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Special Issue "Personalized Therapy in Non-Small Cell Lung Cancer: The Role of Biological Agents and Immunotherapy"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (10 December 2018)

Special Issue Editor

Guest Editor
Prof. David J. Barnes

Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
Website | E-Mail
Interests: infection and immunity; lung cancer; sleep disorders; lung diseases; respiratory tract diseases

Special Issue Information

Dear Colleagues,

It is no longer acceptable to lump lung cancer into either small cell or non-small cell groups. With the advent of targeted therapy for cancers with mutations or rearrangements, and the increasing role for immunotherapy, there is an increasing need for precise pathology assessment and individualized therapy. This is an exciting time in lung cancer care, but these developments also require clinicians involved in lung cancer to be up to date with all new developments. Hopefully this Special Issue will assist clinicians in being aware of state-of-the-art lung cancer care.

Prof. David J. Barnes
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 papers will be 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 short 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. Journal of Clinical Medicine is an international peer-reviewed open access monthly 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 1800 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

  • Personalized therapy
  • Targeted therapy
  • Immunotherapy
  • Lung cancer
  • Biological agents
  • Non-small cell
  • Mutation
  • Rearrangement
  • Pathology assessment

Published Papers (11 papers)

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Research

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Open AccessArticle
Effects of β-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer
J. Clin. Med. 2019, 8(5), 575; https://doi.org/10.3390/jcm8050575
Received: 9 April 2019 / Accepted: 19 April 2019 / Published: 26 April 2019
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Abstract
Introduction: Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies that suggest stimulation of β-adrenergic receptors (β-AR) promotes tumor invasion and therapy resistance. We investigated whether β-AR inhibition with beta-blockers acts as [...] Read more.
Introduction: Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies that suggest stimulation of β-adrenergic receptors (β-AR) promotes tumor invasion and therapy resistance. We investigated whether β-AR inhibition with beta-blockers acts as a chemotherapy and radiation sensitizer in vitro and in patients treated with chemoradiation for locally advanced NSCLC. Methods: We investigated the effects of the non-selective beta-blocker propranolol on two human lung adenocarcinoma cell lines (PC9, A549) treated with radiation or cisplatin. We retrospectively evaluated 77 patients with Stage IIIA NSCLC who received induction chemoradiation followed by surgery. Pathological and imaging response, metastatic rate, and survival were analyzed using SPSS v22.0 and PrismGraphpad6. Results: Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro (p < 0.05). Furthermore, propranolol decreased expression of phospho-protein kinase A (p-PKA), a β-adrenergic pathway downstream activation target, in both cell lines compared to irradiation or cisplatin alone (p < 0.05). In patients treated for Stage IIIA NSCLC, 16 took beta-blockers, and 61 did not. Beta-blockade is associated with a trend to improved overall survival (OS) at 1 year (81.3% vs 57.4%, p = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, p = 0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio (RR) 0.19; p = 0.03), it did not affect primary tumor pathological response (p = 0.40) or imaging response (p = 0.36). Conclusions: β-AR blockade enhanced radiation and cisplatin sensitivity of human lung cancer cells in vitro. Use of beta-blockers is associated with decreased distant metastases and potentially improved OS and DMFS. Additional studies are warranted to evaluate the role of beta-blockers as a chemoradiation sensitizer in locally advanced NSCLC. Full article
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Open AccessArticle
