- Email: [email protected]
Malignant Mesothelioma Biomarkers
Accepted Manuscript Malignant mesothelioma biomarkers – from discovery to use in clinical practise for diagnosis, monitoring, screening and treatment Jenette Creaney, PhD, Bruce W.S. Robinson, MBBS, FRACP, MD PII:
S0012-3692(16)62593-X
DOI:
10.1016/j.chest.2016.12.004
Reference:
CHEST 870
To appear in:
CHEST
Received Date: 30 August 2016 Revised Date:
22 November 2016
Accepted Date: 8 December 2016
Please cite this article as: Creaney J, Robinson BWS, Malignant mesothelioma biomarkers – from discovery to use in clinical practise for diagnosis, monitoring, screening and treatment, CHEST (2017), doi: 10.1016/j.chest.2016.12.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Malignant mesothelioma biomarkers – from discovery to use in clinical practise for diagnosis, monitoring, screening and treatment.
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Jenette Creaney, PhD, [email protected], National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western
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Australia, Australia and Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
Bruce W. S. Robinson, MBBS, FRACP, MD, [email protected], National Centre for
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Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia and Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
Corresponding Author: Prof. Jenette Creaney, [email protected]; School of Medicine
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Australia.
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and Pharmacology, M503, QQ Block, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009,
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The authors have no conflict of interest to disclose.
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Abstract
Malignant pleural mesothelioma is a highly aggressive tumour associated with asbestos exposure. There are few effective treatment options for mesothelioma and patients have a very poor prognosis with a median survival of less than 12 months from diagnosis. Biomarkers have been proposed as a
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cost-effective means of cancer management and the search for a mesothelioma biomarker has been on-going for the past thirty years. Many traditional soluble (glyco)-protein biomarkers have been evaluated over this time and an ever increasing list of new biomarkers, including mRNA, DNA,
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miRNA and antibodies, are being reported from biomarker discovery projects. To date, soluble mesothelin is the only tumour biomarker to receive FDA approval for clinical use in mesothelioma.
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Mesothelin is a glycoprotein normally expressed on the surface of mesothelial cells, and in the cancerous state can be present in the circulation. Mesothelin has a limited expression on normal, non-malignant tissue and is thus an attractive therapeutic target for mesothelin-positive tumours. In this review we will focus on the discovery and clinical usages of mesothelin and provide an update on other mesothelioma biomarkers and show how such biomarker studies might impact on the
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management of this deadly tumour in the future.
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Introduction
Malignant pleural mesothelioma is a highly aggressive tumour commonly associated with asbestos exposure. There are >15,000 cases worldwide and there is real concern that unregulated asbestos use in Asia will see the number of cases significantly increase (1). Clinical management of
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mesothelioma for the majority of patients is largely palliative and based on combination cisplatin and pemetrexed chemotherapy. Recent randomized trial results suggest that bevacizumab may be considered an alternative first line treatment option, but as yet this not been routinely clinically
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adopted (2). A selective, subset of patients with good performance indicators may undergo cytoreductive procedures with curative intent as part of a multimodality approach with
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chemotherapy and radiotherapy, although debulking pleurectomy is sometimes performed with palliative intent for symptom control (2). New therapies are currently being actively explored for this cancer including immunotherapeutic approaches.
Biomarkers, have been proposed as a cost-effective means of cancer management and the search for
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a mesothelioma biomarker has been on-going for the past thirty years. In an appropriate clinical setting tumour biomarkers can play a meaningful role in diagnosis, prognosis, predicting treatment
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responses, monitoring response, as well as screening for the early detection of disease. Many traditional, soluble (glyco)-protein biomarkers have been evaluated in mesothelioma over this time,
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mostly in a case:control setting as diagnostic or screening markers. More recently, through highthroughput biomarker discovery programmes, an ever increasing list of new biomarkers, including mRNA, DNA, miRNA and antibody targets, are being proposed for mesothelioma. This list in general requires further follow-up studies. In the current review we will focus on the discovery and clinical usages of soluble mesothelin which is one of the few blood-based biomarkers to receive US Food and Drug Administration (FDA) approval for clinical use in cancer (3). With the advent of targeted therapy, based on a patient’s individual tumour characteristics, as well as the rapid progress in immunotherapy for mesothelioma treatment, there will be a requirement to extend biomarker 3
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discovery and validation in the future to an individualized approach in order to assess a patient’s suitability to these treatments.
