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Mesothelioma Biomarkers: a Review Highlighting Contributions from the Early Detection 4 Research Network 5 6 Harvey I

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Mesothelioma Biomarkers: a Review Highlighting Contributions from the Early Detection 4 Research Network 5 6 Harvey I Author Manuscript Published OnlineFirst on July 22, 2020; DOI: 10.1158/1055-9965.EPI-20-0083 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 2 3 Mesothelioma Biomarkers: A Review Highlighting Contributions from the Early Detection 4 Research Network 5 6 Harvey I. Pass1, Marjan Alimi1, Michele Carbone2, Haining Yang2, and Chandra M. Goparaju1 7 8 1NYU Langone Medical Center 9 Department of Cardiothoracic Surgery 10 530 First Avenue, 9V 11 New York, NY 10016 12 13 2John A. Burns School of Medicine 14 University of Hawaii Cancer Center 15 Department of Thoracic Oncology 16 701 Ilalo Street, Room 437 17 Honolulu, HI 96813 18 19 20 Running Title: Mesothelioma Biomarkers and EDRN 21 22 Keywords: mesothelioma, biomarkers, asbestos, prognosis, diagnosis 23 24 Financial support for this manuscript was only for HIP: 5U01CA214195-04 The EDRN 25 Mesothelioma Biomarker Discovery Laboratory 26 27 Corresponding Author: 28 Harvey I. Pass MD 29 Stephen E. Banner Professor of Thoracic Oncology 30 Vice-Chairman, Research 31 Department of Cardiothoracic Surgery 32 Director, General Thoracic Surgery 33 NYU Langone Medical Center 34 530 First Avenue, 9V 35 New York, New York 10016 36 212-263-7417 (Academic) 37 212-263-2042 (FAX) 38 39 40 H.I.P. reports funding from the National Cancer Institute, the Department of Defense, the Center for 41 Disease Control, Genentech, and Belluck and Fox.. M.C. and H. Y. report grants from the National 42 Institutes of Health, National Cancer Institute, the US Department of Defense, and the UH Foundation 43 through donations to support research on “Pathogenesis of Malignant Mesothelioma” from Honeywell 44 International Inc, Riviera United‐4‐a Cure, and the Maurice and Joanna Sullivan Family Foundation. 45 M.C. has a patent issued for BAP1. M.C and H.Y. have a patent issued for “Using Anti‐HMGB1 46 Monoclonal Antibody or other HMGB1 Antibodies as a Novel Mesothelioma Therapeutic Strategy,” and 47 a patent issued for “HMGB1 As a Biomarker for Asbestos Exposure and Mesothelioma Early Detection”. 48 M.C. is a board‐certified pathologist who provides consultation for mesothelioma expertise and diagnosis. 49 The remaining authors report no disclosures. 50 51 1 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 22, 2020; DOI: 10.1158/1055-9965.EPI-20-0083 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 3 Background: Malignant Pleural Mesothelioma (MPM) is an asbestos related neoplasm which can only be 4 treated successfully when correctly diagnosed and treated in early stages. The asbestos exposed 5 population serves as a high risk group which could benefit from sensitive and specific blood based or 6 tissue based biomarkers. This review details the recent work with biomarker development in MPM and 7 the contributions of the NCI Early Detection Research Network Biomarker Developmental Laboratory of 8 NYU Langone Medical Center. 9 Methods: The literature of the last 20 years was reviewed in order to comment on the most promising of 10 the blood and tissue based biomarkers. Proteomic, genomic and epigenomic platforms as well as novel 11 studies such as "breath testing" are covered. 12 Results: Soluble Mesothelin-Related Proteins (SMRP) have been characterized extensively and 13 constitute an FDA-approved biomarker in plasmawith diagnostic, monitoring and prognostic value in 14 MPM. Osteopontin is found to be a valuable prognostic biomarker for MPM, while its utility in diagnosis 15 is slightly lower. Other biomarkers such as calretinin, fibulin 3, and High-Mobility Group Box 1 16 (HMGB1) remain under study and need international validation trials with large cohorts of cases and 17 controls to demonstrate any utility. 18 Conclusions: The EDRN has played a key role in the development and testing of MPM biomarkers by 19 enlisting collaborations all over the world. 20 Impact: A comprehensive understanding of previously investigated biomarkers and their utility in 21 screening and early diagnosis of MPM will provide guidance for further future research. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 2 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 22, 2020; DOI: 10.1158/1055-9965.EPI-20-0083 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Introduction 2 3 Malignant pleural mesothelioma (MPM) is a relatively rare malignancy with an estimated 4 incidence of 3,200 cases per year in the United States, and a minimum 34,000 deaths in 2013 5 worldwide.[1-3] Exposure to asbestos is believed to be the main cause, with a long latency period of 6 approximately 20 to 40 years between initiation of exposure and clinical diagnosis.