Prognostic Role of Circulating miRNAs in Early-Stage Non-Small Cell Lung Cancer
J. Clin. Med. 2019, 8(2), 131; https://doi.org/10.3390/jcm8020131
Received: 17 December 2018 / Revised: 17 January 2019 / Accepted: 20 January 2019 / Published: 23 January 2019
Cited by 1 | PDF Full-text (700 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death worldwide, with a low 5-year survival rate even in fully resected early-stage disease. Novel biomarkers to identify patients at higher risk of relapse are needed. We studied the prognostic value of [...] Read more.
Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death worldwide, with a low 5-year survival rate even in fully resected early-stage disease. Novel biomarkers to identify patients at higher risk of relapse are needed. We studied the prognostic value of 84 circulating microRNAs (miRNAs) in 182 patients with resected early-stage NSCLC (99 adenocarcinoma (ADC), 83 squamous cell carcinoma (SCC)) from whom peripheral blood samples were collected pre-surgery. miRNA expression was analyzed in relation to disease-free survival (DFS) and overall survival (OS). In univariable analyses, five miRNAs (miR-26a-5p, miR-126-3p, miR-130b-3p, miR-205-5p, and miR-21-5p) were significantly associated with DFS in SCC, and four (miR-130b-3p, miR-26a-5p, miR-126-3p, and miR-205-5p) remained significantly associated with OS. In ADC, miR-222-3p, miR-22-3p, and mir-93-5p were significantly associated with DFS, miR-22-3p remaining significant for OS. Given the high-dimensionality of the dataset, multivariable models were obtained using a regularized Cox regression including all miRNAs and clinical covariates. After adjustment for disease stage, only miR-126-3p showed an independent prognostic role, with higher values associated with longer DFS in SCC patients. With regard to ADC and OS, no miRNA remained significant in multivariable analysis. Further investigation into the role of miR-126 as a prognostic marker in early-stage NSCLC is warranted. Full article
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Open AccessArticle
Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients
J. Clin. Med. 2019, 8(1), 112; https://doi.org/10.3390/jcm8010112
Received: 13 December 2018 / Revised: 14 January 2019 / Accepted: 15 January 2019 / Published: 18 January 2019
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Abstract
Background: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role [...] Read more.
Background: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role of biologically driven therapies is still underrated. Methods: A single-institution cohort of 76 NSCLCs from octogenarian patients was submitted to molecular analysis using a next-generation sequencing (NGS) multigene panel, fluorescence in situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1 assessment. Treatment and clinical outcome data were available for 33 patients. Results: Most cases (n = 66, 87%) harbored at least one genomic alteration. EGFR and KRAS mutations were detected in 18 (24%) and 20 (26%) patients, respectively. No ALK alterations were found, but in two patients ROS1 translocation was identified. Of 22 cases tested, 17 were positive for PD-L1 staining. Octogenarian patients who received tyrosine kinase inhibitors (TKIs) based on molecular analysis showed clinical benefits, with long progression-free survival as expected in TKI-treated younger cohorts. Conclusions: This study highlights the utility of molecular profiling in all advanced-stage NSCLCs, regardless of the age at diagnosis, to drive personalized treatment. The prevalence of druggable alterations and the clinical benefits obtained by biologically-driven therapies in octogenarians were comparable to those of the younger NSCLC population. Full article
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Open AccessArticle
Low TIP30 Protein Expression is Associated with a High Risk of Metastasis and Poor Prognosis for Non-Small-Cell Lung Cancer
J. Clin. Med. 2019, 8(1), 83; https://doi.org/10.3390/jcm8010083
Received: 6 December 2018 / Revised: 7 January 2019 / Accepted: 8 January 2019 / Published: 12 January 2019
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Abstract