Discovery of mesothelin
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Mesothelin was identified as an antigen on the surface of ovarian cancer cells through an elegant series of experiments in the early 1990’s (reviewed in (4)). The mesothelin gene, MSLN, encodes a precursor protein that is subsequently processed into two proteins, mesothelin and megakaryocyte
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potentiating factor (MPF). Mesothelin is a ~40kDa glycoprotein that is attached to the cell surface by a glycosylphosphatidylinositol anchor and is expressed on mesothelioma, ovarian, pancreatic
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and other cancers, with limited expression on normal tissues. Regulation of mesothelin expression is not fully understood, though a role for the wnt/β-catenin pathway has been suggested (5) and promoter methylation has been demonstrated to be one means of controlling expression (6). In some situations mesothelin can be shed from the cell surface through the actions of TNF-α converting
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enzyme and can be detected in the blood (4).
Mesothelin as a biomarker for malignant mesothelioma
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In 1999, the Hellstrom laboratory reported elevated levels of a soluble serum mesothelin related protein (SMRP) in 23 of 30 ovarian cancer patients using a double determinant ELISA assay they
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had developed with antibodies directed against ovarian cancer antigens (7). As mesothelioma is a mesothelin-positive tumour we performed a collaborative study with them and found that 37 out of 44 (87%) mesothelioma patients also had significantly elevated levels of this protein in the serum compared to apparently healthy asbestos-exposed, non-asbestos-exposed controls and clinically relevant controls (8). Subsequent case:control studies from many centres around the world have confirmed that mesothelin is preferentially elevated in the serum of mesothelioma patients with high specificity for mesothelioma (9).
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The assay to quantitate soluble mesothelin was commercialised by Fujirebio Diagnostics and marketed under the name MESOMARK. In 2007, the MESOMARK assay was approved as a Humanitarian Use Device by the US Food and Drug Administration (10) for the monitoring of epithelioid and biphasic mesothelioma using serum as an analyte. The assay was also approved or
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licenced for use in this setting in many other countries including Australia.
Diagnostics
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None of the FDA approved circulating protein cancer biomarkers are recommended in practise guidelines for cancer diagnosis (11). However, some are used as diagnostic aids in symptomatic
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individuals whereby an elevated level increases the level of suspicion of disease and the need for invasive tissue acquisition steps at an earlier time than otherwise indicated. Prostate specific antigen (PSA), for instance, is a well-known biomarker for prostate cancer, though considerable controversy surrounds its use. PSA can be elevated in individuals with benign prostate enlargement and prostate inflammation and thus lacks specificity for the malignant condition, which has been
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reported to lead to unnecessary biopsies or other invasive procedures (12, 13). This is not the case for mesothelin, which exhibits a high level of specificity relative to benign pleural and pulmonary
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conditions (8), although renal impairment has been shown to elevate serum mesothelin in the absence of malignancy (14). Thus in the absence of renal disease an elevated mesothelin finding
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raises the suspicion of malignancy.
Elevated pleural fluid levels of mesothelin can also be useful in the clinical setting of an individual who is at risk of mesothelioma who presents with a pleural effusion. Elevated soluble mesothelin is more sensitive when measured in the effusion, rather than the serum. In several studies on consecutive series of patients presenting with pleural effusions being investigated for malignancy by cytological examination, it was shown that effusion mesothelin could be clinically useful (1518). In the context of an effusion being reported as being either suspicious of malignancy, atypical, 5
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non-malignant or non-diagnostic, elevated mesothelin had a positive predictive value of over 57% (Table 1), which should prompt further clinical investigation of the patient rather than observation alone. Curiously, effusion mesothelin appears to have specificity for malignancy in general, rarely being positive in benign conditions. This is not the case for other markers such as CA125 which has
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previously been proposed as a marker for effusions. Thus effusion mesothelin has a clinical management role in patients with pleural effusion where malignancy is one of the differential
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diagnoses.
Approximately 10% of mesothelioma cases can occur in the peritoneal cavity, such cases are
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frequently associated with production of serous effusion. To date, only a limited number of studies have examined biomarkers in malignant peritoneal mesothelioma, and most of those have consisted of a small number of peritoneal cases within a larger cohort of pleural cases. From the limited data available it appears that elevated mesothelin concentration in ascites of mesothelioma patients are
Monitoring
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also indicative of malignancy (19).
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Most FDA approved circulating cancer biomarkers are used for monitoring therapeutic response to treatment, particularly for early detection of relapse so that a new treatment strategy can be pursued.
