addition to a better understanding of the immune context of the tumor, are dramatically changing the course of NSCLC patients. The advent of targeted therapies and of immunotherapies has been driven by the expanding number of biomarkers that can predict sensitivity to novel agents. In fact, all patients with advanced NSCLC now require a comprehensive screening of biomarkers to select patients for targeted therapy or immunotherapy with or without chemotherapy. Consequently, to meet current diagnostic demands, the adoption of new technologies, such as next-generation sequencing (NGS), has also been implemented.

This Special Issue, involving experts in the field, plans to offer an overview of recent advances in biomarker discovery in NSCLC, with particular emphasis on the use of technologies that are needed for their detection and on their applicability in clinical practice

Dr. Alfredo Tartarone
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • NSCLC
  • biomarkers
  • next-generation sequencing (NGS)
  • liquid biopsy
  • immunotherapy
  • targeted therapies

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Published Papers (8 papers)

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Research

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22 pages, 2110 KiB  
Article
Peripheral Blood TCRβ Repertoire, IL15, IL2 and Soluble Ligands for NKG2D Activating Receptor Predict Efficacy of Immune Checkpoint Inhibitors in Lung Cancer
by Andrea Sesma, Julian Pardo, Dolores Isla, Eva M. Gálvez, Marta Gascón-Ruiz, Luis Martínez-Lostao, Alba Moratiel, J. Ramón Paño-Pardo, Elisa Quílez, Irene Torres-Ramón, Alfonso Yubero, María Zapata-García, María Pilar Domingo, Patricia Esteban, Rebeca Sanz Pamplona, Rodrigo Lastra and Ariel Ramírez-Labrada
Cancers 2024, 16(16), 2798; https://doi.org/10.3390/cancers16162798 - 8 Aug 2024
Viewed by 1039
Abstract
The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted [...] Read more.
The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted in significant survival benefits. However, not all patients respond; hence, molecular biomarkers are needed to help us predict which patients will respond. With this objective, a prospective observational study was designed, including a cohort of 55 patients with NSCLC who received ICIs. We studied whether biomarkers such as TCRβ and specific cytokines involved in the regulation of T cell activity were related to the immunotherapy response. In the survival analysis, it was found that patients with higher TCRβ clonality, lower TCRβ evenness, higher TCRβ Shannon diversity and lower TCRβ convergence had higher overall survival (OS) and progression-free survival (PFS). However, no statistically significant association was observed. Regarding cytokines, those patients with higher levels of IL-2 and IL-15 presented statistically significantly shorter OS and PFS, respectively. In fact, in the multivariable analysis, the high IL-15 level increased the risk of death by three times. Although the sample size was small and more studies are needed to confirm our results, our study reveals promising markers of responses to ICIs. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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12 pages, 1806 KiB  
Article
Baseline Blood CD8+ T Cell Activation Potency Discriminates Responders from Non-Responders to Immune Checkpoint Inhibition Combined with Stereotactic Radiotherapy in Non-Small-Cell Lung Cancer
by Hanneke Kievit, M. Benthe Muntinghe-Wagenaar, Wayel H. Abdulahad, Abraham Rutgers, Lucie B. M. Hijmering-Kappelle, Birgitta I. Hiddinga, J. Fred Ubbels, Robin Wijsman, Marcel J. van der Leij, Johan Bijzet, Harry J. M. Groen, Huib A. M. Kerstjens, Anthonie J. van der Wekken, Bart-Jan Kroesen and T. Jeroen N. Hiltermann
Cancers 2024, 16(14), 2592; https://doi.org/10.3390/cancers16142592 - 19 Jul 2024
Viewed by 972
Abstract
Background: Tumor-infiltrating immune cells have been correlated with prognosis for patients treated with immune checkpoint inhibitor (ICI) treatment of various cancers. However, no robust biomarker has been described to predict treatment response yet. We hypothesized that the activation potency of circulating T cells [...] Read more.
