Diagnostics

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11 pages, 9314 KiB

Open AccessArticle

PD-L1 Expression in Non-Small Cell Lung Cancer: Data from a Referral Center in Spain

by Karmele Saez de Gordoa, Ingrid Lopez, Marta Marginet, Berta Coloma, Gerard Frigola, Naiara Vega, Daniel Martinez and Cristina Teixido

Diagnostics 2021, 11(8), 1452; https://doi.org/10.3390/diagnostics11081452 - 11 Aug 2021

Cited by 4 | Viewed by 2983

Abstract

Anti-programmed cell death (PD1)/ligand-1 (PD-L1) checkpoint inhibitors have improved the survival of non-small cell lung cancer (NSCLC) patients. Additionally, PD-L1 has emerged as a predictive biomarker of response. Our goal was to examine the histological features of all PD-L1 cases of NSCLC analyzed [...] Read more.

Anti-programmed cell death (PD1)/ligand-1 (PD-L1) checkpoint inhibitors have improved the survival of non-small cell lung cancer (NSCLC) patients. Additionally, PD-L1 has emerged as a predictive biomarker of response. Our goal was to examine the histological features of all PD-L1 cases of NSCLC analyzed in our center between 2017 and 2020, as well as to correlate the expression values of the same patient in different tested samples. PD-L1 immunohistochemistry (IHC) was carried out on 1279 external and internal samples: 482 negative (tumor proportion score, TPS < 1%; 37.7%), 444 low-expression (TPS 1–49%; 34.7%) and 353 high-expression (TPS ≥ 50%; 27.6%). Similar results were observed with samples from our institution (N = 816). Significant differences were observed with respect to tumor histological type (p = 0.004); squamous carcinoma was positive in a higher proportion of cases than other histological types. There were also differences between PD-L1 expression and the type of sample analyzed (surgical, biopsy, cytology; p < 0.001), with a higher frequency of negative cytology. In addition, there were cases with more than one PD-L1 determination, showing heterogeneity. Our results show strong correlation with the literature data and reveal heterogeneity between tumors and samples from the same patient, which could affect eligibility for treatment with immunotherapy. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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10 pages, 1802 KiB

Open AccessArticle

RNA-Based Multiplexing Assay for Routine Testing of Fusion and Splicing Variants in Cytological Samples of NSCLC Patients

by Cristina Aguado, Ana Giménez-Capitán, Ruth Román, Sonia Rodríguez, Núria Jordana-Ariza, Andrés Aguilar, Carlos Cabrera-Gálvez, Carlos Rivas-Corredor, Pilar Lianes, Santiago Viteri, Irene Moya and Miguel A. Molina-Vila

Diagnostics 2021, 11(1), 15; https://doi.org/10.3390/diagnostics11010015 - 23 Dec 2020

Cited by 10 | Viewed by 2267

Abstract

The detection of ALK receptor tyrosine kinase (ALK), ROS proto-oncogen1, receptor tyrosine kinase (ROS1), ret proto-oncogen (RET), and MET proto-oncogen exon 14 skipping (METΔex14) allows for the selection of specific kinase inhibitor treatment in patients with non-small cell lung [...] Read more.

The detection of ALK receptor tyrosine kinase (ALK), ROS proto-oncogen1, receptor tyrosine kinase (ROS1), ret proto-oncogen (RET), and MET proto-oncogen exon 14 skipping (METΔex14) allows for the selection of specific kinase inhibitor treatment in patients with non-small cell lung cancer (NSCLC). Multiplex technologies are recommended in this setting. We used nCounter, a multiplexed technology based on RNA hybridization, to detect ALK, ROS1, RET, and METΔex14 in RNA purified from cytological specimens (n = 16) and biopsies (n = 132). Twelve of the 16 cytological samples (75.0%) were evaluable by nCounter compared to 120 out of 132 (90.9%) biopsies. The geometrical mean (geomean) of the housekeeping genes of the nCounter panel, but not the total amount of RNA purified, was significantly higher in biopsies vs. cytological samples. Among cytological samples, we detected ALK (n = 3), METΔex14 (n = 1) and very high MET expression (n = 1) positive cases. The patient with METΔex14 had a partial response to tepotinib, one of the patients with ALK fusions was treated with crizotinib with a complete response. Cell blocks and cytological extensions can be successfully used for the detection of fusions and splicing variants using RNA-based methods such as nCounter. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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14 pages, 2429 KiB

Open AccessArticle

Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors

by Younosuke Sato, Isamu Okamoto, Hiroki Kameyama, Shinji Kudoh, Haruki Saito, Mune Sanada, Noritaka Kudo, Joeji Wakimoto, Kosuke Fujino, Yuki Ikematsu, Kentaro Tanaka, Ayako Nishikawa, Ryo Sakaguchi and Takaaki Ito

Diagnostics 2020, 10(11), 949; https://doi.org/10.3390/diagnostics10110949 - 13 Nov 2020

Cited by 14 | Viewed by 2983

Abstract

Small-cell lung cancer (SCLC) is an aggressive malignant cancer that is classified into four subtypes based on the expression of the following key transcription and co-transcription factors: ASCL1, NEUROD1, YAP1, and POU2F3. The protein expression levels of these key molecules may be important [...] Read more.