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Several studies have indicated that mesothelin is useful as a monitoring biomarker. Various treatments have resulted in a decrease in serum mesothelin level that was associated with treatment response, tumour shrinkage, or survival (Table 2). Our own study found that, in addition to treatment related reduction in mesothelin level being predictive of survival, a greater number of patients could be evaluated using the biomarker than could be evaluated by radiological methods (20). Unfortunately, clinical utility is not universal because even with advanced stage disease there are mesothelioma patients in whom serum mesothelin is not detectable. The clinical reality of mesothelioma’s progression and the limited treatment options available has meant that mesothelin 6
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has not been widely adopted as a monitoring tool, with clinicians relying primarily upon imaging such as computed tomography (CT) and positron emission tomography (PET). However, the characteristic morphology of mesothelioma, which usually forms a rind surrounding the lung rather than having a classical spheroid shape, presents significant quantitative difficulties for tumour
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treatment response measurement. Furthermore, quantitating response to immunotherapies by imaging can be confounded by the infiltration of tumour by immune cells, which appears as ‘pseudo-progression’ before effective tumour reduction can be observed. Clinical adoption of
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tumour biomarkers for mesothelioma, including mesothelin, warrants further study in order to extend their usefulness. For example, monitoring the response of mesothelioma to therapies and
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guiding therapeutic decisions, including identification of ineffective toxic therapies much earlier and identification of effective therapies warrants further study.
Screening
Great interest in biomarker research centres on their potential use in screening for the early
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detection of cancer. In principal, mesothelioma is a cancer that is amenable to early screening for a number of reasons. Firstly, high risk individuals can be readily identified as a result of their level of
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asbestos exposure and individuals can therefore be identified as being at risk from, for example, their occupational asbestos exposure history. Mesothelioma is a localised, non-metastatic cancer in
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its early stages and is therefore potentially curable if detected at an early stage. It is therefore logical to search for a suitable biomarker so that early intervention therapeutic strategies can be tested. Whilst retrospective studies have been encouraging (22), several prospective studies have shown that monitoring serum mesothelin levels in asbestos exposed cohorts shows false positive rates above 90% and thus does not assist in the early detection of mesothelioma (23). The combination of a low sensitivity and low pre-test probability is likely to result in a falsely high positive rate (2428), with associated unnecessary procedures and subjective anxiety, as previously seen when CA125 was used alone in screening for ovarian cancer (29). 7
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four to ten years prior to clinical diagnosis of mesothelioma (30). This is an exciting preliminary finding that, in common with all new potential biomarkers at the discovery stage, requires extensive validation. If the potential of ENOX2 as an early mesothelioma biomarker is realized and a suitable
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high-throughput screening assay becomes available, the ability to diagnose mesothelioma before clinical symptoms are present in at-risk individuals will be realized. This will have the potential to
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increase the efficacy of the treatment options for mesothelioma that are available, or may become available, in the future.
Treatment
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The limited expression of mesothelin on normal tissues has provided the impetus to test mesothelin as a target for immune-based therapies in mesothelioma and other tumour types with high mesothelin expression such as pancreatic and ovarian cancers. Several Phase I clinical studies have been performed to determine safety and dose of the anti-mesothelin immunotoxin, SS1P and also of
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a chimeric anti-mesothelin antibody construct, MORAb-009 (amatuximab) (4). Issues arose with both strategies with patients developing anti-SS1P or anti-MORAb009 neutralising antibodies that
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may have limited efficacy. Currently, strategies are being trialled to mitigate these autoantibody responses.
The efficacy of several other mesothelin-directed treatment approaches are being investigated including of mesothelin antibody-drug conjugates (anetumab ravtansine), vaccines and chimeric antigen receptors (CAR) (4). Anetumab ravtansine consists of a human anti-mesothelin antibody coupled to a microtubule-targeting esterified maytansinol (DM4); in preclinical studies efficacy has been demonstrated in mesothelioma, pancreatic and ovarian cancer patient-derived xenografts (31). A phase II trial is underway comparing antumab ravansine against vinorelbine in a second line setting in mesothelioma patients. A live-attenuated strain of Listeria which expresses human mesothelin has been developed as a vaccine. So far minimal toxicity has been reported (32) and the 8
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results of a clinical trial of the vaccine in mesothelioma patients used in combination with standard of care chemotherapy are expected by early next year. Another approach being investigated is the adoptive transfer of anti-mesothelin CAR T cells as a means of directly targeting mesothelinexpressing tumour cells. Efficacy has been demonstrated in preclinical in vitro and in vivo studies (33). Several clinical trials are reportedly ongoing that are examining various different preparations of mesothelin targeted T cells at clinicaltrials.gov (accessed 1/8/2016). Several dramatic clinical
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responses have been demonstrated in patients with advanced mesothelioma using these approaches (34) and the results of current trials are eagerly awaited.