Non-small-cell lung cancer (NSCLC) is a deadly malignancy with a high prevalence worldwide. A reliable biomarker that can predict the prognosis is required to determine the therapeutic strategy. TIP30 was first identified as a tumor suppressor. A number of mechanistic studies indicated that [...] Read more.
Non-small-cell lung cancer (NSCLC) is a deadly malignancy with a high prevalence worldwide. A reliable biomarker that can predict the prognosis is required to determine the therapeutic strategy. TIP30 was first identified as a tumor suppressor. A number of mechanistic studies indicated that the downregulation of TIP30 enhances the stemness, migration and survival of NSCLC cells. However, the clinical relevance of TIP30 for the prognosis of NSCLC is unknown. From a meta-analysis of public microarray datasets, we showed the upregulation of TIP30 mRNA expression was associated with worse overall survival of NSCLC patients, which contradicted the tumor suppressive role of TIP30. It is worth noting that the TIP30 mRNA expression was not correlated with its protein expression in 15 NSCLC cell lines. The results from the immunohistochemistry of a tissue microarray showed the downregulation of the TIP30 protein expression was associated with a higher risk of metastasis. In addition, the decrease in TIP30 protein was correlated with worse overall and progression-free survival of the NSCLC patients. Multivariate analysis suggested the loss of TIP30 protein was an independent factor to predict the poor prognosis of NSCLC. Our data indicated that TIP30 protein, not mRNA, would be a potential prognostic biomarker of NSCLC. Full article
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Open AccessArticle
Real-World Use and Outcomes of ALK-Positive Crizotinib-Treated Metastatic NSCLC in US Community Oncology Practices: A Retrospective Observational Study
J. Clin. Med. 2018, 7(6), 129; https://doi.org/10.3390/jcm7060129
Received: 8 May 2018 / Accepted: 15 May 2018 / Published: 29 May 2018
Cited by 1 | PDF Full-text (571 KB) | HTML Full-text | XML Full-text
Abstract
Introduction: Around 3–5% of non-small cell lung cancers (NSCLC) are ALK-positive. Crizotinib was the first approved ALK inhibitor from clinical trials. However, there are less data on the utilization and patient outcomes associated with crizotinib in real-world clinical practice. Methods: This was a [...] Read more.
Introduction: Around 3–5% of non-small cell lung cancers (NSCLC) are ALK-positive. Crizotinib was the first approved ALK inhibitor from clinical trials. However, there are less data on the utilization and patient outcomes associated with crizotinib in real-world clinical practice. Methods: This was a retrospective, observational study of adult crizotinib-treated ALK-positive metastatic NSCLC patients who received treatment between 1 September 2011 and 31 October 2014, with follow up through 31 December 2015. Data were obtained via programmatic queries of the US Oncology Network/McKesson Specialty Health electronic health record database, supplemented with chart abstraction. Overall survival (OS) and time to treatment failure (TTF) were estimated from crizotinib initiation using the Kaplan–Meier (KM) method. Results: Of the n = 199 ALK-positive crizotinib-treated patients meeting eligibility criteria, crizotinib was prescribed as first line (1 L) in n = 123 (61.8%). The majority (88.9%) had confirmed adenocarcinoma histology and 32.2% had brain metastases at initial diagnosis. Median age at crizotinib initiation was 60.2 years (range 27.1–88.2); 54.8% were never smokers, 33.7% were former smokers. Treatment of 250 mg, twice daily, was most commonly prescribed (89.5%) with the dose unchanged from an initial dose in 79.4% of patients. The primary discontinuation reason was progression (n = 91, 58.7%). Patients (3.2%) were identified as discontinuing crizotinib as a result of treatment-related toxicity. With median follow-up time of 13.0 months (min–max = 0.03–46.6), median OS from crizotinib initiation was 33.8 months (95% CI = 24.3–38.8). Median TTF was 10.4 months. Conclusions: Crizotinib usage evaluated within the real-world setting is consistent with prior phase III clinical trial data, and illustrates the real-world effectiveness of crizotinib. Full article
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Review