Small-cell lung cancer (SCLC) is an aggressive malignant cancer that is classified into four subtypes based on the expression of the following key transcription and co-transcription factors: ASCL1, NEUROD1, YAP1, and POU2F3. The protein expression levels of these key molecules may be important for the formation of SCLC characteristics in a molecular subtype-specific manner. We expect that immunohistochemistry (IHC) of these molecules may facilitate the diagnosis of the specific SCLC molecular subtype and aid in the appropriate selection of individualized treatments. We attempted IHC of the four key factors and 26 candidate SCLC target molecules selected from the gene expression omnibus datasets of 47 SCLC samples, which were grouped based on positive or negative results for the four key molecules. We examined differences in the expression levels of the candidate targets and key molecules. ASCL1 showed the highest positive rate in SCLC samples, and significant differences were observed in the expression levels of some target molecules between the ASCL1-positive and ASCL1-negative groups. Furthermore, the four key molecules were coordinately and simultaneously expressed in SCLC cells. An IHC study of ASCL1-positive samples showed many candidate SCLC target molecules, and IHC could become an essential method for determining SCLC molecular subtypes. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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13 pages, 6788 KiB

Open AccessArticle

Prospective Evaluation of Single Nucleotide Variants by Two Different Technologies in Paraffin Samples of Advanced Non-Small Cell Lung Cancer Patients

by Elba Marin, Roxana Reyes, Ainara Arcocha, Nuria Viñolas, Laura Mezquita, Elena Gonzalvo, Karmele Saez de Gordoa, Pedro Jares, Noemi Reguart and Cristina Teixido

Diagnostics 2020, 10(11), 902; https://doi.org/10.3390/diagnostics10110902 - 03 Nov 2020

Cited by 2 | Viewed by 2007

Abstract

Targeted therapies are a new paradigm in lung cancer management. Next-generation sequencing (NGS) techniques have allowed for simultaneous testing of several genes in a rapid and efficient manner; however, there are other molecular diagnostic tools such as the nCounter^® Vantage 3D single [...] Read more.

Targeted therapies are a new paradigm in lung cancer management. Next-generation sequencing (NGS) techniques have allowed for simultaneous testing of several genes in a rapid and efficient manner; however, there are other molecular diagnostic tools such as the nCounter^® Vantage 3D single nucleotide variants (SNVs) solid tumour panel which also offer important benefits regarding sample input and time-to-response, making them very attractive for daily clinical use. This study aimed to test the performance of the Vantage panel in the routine workup of advanced non-squamous non-small cell lung cancer (NSCLC) patients and to validate and compare its outputs with the Oncomine Solid Tumor (OST) panel DNA kit, the standard technique in our institution. Two parallel multiplexed approaches were performed based on DNA NGS and direct digital detection of DNA with nCounter^® technology to evaluate SNVs. A total of 42 advanced non-squamous NSCLC patients were prospectively included in the study. Overall, 95% of samples were successfully characterized by both technologies. The Vantage panel accounted for a sensitivity of 95% and a specificity of 82%. In terms of predictive values, the probability of truly presenting the SNV variant when it is detected by the nCounter panel was 82%, whereas the probability of not presenting the SNV variant when it is not detected by the platform was 95%. Finally, Cohen’s Kappa coefficient was 0.76, indicating a substantial correlation grade between OST and Vantage panels. Our results make nCounter an analytically sensitive, practical and cost-effective tool. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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7 pages, 517 KiB

Open AccessArticle

A Multi-Center, Real-Life Experience on Liquid Biopsy Practice for EGFR Testing in Non-Small Cell Lung Cancer (NSCLC) Patients

by Francesco Cortiula, Giulia Pasello, Alessandro Follador, Giorgia Nardo, Valentina Polo, Elisa Scquizzato, Alessandro Del Conte, Marta Miorin, Petros Giovanis, Alessandra D’Urso, Salvator Girlando, Giulio Settanni, Vincenzo Picece, Antonello Veccia, Carla Corvaja, Stefano Indraccolo and Giovanna De Maglio

Diagnostics 2020, 10(10), 765; https://doi.org/10.3390/diagnostics10100765 - 28 Sep 2020

Cited by 6 | Viewed by 2040

Abstract

Background: circulating tumor DNA (ctDNA) is a source of tumor genetic material for EGFR testing in NSCLC. Real-word data about liquid biopsy (LB) clinical practice are lacking. The aim of the study was to describe the LB practice for EGFR detection in North [...] Read more.