[4-6] Asbestos 7 continues to be used worldwide and still exists in previously constructed buildings’ walls and ceilings, 8 resulting in occasional exposure of the residents and construction workers; therefore the incidence of 9 MPM is not expected to decrease.[7-9] Additional risk factors include high dose radiation exposure and 10 other mineral fibers; the role of SV40 infection remains controversial.[10-14] 11 Prolonged asbestos exposure induces a sustained inflammatory response (the inflammasome), resulting in 12 the release of cytokines and an increase in reactive oxygen species (ROS) that can initiate MPM 13 carcinogenesis.[15-19] Current data suggest that MPM has a low mutation burden and tumor suppressors 14 BAP1, NF2, and CDKN2A are the most frequently mutated genes involved in pathogenesis of MPM.[20- 15 24] 16 Despite aggressive multi-modality therapy with surgery, chemotherapy, and radiation therapy, 17 MPM’s prognosis continues to be poor due to its unpredictable growth and minimal response to current 18 treatments.[4, 25-28] Diagnosis and treatment of MPM at an early stage (stage I) is shown to have a 19 significantly better outcome and overall survival [29, 30]; however, this constitutes only 5% of the 20 patients. Average survival for all patients is close to 13 months, largely due to late diagnosis.[1] 21 Several strategies have been explored to screen the population at high risk for developing 22 MPM.[31, 32] The ideal biomarker-based screening test should be concomitantly highly sensitive and 23 specific (highly accurate), preferably non-invasive, easily accessible and also cost effective. While both 24 sensitivity and specificity are essential elements of an effective screening test, sensitivity has higher 25 priority to ensure the lowest false negative rate. While there are currently no accurate evidence-based cut 26 off values, based on MPM incidence rate, a minimum sensitivity of 85% with a concurrent specificity of 27 75-80% is desired. Imaging modalities are non-specific in differentiating between MPM and benign 28 pleural pathologies, and CT screening trials for the disease have been disappointing.[33] There is a 29 critical need for a sensitive and specific non-invasive screening method of high risk, asbestos-exposed 30 populations in order to potentially diagnose and treat mesothelioma at earlier stages. In the absence of 31 strong and reliable noninvasive diagnostic tests, currently, pleural biopsy remains the only standard 32 diagnostic method for MPM, associated with considerable morbidity and costs.[34] The complication rate 33 and morbidity associated with pleural biopsy depends on various patient and procedure related factors. 34 The total complication rate is around 20%, with major morbidities including pneumothorax requiring 35 chest tube placement and hemorrhage being 7.3% and 2.8%, respectively. [35] Similarly, costs depend on 36 the procedure utilized to attain the specimen (Thoracoscopic surgery versus transthoracic imaging guided 37 biopsy) and the potential hospital stay associated with each procedure. In one study with approximately 38 9,000 patients, the average cost of lung biopsy was $3,784, with a mean overall healthcare costs of 39 $14,634 per patient (the average cost of a lung biopsy with complications was $37,745, observed in 40 19.3% of patients with biopsies.)[36] Although certain imaging modalities and blood tests can be used as 41 helpful adjuncts, they lack sufficient sensitivity or specificity to be utilized as solitary tests. Moreover, 42 accurate biomarker prognostication could potentially spare MPM patients from having potentially morbid 43 resections for disease with a high propensity for early recurrence. 44 Given that MPM is a relatively rare malignancy with a low incidence rate, majority of which 45 occurs in the high risk asbestos-exposed population, the role of screening the general population is 46 currently unclear. While at this time it is unlikely that it would yield in significantly higher rate of early 47 diagnosis to potentially improve the overall survival, this topic needs to be viewed in the context of 48 accuracy, availability and cost effectiveness of the test/tests utilized 49 50 51 3 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 22, 2020; DOI: 10.1158/1055-9965.EPI-20-0083 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 2 Materials and Methods 3 4 Role of the EDRN 5 The contributions of the EDRN in the investigation of diagnostic and prognostic biomarkers for 6 mesothelioma cannot be overstated. The first Biomarker Discovery Laboratory at NYU Langone Medical 7 Center specifically devoted to MPM was funded in 2005, and this was facilitated through the EDRN 8 Associate Membership Program in 2003-2004.
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