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Open AccessReview
CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)
J. Clin. Med. 2018, 7(10), 303; https://doi.org/10.3390/jcm7100303
Received: 12 August 2018 / Revised: 16 September 2018 / Accepted: 23 September 2018 / Published: 25 September 2018
Cited by 1 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text
Abstract
Lung cancer is the second most common malignancy. Unfortunately, despite advances in multimodality therapeutics for the disease, the overall five-year survival rate among newly diagnosed lung cancer patients remains in the range region of 15%. In addition, although immune checkpoint inhibitors are increasingly [...] Read more.
Lung cancer is the second most common malignancy. Unfortunately, despite advances in multimodality therapeutics for the disease, the overall five-year survival rate among newly diagnosed lung cancer patients remains in the range region of 15%. In addition, although immune checkpoint inhibitors are increasingly being incorporated into lung cancer treatment protocols, the proportion of patients that respond to these agents remains low and the duration of response is often short. Therefore, novel methodologies to enhance the efficacy of immunotherapy in lung cancer are highly desirable. Chemokines are small chemotactic cytokines that interact with their 7 transmembrane G-protein–coupled receptors, to guide immune cell trafficking in the body under both physiologic and pathologic conditions. Tumor cells highjack a small repertoire of the chemokine/chemokine receptor system and utilize it in a manner that benefits local tumor growth and distant spread. The chemokine receptor, CXCR4 is expressed in over 30 types of malignant tumors and, through interaction with its ligand CXCL12, was shown exert pleotropic pro-tumorigenic effects. In this review, the pathologic roles that CXCL12/CXCR4 play in lung cancer propagation are presented. Furthermore, the challenges and potential benefits of incorporating drugs that target CXCL12/CXCR4 into immune-based lung cancer therapeutic protocols are discussed. Full article
Open AccessReview
Targeted Molecular Treatments in Non-Small Cell Lung Cancer: A Clinical Guide for Oncologists
J. Clin. Med. 2018, 7(8), 192; https://doi.org/10.3390/jcm7080192
Received: 20 July 2018 / Revised: 30 July 2018 / Accepted: 30 July 2018 / Published: 31 July 2018
Cited by 4 | PDF Full-text (339 KB) | HTML Full-text | XML Full-text
Abstract
Targeted molecular treatments have changed the way non-small cell lung cancer (NSCLC) is managed. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and c-ros oncogene 1 (ROS1 [...] Read more.
Targeted molecular treatments have changed the way non-small cell lung cancer (NSCLC) is managed. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), and c-ros oncogene 1 (ROS1) mutations are now used to guide specific anti-cancer therapies to improve patient outcomes. New targeted molecular treatments are constantly being developed and evaluated as a means to improve efficacy, overcome resistance, or minimise toxicity. This review article summarises the current evidence for the efficacy, resistance mechanisms, and safety of targeted molecular treatments against specific mutations in NSCLC. Full article
Open AccessReview
Diagnosing Lung Cancer: The Complexities of Obtaining a Tissue Diagnosis in the Era of Minimally Invasive and Personalised Medicine
J. Clin. Med. 2018, 7(7), 163; https://doi.org/10.3390/jcm7070163
Received: 7 June 2018 / Revised: 25 June 2018 / Accepted: 27 June 2018 / Published: 29 June 2018
Cited by 3 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text
Abstract
The role of the respiratory physician in diagnosing lung cancer has increased in complexity over the last 20 years. Adenocarcinoma is now the prevailing histopathological sub-type of non-small cell lung cancer (NSCLC) resulting in more peripheral cancers. Conventional bronchoscopy is often not sufficient [...] Read more.
The role of the respiratory physician in diagnosing lung cancer has increased in complexity over the last 20 years. Adenocarcinoma is now the prevailing histopathological sub-type of non-small cell lung cancer (NSCLC) resulting in more peripheral cancers. Conventional bronchoscopy is often not sufficient to obtain adequate tissue samples for diagnosis. Radiologically guided transthoracic biopsy is a sensitive alternative, but carries significant risks. These limitations have driven the development of complimentary bronchoscopic navigation techniques for peripheral tumour localisation and sampling. Furthermore, linear endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is increasingly being chosen as the initial diagnostic procedure for those with central lesions and/or radiological evidence of node-positive disease. This technique can diagnose and stage patients in a single, minimally invasive procedure with a diagnostic yield equivalent to that of surgical mediastinoscopy. The success of molecular targeted therapies and immune checkpoint inhibitors in NSCLC has led to the increasing challenge of obtaining adequate specimens for accurate tumour subtyping through minimally invasive procedures. This review discusses the changing epidemiology and treatment landscape of lung cancer and explores the utility of current diagnostic options in obtaining a tissue diagnosis in this new era of precision medicine. Full article