Background: circulating tumor DNA (ctDNA) is a source of tumor genetic material for EGFR testing in NSCLC. Real-word data about liquid biopsy (LB) clinical practice are lacking. The aim of the study was to describe the LB practice for EGFR detection in North Eastern Italy. Methods: we conducted a multi-regional survey on ctDNA testing practices in lung cancer patients. Results: Median time from blood collection to plasma separation was 50 min (20–120 min), median time from plasma extraction to ctDNA analysis was 24 h (30 min–5 days) and median turnaround time was 24 h (6 h–5 days). Four hundred and seventy five patients and 654 samples were tested. One hundred and ninety-two patients were tested at diagnosis, with 16% EGFR mutation rate. Among the 283 patients tested at disease progression, 35% were T790M+. Main differences in LB results between 2017 and 2018 were the number of LBs performed for each patient at disease progression (2.88 vs. 1.2, respectively) and the percentage of T790M+ patients (61% vs. 26%). Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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12 pages, 1098 KiB

Open AccessArticle

Budget Impact Analysis of EGFR Mutation Liquid Biopsy for First- and Second-Line Treatment of Metastatic Non-Small Cell Lung Cancer in Greece

by Mindy Cheng, Athanasios Akalestos and Sidney Scudder

Diagnostics 2020, 10(6), 429; https://doi.org/10.3390/diagnostics10060429 - 24 Jun 2020

Cited by 5 | Viewed by 3059

Abstract

Within the European Union, Greece has the highest incidence of lung cancer among people under 45 years of age. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are indicated for the treatment of patients with EGFR mutation-positive metastatic non-small cell lung [...] Read more.

Within the European Union, Greece has the highest incidence of lung cancer among people under 45 years of age. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are indicated for the treatment of patients with EGFR mutation-positive metastatic non-small cell lung cancer (mNSCLC). Tumor tissue biopsy is the standard method for EGFR mutation detection but is invasive, is resource-intensive, and has risks of complications. The objective of this analysis was to estimate the financial impact on the Greek National Health System of adopting plasma biopsy and to identify the cost-optimal approach for EGFR mutation testing of patients with mNSCLC. We developed a budget impact model to estimate total costs for three EGFR mutation testing approaches: (1) plasma test, (2) combined testing (tissue and plasma test), and (3) reflex testing, compared to the current scenario of tissue biopsy only. One-way sensitivity and scenario analyses were conducted to evaluate the impact of uncertainty and variance of different input parameters on the results. In the first-line (1L) setting, base-case results showed that adopting plasma testing in a combined testing approach identified more EGFR mutation-positive patients and yielded cost savings (−€17 per correctly classified patient) relative to tissue testing alone. The reflex testing approach was the cost-optimal strategy in the second-line (2L) setting as it identified the most EGFR mutation-positive patients with cost savings of −€42 per correctly classified patient relative to tissue testing alone. This analysis suggests that access to both EGFR mutation tissue and plasma testing are important for optimizing mNSCLC treatment decisions in Greece. Inclusion of plasma testing in either a combined or reflex testing approach may be cost optimal for EGFR mutation plasma test implementation. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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Review

Jump to: Research, Other

16 pages, 1892 KiB

Open AccessReview

The Importance of STK11/LKB1 Assessment in Non-Small Cell Lung Carcinomas

by Baharia Mograbi, Simon Heeke and Paul Hofman

Diagnostics 2021, 11(2), 196; https://doi.org/10.3390/diagnostics11020196 - 29 Jan 2021

Cited by 24 | Viewed by 7156

Abstract

Despite the recent implementation of immunotherapy as a single treatment or in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer (NSCLC), many patients do not benefit from this regimen due to primary treatment resistance or toxicity. Consequently, there is [...] Read more.