Background: Tumor-infiltrating immune cells have been correlated with prognosis for patients treated with immune checkpoint inhibitor (ICI) treatment of various cancers. However, no robust biomarker has been described to predict treatment response yet. We hypothesized that the activation potency of circulating T cells may predict response to ICI treatment. Methods: An exploratory analysis was conducted to investigate the association between the response to immune checkpoint inhibition (ICI) combined with stereotactic radiotherapy (SBRT) and the potency of circulating T cells to be activated. Blood-derived lymphocytes from 14 patients were stimulated ex vivo with, among others, Staphylococcal enterotoxin B (SEB) and compared to healthy controls (HCs). Patients were grouped into responders (>median progression free survival (PFS)) and non-responders (<median PFS). The expression of the T cell activation marker CD69 and intracellular cytokines (IL-2, IFNγ, TNFα) in both CD4+ and CD8+ T cells in response to stimulation was measured using flow cytometry. In addition, serum levels of BAFF, IFNγ, and IL-2 receptor (sIL-2R) were measured by Luminex. Results: At baseline, a higher percentage of activated CD8+ T cells (15.8% vs. 3.5% (p = <0.01)) and IL-2+CD69+CD8+ T cells (8.8% vs. 2.9% (p = 0.02)) was observed in responders compared to non-responders upon ex vivo stimulation with SEB. The concurrently measured serum cytokine levels were not different between responders and non-responders. Conclusion: Baseline blood CD8+ T cell activation potency, measured by intracellular cytokine production after ex vivo stimulation, is a potential biomarker to discriminate responders from non-responders to SBRT combined with ICI. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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16 pages, 1875 KiB  
Article
Combining Classic and Novel Neutrophil-Related Biomarkers to Identify Non-Small-Cell Lung Cancer
by Yunzhao Ren, Qinchuan Wang, Chenyang Xu, Qian Guo, Ruoqi Dai, Xiaohang Xu, Yuhao Zhang, Ming Wu, Xifeng Wu and Huakang Tu
Cancers 2024, 16(3), 513; https://doi.org/10.3390/cancers16030513 - 25 Jan 2024
Cited by 1 | Viewed by 1571
Abstract
Background: Recent studies have revealed that neutrophils play a crucial role in cancer progression. This study aimed to explore the diagnostic value of neutrophil-related biomarkers for non-small-cell lung cancer (NSCLC). Methods: We initially assessed the associations between classic neutrophil-related biomarkers (neutrophil-to-lymphocyte ratio (NLR), [...] Read more.
Background: Recent studies have revealed that neutrophils play a crucial role in cancer progression. This study aimed to explore the diagnostic value of neutrophil-related biomarkers for non-small-cell lung cancer (NSCLC). Methods: We initially assessed the associations between classic neutrophil-related biomarkers (neutrophil-to-lymphocyte ratio (NLR), absolute neutrophil counts (NEU), absolute lymphocyte counts (LYM)) and NSCLC in 3942 cases and 6791 controls. Then, we measured 11 novel neutrophil-related biomarkers via Luminex Assays in 132 cases and 66 controls, individually matching on sex and age (±5 years), and evaluated their associations with NSCLC risk. We also developed the predictive models by sequentially adding variables of interest and assessed model improvement. Results: Interleukin-6 (IL-6) (odds ratio (OR) = 10.687, 95% confidence interval (CI): 3.875, 29.473) and Interleukin 1 Receptor Antagonist (IL-1RA) (OR = 8.113, 95% CI: 3.182, 20.689) shows strong associations with NSCLC risk after adjusting for body mass index, smoking status, NLR, and carcinoembryonic antigen. Adding the two identified biomarkers to the predictive model significantly elevated the model performance from an area under the receiver operating characteristic curve of 0.716 to 0.851 with a net reclassification improvement of 97.73%. Conclusions: IL-6 and IL-1RA were recognized as independent risk factors for NSCLC, improving the predictive performance of the model in identifying disease. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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12 pages, 4039 KiB  
Article
Pretreatment Tumor Growth Rate and Radiological Response as Predictive Markers of Pathological Response and Survival in Patients with Resectable Lung Cancer Treated by Neoadjuvant Treatment
by Toulsie Ramtohul, Léa Challier, Vincent Servois and Nicolas Girard
Cancers 2023, 15(16), 4158; https://doi.org/10.3390/cancers15164158 - 17 Aug 2023
Viewed by 1281
Abstract
Introduction: Predictive biomarkers associated with pathological response, progression precluding surgery, and/or recurrence after surgery are needed for patients with resectable non-small cell lung carcinoma (NSCLC) treated by neoadjuvant treatment. We evaluated the clinical impact of the pretreatment tumor growth rate (TGR0) [...] Read more.