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Open AccessReview
An Update on Predictive Biomarkers for Treatment Selection in Non-Small Cell Lung Cancer
J. Clin. Med. 2018, 7(6), 153; https://doi.org/10.3390/jcm7060153
Received: 17 May 2018 / Revised: 12 June 2018 / Accepted: 12 June 2018 / Published: 15 June 2018
Cited by 4 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
It is now widely established that management of lung cancer is much more complex and cannot be centered on the binary classification of small-cell versus non-small cell lung cancer (NSCLC). Lung cancer is now recognized as a highly heterogeneous disease that develops from [...] Read more.
It is now widely established that management of lung cancer is much more complex and cannot be centered on the binary classification of small-cell versus non-small cell lung cancer (NSCLC). Lung cancer is now recognized as a highly heterogeneous disease that develops from genetic mutations and gene expression patterns, which initiate uncontrolled cellular growth, proliferation and progression, as well as immune evasion. Accurate biomarker assessment to determine the mutational status of driver mutations such as EGFR, ALK and ROS1, which can be targeted by specific tyrosine kinase inhibitors, is now essential for treatment decision making in advanced stage NSCLC and has shifted the treatment paradigm of NSCLC to more individualized therapy. Rapid advancements in immunotherapeutic approaches to NSCLC treatment have been paralleled by development of a range of potential predictive biomarkers that can enrich for patient response, including PD-L1 expression and tumor mutational burden. Here, we review the key biomarkers that help predict response to treatment options in NSCLC patients. Full article
Open AccessReview
Immunotherapy in Non-Small Cell Lung Cancer: Shifting Prognostic Paradigms
J. Clin. Med. 2018, 7(6), 151; https://doi.org/10.3390/jcm7060151
Received: 4 May 2018 / Revised: 8 June 2018 / Accepted: 12 June 2018 / Published: 14 June 2018
Cited by 2 | PDF Full-text (272 KB) | HTML Full-text | XML Full-text
Abstract
Immune checkpoint inhibitors have shown efficacy in the treatment of non-small cell lung cancer (NSCLC) in the adjuvant, first- and subsequent-line settings. In metastatic disease, they provide hope of durable response where “best-case” scenario has long been inadequate. This progress has highlighted the [...] Read more.
Immune checkpoint inhibitors have shown efficacy in the treatment of non-small cell lung cancer (NSCLC) in the adjuvant, first- and subsequent-line settings. In metastatic disease, they provide hope of durable response where “best-case” scenario has long been inadequate. This progress has highlighted the immunogenic nature of NSCLC and invigorated research into immunotherapy in the field. In this review we consider the foundations of immunotherapy in NSCLC, canvass the current research and summarise the evidence guiding clinical practice. Full article
Open AccessReview
Current and Future Molecular Testing in NSCLC, What Can We Expect from New Sequencing Technologies?
J. Clin. Med. 2018, 7(6), 144; https://doi.org/10.3390/jcm7060144
Received: 24 May 2018 / Revised: 5 June 2018 / Accepted: 6 June 2018 / Published: 9 June 2018
Cited by 4 | PDF Full-text (1397 KB) | HTML Full-text | XML Full-text
Abstract
Recent changes in lung cancer care, including new approvals in first line and the introduction of high-throughput molecular technologies in routine testing led us to question ourselves on how deeper molecular testing may be helpful for the optimal use of targeted drugs. In [...] Read more.
Recent changes in lung cancer care, including new approvals in first line and the introduction of high-throughput molecular technologies in routine testing led us to question ourselves on how deeper molecular testing may be helpful for the optimal use of targeted drugs. In this article, we review recent results in the scope of personalized medicine in lung cancer. We discuss biomarkers that have a therapeutic predictive value in lung cancer with a focus on recent changes and on the clinical value of large scale sequencing strategies. We review the use of second- and third-generation EGFR and ALK inhibitors with a focus on secondary resistance alterations. We discuss anti-BRAF and anti-MEK combo, emerging biomarkers as NRG1 and NTRKs fusions and immunotherapy. Finally, we discuss the different technical issues of comprehensive molecular profiling and show how large screenings might refine the prediction value of individual markers. Based on a review of recent publications (2012–2018), we address promising approaches for the treatment of patients with lung cancers and the technical challenges associated with the identification of new predictive markers. Full article
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J. Clin. Med. EISSN 2077-0383 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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