Despite the recent implementation of immunotherapy as a single treatment or in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer (NSCLC), many patients do not benefit from this regimen due to primary treatment resistance or toxicity. Consequently, there is an urgent need to develop efficient biomarkers that can select patients who will benefit from immunotherapy thereby providing the appropriate treatment and avoiding toxicity. One of the biomarkers recently described for the stratification of NSCLC patients undergoing immunotherapy are mutations in STK11/LKB1, which are often associated with a lack of response to immunotherapy in some patients. Therefore, the purpose of this review is to describe the different cellular mechanisms associated with STK11/LKB1 mutations, which may explain the lack of response to immunotherapy. Moreover the review addresses the co-occurrence of additional mutations that may influence the response to immunotherapy and the current clinical studies that have further explored STK11/LKB1 as a predictive biomarker. Additionally this work includes the opportunities and limitations to look for the STK11/LKB1 status in the therapeutic strategy for NSCLC patients. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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12 pages, 822 KiB

Open AccessReview

Next Generation Sequencing in Non-Small Cell Lung Cancer: Pitfalls and Opportunities

by Chiara Lazzari, Alessandra Bulotta, Maria Giulia Cangi, Gabriele Bucci, Lorenza Pecciarini, Silvia Bonfiglio, Vincenza Lorusso, Stefania Ippati, Gianluigi Arrigoni, Greta Grassini, Claudio Doglioni and Vanesa Gregorc

Diagnostics 2020, 10(12), 1092; https://doi.org/10.3390/diagnostics10121092 - 15 Dec 2020

Cited by 13 | Viewed by 2680

Abstract

Lung cancer remains the first cause of cancer-related deaths worldwide. Thanks to the improvement in the knowledge of the biology of non-small cell lung cancer (NSCLC), patients’ survival has significantly improved. A growing number of targetable molecular alterations have been identified. Next-generation sequencing [...] Read more.

Lung cancer remains the first cause of cancer-related deaths worldwide. Thanks to the improvement in the knowledge of the biology of non-small cell lung cancer (NSCLC), patients’ survival has significantly improved. A growing number of targetable molecular alterations have been identified. Next-generation sequencing (NGS) has become one of the methodologies entered in clinical practice and was recently recommended by the European society for medical oncology (ESMO) to perform a comprehensive molecular characterization in patients with cancer. The current review provides an overview of the clinical trials that have explored the impact of NGS in patients with cancer, its limits, and advantages. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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17 pages, 443 KiB

Open AccessReview

Next Generation Sequencing for Gene Fusion Analysis in Lung Cancer: A Literature Review

by Rossella Bruno and Gabriella Fontanini

Diagnostics 2020, 10(8), 521; https://doi.org/10.3390/diagnostics10080521 - 27 Jul 2020

Cited by 89 | Viewed by 8638

Abstract

Gene fusions have a pivotal role in non-small cell lung cancer (NSCLC) precision medicine. Several techniques can be used, from fluorescence in situ hybridization and immunohistochemistry to next generation sequencing (NGS). Although several NGS panels are available, gene fusion testing presents more technical [...] Read more.

Gene fusions have a pivotal role in non-small cell lung cancer (NSCLC) precision medicine. Several techniques can be used, from fluorescence in situ hybridization and immunohistochemistry to next generation sequencing (NGS). Although several NGS panels are available, gene fusion testing presents more technical challenges than other variants. This is a PubMed-based narrative review aiming to summarize NGS approaches for gene fusion analysis and their performance on NSCLC clinical samples. The analysis can be performed at DNA or RNA levels, using different target enrichment (hybrid-capture or amplicon-based) and sequencing chemistries, with both custom and commercially available panels. DNA sequencing evaluates different alteration types simultaneously, but large introns and repetitive sequences can impact on the performance and it does not discriminate between expressed and unexpressed gene fusions. RNA-based targeted approach analyses and quantifies directly fusion transcripts and is more accurate than DNA panels on tumor tissue, but it can be limited by RNA quality and quantity. On liquid biopsy, satisfying data have been published on circulating tumor DNA hybrid-capture panels. There is not a perfect method for gene fusion analysis, but NGS approaches, though still needing a complete standardization and optimization, present several advantages for the clinical practice. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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Other

Jump to: Research, Review

15 pages, 960 KiB

Open AccessProtocol

Influence of Biopsy Technique on Molecular Genetic Tumor Characterization in Non-Small Cell Lung Cancer—The Prospective, Randomized, Single-Blinded, Multicenter PROFILER Study Protocol

by Maik Haentschel, Michael Boeckeler, Irina Bonzheim, Florian Schimmele, Werner Spengler, Franz Stanzel, Christoph Petermann, Kaid Darwiche, Lars Hagmeyer, Reinhard Buettner, Markus Tiemann, Hans-Ulrich Schildhaus, Rainer Muche, Hans Boesmueller, Felix Everinghoff, Robert Mueller, Bijoy Atique, Richard A. Lewis, Lars Zender, Falko Fend and Juergen Hetzel Show full author list Hide full author list

Diagnostics 2020, 10(7), 459; https://doi.org/10.3390/diagnostics10070459 - 06 Jul 2020

Cited by 3 | Viewed by 3584

Abstract

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient’s progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; [...] Read more.

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient’s progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival. Full article

(This article belongs to the Special Issue Lung Cancer Molecular Pathology)

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