Introduction: Predictive biomarkers associated with pathological response, progression precluding surgery, and/or recurrence after surgery are needed for patients with resectable non-small cell lung carcinoma (NSCLC) treated by neoadjuvant treatment. We evaluated the clinical impact of the pretreatment tumor growth rate (TGR0) and radiological response for patients with resectable NSCLC treated with neoadjuvant therapies. Methods: Consecutive patients with resectable stage IB (≥4 cm) to IIIA NSCLC treated by neoadjuvant platinum-doublet chemotherapy with or without nivolumab at our tertiary center were retrospectively analyzed. TGR0 and RECIST objective responses were determined. Multivariable analyses identified independent predictors of event-free survival (EFS), overall survival (OS), and major pathological response (MPR). Results: Between November 2017 and December 2022, 32 patients (mean [SD] age, 63.8 [8.0] years) were included. At a median follow-up of 54.8 months (95% CI, 42.3–60.4 months), eleven patients (34%) experienced progression or recurrence, and twelve deaths (38%) were recorded. The TGR0 cutoff of 30%/month remained the only independent factor associated with EFS (HR = 0.04; 95% CI, 0.01–0.3; p = 0.003) and OS (HR = 0.2; 95% CI, 0.03–0.7; p = 0.01). The TGR0 cut-off had a mean time-dependent AUC of 0.83 (95% CI, 0.64–0.95) and 0.80 (95% CI, 0.62–0.97) for predicting EFS and OS, respectively. Fifteen of 26 resection cases (58%) showed MPR including nine with pathological complete responses (35%). Only the objective response of the primary tumor was associated with MPR (OR = 27.5; 95% CI, 2.6–289.1; p = 0.006). Conclusions: Assessment of TGR0 can identify patients who should benefit from neoadjuvant treatment. A tumor objective response might be a predictor of MPR after neoadjuvant treatment, which will help to adapt surgical management. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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Review

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14 pages, 1651 KiB  
Review
NRG1 Gene Fusions—What Promise Remains Behind These Rare Genetic Alterations? A Comprehensive Review of Biology, Diagnostic Approaches, and Clinical Implications
by Tomasz Kucharczyk, Marcin Nicoś, Marek Kucharczyk and Ewa Kalinka
Cancers 2024, 16(15), 2766; https://doi.org/10.3390/cancers16152766 - 5 Aug 2024
Viewed by 1244
Abstract
Non-small cell lung cancer (NSCLC) presents a variety of druggable genetic alterations that revolutionized the treatment approaches. However, identifying new alterations may broaden the group of patients benefitting from such novel treatment options. Recently, the interest focused on the neuregulin-1 gene (NRG1 [...] Read more.
Non-small cell lung cancer (NSCLC) presents a variety of druggable genetic alterations that revolutionized the treatment approaches. However, identifying new alterations may broaden the group of patients benefitting from such novel treatment options. Recently, the interest focused on the neuregulin-1 gene (NRG1), whose fusions may have become a potential predictive factor. To date, the occurrence of NRG1 fusions has been considered a negative prognostic marker in NSCLC treatment; however, many premises remain behind the targetability of signaling pathways affected by the NRG1 gene. The role of NRG1 fusions in ErbB-mediated cell proliferation especially seems to be considered as a main target of treatment. Hence, NSCLC patients harboring NRG1 fusions may benefit from targeted therapies such as pan-HER family inhibitors, which have shown efficacy in previous studies in various cancers, and anti-HER monoclonal antibodies. Considering the increased interest in the NRG1 gene as a potential clinical target, in the following review, we highlight its biology, as well as the potential clinical implications that were evaluated in clinics or remained under consideration in clinical trials. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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14 pages, 593 KiB  
Review
HER2-Altered Non-Small Cell Lung Cancer: A Journey from Current Approaches to Emerging Strategies
by Giorgia Ferrari, Benedetta Del Rio, Silvia Novello and Francesco Passiglia
Cancers 2024, 16(11), 2018; https://doi.org/10.3390/cancers16112018 - 26 May 2024
Cited by 1 | Viewed by 2699
Abstract
For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy. Different pan-HER tyrosine kinase inhibitors have been evaluated in limited phase II trials, yielding generally unsatisfactory [...] Read more.