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Other biomarkers
Hyaluronic acid has been shown in studies going back to the 1980’s to be elevated in mesothelioma
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associated pleural effusions (35). The technical expertise previously required to measure hyaluronic acid by high performance liquid chromatography may have limited the number of follow-up studies into this biomarker. However, recent studies using a more user-friendly assay system have shown that mesothelin and hyaluronic acid levels in effusion have similar diagnostic accuracy (36) and that by combining the two markers in a two-step model diagnostic accuracy can be improved (37).
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Guidelines for cytological diagnosis of mesothelioma recommend the use of ancillary tests in addition to traditional morphology analysis which may include hyaluronic acid and mesothelin
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effusion biomarkers (38).
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MPF, the N-terminal fragment of the mesothelin gene product (also referred to as NERC/mesothelin) appears to have a similar profile of expression to mesothelin. And several studies have reported similar diagnostic accuracy and monitoring results with the two markers (39, 40). However, it is unlikely from a commercial point of view that, with the presently available data, MPF would be pursued as a clinical biomarker for mesothelioma.
Various other potential biomarkers have been reported for mesothelioma, some with very high reported diagnostic accuracy including a 13-component aptamer panel (41), fibulin-3 (42) and an 9
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autoantibody biomarker panel (43). Unfortunately, the high diagnostic accuracy of fibulin-3 has not been subsequently validated in independent studies (44), and independent validation studies for the aptamer and autoantibody panel have not been reported. Other studies have explored the use of biomarker panels, particularly combining different markers with mesothelin as a means of
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improving disease predictive power in a diagnostic setting. One promising study found combining mesothelin with mir103a-3p increases diagnostic performance and the authors suggest that this improvement may be due in part to the combination of different molecular classes of biomarkers
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(45).
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Several studies have evaluated the clinical utility of osteopontin as a mesothelioma biomarker. Osteopontin lacks the specificity to be a diagnostic aid, but levels may reflect inflammatory and wound healing status. Indeed several studies have shown that osteopontin levels have prognostic and/or predictive value, but as yet this work has not seen significant clinical translation.
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These and other reported biomarkers offer promise for future mesothelioma screening, diagnosis, and monitoring, however further investigations are needed to support the original findings and
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Conclusion
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demonstrate clinical utility.
Mesothelin remains one of the most promising biomarkers for malignant mesothelioma diagnosis and monitoring, however, low sensitivity limits its utility as a screening tool. If results from clinical trials targeting tumours expressing mesothelin bear fruit then the promise, in terms of the sought after precision medicine goal, of having a diagnostic test to guide therapy could be soon realised. New biomarkers for mesothelioma are being actively investigated, but without validation studies clinical adoption is unlikely in the near future. Many new mesothelioma biomarker candidates that are reported are not evaluated beyond the discovery phase, therefore the potential of these 10
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biomarkers as diagnostic or monitoring tools remains unfulfilled. However, the promise of new therapeutic approaches that could significantly improve treatment outcomes for mesothelioma may
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spur a resurgence of interest in the use of biomarkers in this disease.
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Table 1:
Davies et al. 2009 (15)
Oxford Centre for Respiratory Medicine, Oxford, UK North Bristol Lung Centre, Bristol, UK Division of Pneumology, La Spezia, Italy PathWest diagnostic laboratory, Perth Australia
166 consecutive patients with possible malignant PE Non diagnostic/ non-malignant 206 consecutive Atypical patients with a new undiagnosed PE Non-diagnostic 275 consecutive Undiagnosed patients with undiagnosed PE 1331 consecutive Atypical/ patients with possible suspicious malignant PE Non-diagnostic/ non-malignant
Hooper et al. 2013 (16) Canessa et al. 2013 (17)
a
Total No. 11 94
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Creaney et al. 2014 (18)
Cytological analysis Atypical
No. MM 8
Sensa % 63
Spec %
NPV %
PPV %
100
50
100
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Study cohort
7
57
97
97
57
26
13
73
70
70
73
148 NRb
15 NR
64 76
96 94
96 NR
69 NR
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Study setting
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Study
81
34
62
98
78
95
855
43
44
99
97
65
Sensitivity, specificity negative predictive value (NPV) and positive predictive value as reported by authors, note that different threshold cut-off
NR – not reported
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b
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values were used in different studies. Davies et al, Hooper et al., and Creaney et al., used a 20nM cut-off, whilst Canessa et al. used a 9.3 nM cut off.
