Imaging as a Tumor Biomarker in Oncology Drug Trials for Lung Cancer: The FDA Perspective

Neuron-specific enolase (NSE) is one of the most commonly used serum tumor biomarker in clinical practice for small cell lung cancer screening, early diagnosis, evaluation of therapeutic efficacy and prognosis.

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A clinical trial design applying Bayesian adaptive randomization for targeted therapy development in lung cancer: A step toward personalized medicine

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7697 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7697-7697

Author(s):

X. Zhou ◽

E. S. Kim ◽

R. S. Herbst ◽

S. Liu ◽

I. I. Wistuba ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Response Rate ◽

Clinical Trial Design ◽

Probit Model ◽

Stopping Rules ◽

Response To Treatment ◽

Tumor Biomarker ◽

Lung Carcinogenesis ◽

Operating Characteristics

7697 Background: Multiple axes of signaling pathways are associated with lung carcinogenesis. These signaling axes are different in pts (pts) and their cancers. Utilization of molecularly targeted agents may inhibit these specific aberrant pathways and lead to clinical efficacy. Biomarkers expressions can be used as indicators for the aberrant signaling to identify effective targeted therapy. Methods: The program, “Biomarker-integrated Approaches of Targeted Therapy of Lung Cancer Elimination (BATTLE),” consists of an umbrella screening trial and 4 parallel phase II targeted therapies trials (with erlotinib, sorafenib, vandetanib, and the combination of erlotinib and bexarotene) in advanced non-small cell lung cancer pts with prior chemotherapy. All pts will have biopsy samples taken for biomarker profile assessment prior to the randomization. A ‘surrogate response‘ to treatment is defined as progression free at 8 weeks after randomization. The Bayesian ordinal probit model is used to characterize the response rate. Pts with certain biomarker profile will be adaptively randomized (AR) to one of the 4 treatment arms with the randomization rate based on the updated response rate based on accumulated data in the trial. For each biomarker profile, better performing arms will have higher randomization rates and vise versa. Early stopping rules are set so that low-performing arms may be suspended for new patient entry. Results: Based on extensive simulation studies, the proposed design with a total of 200 pts has desirable operating characteristics to: (1) identify effective agents with high probability; (2) suspend ineffective agents; and (3) treat more pts with effective agents according to their biomarker profiles. The Bayesian design incorporates prior data and findings from the current pts to form better estimates of the treatment efficacy for pts with different biomarker profiles. The design continues to “learn” and improve the estimates as the trial moves along. Conclusion: The Bayesian AR design is a smart and ethical design and ideally suitable for the development of targeted therapy. It may help in identifying effective agents based on pts’ tumor biomarker profile and thus treat more pts with effective therapies. No significant financial relationships to disclose.

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Biomarker Identification and Pathway Analysis by Serum Metabolomics of Lung Cancer

BioMed Research International ◽

10.1155/2015/183624 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Yingrong Chen ◽

Zhihong Ma ◽

Lishan Min ◽

Hongwei Li ◽

Bin Wang ◽

...

Keyword(s):

Lung Cancer ◽

Pathway Analysis ◽

Area Under The Curve ◽

Sphingolipid Metabolism ◽

Cytokeratin 19 ◽

Tumor Biomarker ◽

Diagnostic Model ◽

Roc Curve Analysis ◽

Metabolic Alterations ◽

Specificity And Sensitivity

Lung cancer is one of the most common causes of cancer death, for which no validated tumor biomarker is sufficiently accurate to be useful for diagnosis. Additionally, the metabolic alterations associated with the disease are unclear. In this study, we investigated the construction, interaction, and pathways of potential lung cancer biomarkers using metabolomics pathway analysis based on the Kyoto Encyclopedia of Genes and Genomes database and the Human Metabolome Database to identify the top altered pathways for analysis and visualization. We constructed a diagnostic model using potential serum biomarkers from patients with lung cancer. We assessed their specificity and sensitivity according to the area under the curve of the receiver operator characteristic (ROC) curves, which could be used to distinguish patients with lung cancer from normal subjects. The pathway analysis indicated that sphingolipid metabolism was the top altered pathway in lung cancer. ROC curve analysis indicated that glycerophospho-N-arachidonoyl ethanolamine (GpAEA) and sphingosine were potential sensitive and specific biomarkers for lung cancer diagnosis and prognosis. Compared with the traditional lung cancer diagnostic biomarkers carcinoembryonic antigen and cytokeratin 19 fragment, GpAEA and sphingosine were as good or more appropriate for detecting lung cancer. We report our identification of potential metabolic diagnostic and prognostic biomarkers of lung cancer and clarify the metabolic alterations in lung cancer.

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Electrochemiluminescence immunosensor for cytokeratin fragment antigen 21-1 detection using electrochemically mediated atom transfer radical polymerization

Microchimica Acta ◽

10.1007/s00604-020-04677-x ◽

2021 ◽

Vol 188 (4) ◽

Author(s):

Lihe Jian ◽

Xiaolan Wang ◽

Lulu Hao ◽

Yanju Liu ◽

Huaixia Yang ◽

...