For patients diagnosed with advanced HER2-altered non-small cell lung cancer (NSCLC), the current standard of care is represented by a platinum-pemetrexed-based chemotherapy, eventually in combination with immunotherapy. Different pan-HER tyrosine kinase inhibitors have been evaluated in limited phase II trials, yielding generally unsatisfactory outcomes, although certain genotypes demonstrated some clinical benefit. Conversely, antibody-drug conjugates (ADCs) targeting HER2, particularly trastuzumab-deruxtecan, have shown promising results against HER2-mutant disease, including a great intracranial activity in patients with brain metastasis. Based on the results obtained from DESTINY-Lung01 and DESTINY-Lung02 trials, trastuzumab deruxtecan received regulatory approval as the first targeted therapy for pre-treated, HER2-mutant, advanced NSCLC patients. More recently, the Food and Drug Administration (FDA) granted the accelerated approval of trastuzumab deruxtecan for advanced, pre-treated HER2-positive solid tumours with no other treatment options. In this scenario, emerging evidence is increasingly pointing towards the exploration of combination regimens with synergistic effects in the advanced disease. In this review, we provide a detailed summary of current approaches and emerging strategies in the management of HER2-altered NSCLC, also focusing on unmet needs, including the treatment of patients with brain metastases. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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14 pages, 1062 KiB  
Review
Gut Microbiota Are a Novel Source of Biomarkers for Immunotherapy in Non-Small-Cell Lung Cancer (NSCLC)
by Teresa Del Giudice, Nicoletta Staropoli, Pierfrancesco Tassone, Pierosandro Tagliaferri and Vito Barbieri
Cancers 2024, 16(10), 1806; https://doi.org/10.3390/cancers16101806 - 9 May 2024
Cited by 2 | Viewed by 1839
Abstract
Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small-Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies on a variety of factors which may allow for the identification of novel biomarkers. Presently, a variety [...] Read more.
Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small-Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies on a variety of factors which may allow for the identification of novel biomarkers. Presently, a variety of biomarkers are under investigation, including the PD1/PDL1 axis, the tumor mutational burden, and the microbiota. The latter is made by all the bacteria and other microorganisms hosted in our body. The gut microbiota is the most represented and has been involved in different physiological and pathological events, including cancer. In this light, it appears that all conditions modifying the gut microbiota can influence cancer, its treatment, and its treatment-related toxicities. The aim of this review is to analyze all the conditions influencing the gut microbiota and, therefore, affecting the response to immunotherapy, iRAEs, and their management in NSCLC patients. The investigation of the landscape of these biological events can allow for novel insights into the optimal management of NSCLC immunotherapy. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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17 pages, 704 KiB  
Review
Variant Allele Frequency Analysis of Circulating Tumor DNA as a Promising Tool in Assessing the Effectiveness of Treatment in Non-Small Cell Lung Carcinoma Patients
by Natalia Galant, Marcin Nicoś, Barbara Kuźnar-Kamińska and Paweł Krawczyk
Cancers 2024, 16(4), 782; https://doi.org/10.3390/cancers16040782 - 14 Feb 2024
Cited by 1 | Viewed by 6505
Abstract
Despite the different possible paths of treatment, lung cancer remains one of the leading causes of death in oncological patients. New tools guiding the therapeutic process are under scientific investigation, and one of the promising indicators of the effectiveness of therapy in patients [...] Read more.
Despite the different possible paths of treatment, lung cancer remains one of the leading causes of death in oncological patients. New tools guiding the therapeutic process are under scientific investigation, and one of the promising indicators of the effectiveness of therapy in patients with NSCLC is variant allele frequency (VAF) analysis. VAF is a metric characterized as the measurement of the specific variant allele proportion within a genomic locus, and it can be determined using methods based on NGS or PCR. It can be assessed using not only tissue samples but also ctDNA (circulating tumor DNA) isolated from liquid biopsy. The non-invasive characteristic of liquid biopsy enables a more frequent collection of material and increases the potential of VAF analysis in monitoring therapy. Several studies have been performed on patients with NSCLC to evaluate the possibility of VAF usage. The research carried out so far demonstrates that the evaluation of VAF dynamics may be useful in monitoring tumor progression, remission, and recurrence during or after treatment. Moreover, the use of VAF analysis appears to be beneficial in making treatment decisions. However, several issues require better understanding and standardization before VAF testing can be implemented in clinical practice. In this review, we discuss the difficulties in the application of ctDNA VAF analysis in clinical routine, discussing the diagnostic and methodological challenges in VAF measurement in liquid biopsy. We highlight the possible applications of VAF-based measurements that are under consideration in clinical trials in the monitoring of personalized treatments for patients with NSCLC. Full article
(This article belongs to the Special Issue Novel Biomarkers in Non-Small Cell Lung Cancer (NSCLC))
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