Keyword(s):

Lung Cancer ◽

Atom Transfer Radical Polymerization ◽

Radical Polymerization ◽

Signal Amplification ◽

Limit Of Detection ◽

Tumor Biomarker ◽

Atom Transfer ◽

Sandwich Type ◽

Diagnosis Of Lung Cancer ◽

Antigen Antibody

AbstractThe cytokeratin fragment antigen 21-1 (CYFRA 21-1) protein is a critical tumor biomarker tightly related to non-small cell lung cancer (NSCLC). Herein, we prepared an effective electrochemiluminescence (ECL) immunosensor for CYFRA 21-1 detection using electrochemically mediated atom transfer radical polymerization (eATRP). The CYFRA 21-1 antigen was fixed on the electrode surface by constructing a sandwich type antibody-antigen-antibody immune system. The sensitivity of ECL was improved by using the eATRP reaction. In this method, eATRP was applied to CYFRA 21-1 detection antibody with N-acryloyloxysuccinimide as functional monomer. This is the first time that ECL and eATRP signal amplification technology had been combined. Under the optimized testing conditions, the immunosensor showed a good linear relation in the range from 1 fg mL−1 to 1 μg mL−1 at a limit of detection of 0.8 fg mL−1 (equivalent to ~ 134 molecules in a 10 μL sample). The ECL immunosensing system based on eATRP signal amplification technology provided a new way for rapid diagnosis of lung cancer by detecting CYFRA 21-1. Graphical abstract

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Evaluation of Monocarboxylate Transporter 4 (MCT4) Expression and Its Prognostic Significance in Circulating Tumor Cells From Patients With Early Stage Non-Small-Cell Lung Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.641978 ◽

2021 ◽

Vol 9 ◽

Author(s):

Athina Markou ◽

E. Tzanikou ◽

G. Kallergi ◽

E. Pantazaka ◽

V. Georgoulias ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Cells ◽

Peripheral Blood ◽

Early Stage ◽

Small Cell ◽

Monocarboxylate Transporter ◽

Tumor Biomarker ◽

Small Cell Lung ◽

Nsclc Patients ◽

Monocarboxylate Transporter 4

Purpose: Monocarboxylate transporter 4 (MCT4) can influence the amount of lactate in the tumor microenvironment and further control cancer cell proliferation, migration, and angiogenesis. We investigated for the first time the expression of MCT4 in circulating tumor cells (CTCs) derived from early stage Non-Small Cell Lung Cancer patients (NSCLC) and whether this is associated with clinical outcome.Experimental Design: A highly sensitive RT-qPCR assay for quantification of MCT4 transcripts was developed and validated and applied to study MCT4 expression in CTC isolated through the Parsortix size-dependent microfluidic device from 53 and 9 peripheral blood (PB) samples of NSCLC patients at baseline (pre-surgery) and at relapse, respectively, as well as the “background noise” was evaluated using peripheral blood samples from 10 healthy donors (HD) in exactly the same way as patients.Results:MCT4 was differentially expressed between HD and NSCLC patients. Overexpression of MCT4 was detected in 14/53 (26.4%) and 3/9 (33.3%) patients at baseline and at progression disease (PD), respectively. The expression levels of MCT4 was found to increase in CTCs at the time of relapse. Kaplan-Meier analysis showed that the overexpression of MCT4 was significantly (P = 0.045) associated with progression-free survival (median: 12.5 months, range 5–31 months).Conclusion:MCT4 overexpression was observed at a high frequency in CTCs from early NSCLC patients supporting its role in metastatic process. MCT4 investigated as clinically relevant tumor biomarker characterizing tumor aggressiveness and its potential value as target for cancer therapy. We are totally convinced that MCT4 overexpression in CTCs merits further evaluation as a non-invasive circulating tumor biomarker in a large and well-defined cohort of patients with NSCLC.

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A Pilot Prospective Study of Plasma Cell free DNA Whole Genome Sequencing Identified Chromosome 7p Copy Number Gains is a Specific Biomarker for Early Lung Cancer detection

10.21203/rs.3.rs-80693/v1 ◽

2020 ◽

Author(s):

Hongjie Yu ◽

Xiaojun Yu ◽

Jia Tang ◽

Xun Lu ◽

Haitao Ma

Keyword(s):

Lung Cancer ◽

Plasma Cell ◽

Cancer Detection ◽

Copy Number ◽

Chromosome 7 ◽

P Value ◽

Tumor Biomarker ◽

Cell Free Dna ◽

Free Dna ◽

Lung Cancer Detection

Abstract purpose: Chromosome 7 is playing an important role in lung tumorigenesis. Here we investigate whether chromosome 7p copy number gain as a detectable genetic events with plasma cell free DNA for early lung cancer detection biomarker. Methods: Eighteen surgical eligible lung cancer patients and eighteen non-cancer controls were recruited. Peripheral blood was collected before surgery. Cell free DNA was profiled with low coverage whole genome sequencing. Chromosome 7 copy number gains were defined as chr7 normalized coverage≥1.0005 and P value<0.05. Plasma cell-free DNA chr7 copy gains were then compared to pathological examinations on surgical tissues.Results: 83.3% patients were confirmed as malignancy post-operation, with 12 adenocarcinoma and 3 squamous-carcinoma. The other 16.7% were benign lesions. Cell free DNA was successfully extracted from pre-surgical plasma samples, with concentration range from 0.18 to 0.49 ng/ul. Chromosome 7 short arm copy gains were found in 66.7% (10/15) patients, including 66.7% (4/6) T1aN0M0 and 50.0% (1/2) Tis patients, otherwise, chr7p gain was found in 0% (0/3) benign lesions. The specificity was further examined in 18 volunteers who undergoing routine body examinations. Meanwhile, positive CEA and CYFRA21-1 was only found in 1/18 (5.7%) and 4/18 (22.2%). Taking together, UCAD chr7p or UCAD chr7p and tumor biomarker positivity can predict 12/15(80%, 95% CI:49.0-94.3%) early lung cancers. Further analyses showed that chr7p copy number gains tends to be enriched in EGFR/KRAS silent patients (fisher. test, P value=0.077). Conclusions: Chromosome 7p copy gains might be a useful peripheral blood tumor biomarker from lung cancer detection.

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