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Table 2: Studies reporting the use of mesothelin for monitoring response in treated patients Study
Treatmenta
Grigoriu et al., 2009 (46)
various (CT ± RT and surgery; or BSC; or clinical trial with gene transfer Ad.huIFN-β)
Wheatley-Price et al., 2010 (47)
various (CT; surgery; or BSC; or clinical trial with biological therapy) various (CT; RT; surgery; or BSC)
41
A 10% change in mesothelin correlated with radiological response (n=21) (p<0.001)
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Change in mesothelin correlated with radiological response in chemotherapy treated patients (n=55) (p=0.023)
Hollevoet et al., 2011 (39)
various (CT; or multimodality)
62
Significant association between best overall response to chemotherapy (n=57) and 15% change in mesothelin (p<0.001).
Nowak et al., 2013 (48)
clinical trial (biological agent)
30
Hassan et al., 2014 (49) Hooper et al., 2015 (50)
clinical trial (biological agent) CT
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Significant correlation between change in tumour measurement (n=27) and change in mesothelin (p=0.012). Radiological response significantly associated with reduction in mesothelin (n=20; p=0.003) not reported
Correlation of change in mesothelin levels with survival * Subgroup analysis Significantly shorter survival for patients with 10% increase in baseline mesothelin levels: median survival -increasing mesothelin group - 4.4 months (n=10) -decreasing group - 28 months (n=7) (p=0.012) not reported
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* In majority of cases with progressive disease (n=16) mesothelin increases over time; * In majority of cases with stable disease or a partial response (n=9) mesothelin decreases
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Summary results with response to treatment
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Creaney et al., 2011 (20)
Study cohort 40
a – CT – chemotherapy; RT – radiotherapy; BSC – best supportive care * for cases where baseline mesothelin levels >1nM
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Significantly longer median survival for patients with reduction in mesothelin following chemotherapy (19 months) compare to patients with increased mesothelin (5 months; p<0.001) not reported
not reported
not reported significant longer median survival for patients with reduction mesothelin following chemotherapy (481 days) compared to increased mesothelin (293 days) (p=0.031)
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1. Leong SL, Zainudin R, Kazan-Allen L, Robinson BW. Asbestos in Asia. Respirology. 2015;20(4):548-55. 2. Kondola S, Manners D, Nowak AK. Malignant pleural mesothelioma: an update on diagnosis and treatment options. Therapeutic advances in respiratory disease. 2016;10(3):275-88. 3. Pavlou MP, Diamandis EP. Validation of candidate protein biomarkers. In: Ginsburg GS, Willard HF, editors. Genomic and personalized medicine. 1. 2nd ed. London: Elsevier; 2013. p. 263-70. 4. Pastan I, Hassan R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 2014;74(11):2907-12. 5. Prieve MG, Moon RT. Stromelysin-1 and mesothelin are differentially regulated by Wnt-5a and Wnt-1 in C57mg mouse mammary epithelial cells. BMC developmental biology. 2003;3:2. 6. Hollevoet K, Mason-Osann E, Muller F, Pastan I. Methylation-associated partial downregulation of mesothelin causes resistance to anti-mesothelin immunotoxins in a pancreatic cancer cell line. PLoS One. 2015;10(3):e0122462. 7. Scholler N, Fu N, Yang Y, Ye Z, Goodman GE, Hellstrom KE, et al. Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. Proc Natl Acad Sci U S A. 1999;96(20):11531-6. 8. Robinson BW, Creaney J, Lake R, Nowak A, Musk AW, de Klerk N, et al. Mesothelinfamily proteins and diagnosis of mesothelioma. Lancet. 2003;362(9396):1612-6. 9. Hollevoet K, Reitsma JB, Creaney J, Grigoriu BD, Robinson BW, Scherpereel A, et al. Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data metaanalysis. J Clin Oncol. 2012;30(13):1541-9. 10. Li ZQ, Verch T, Allard WJ. MESOMARK((R)) in vitro diagnostic test for mesothelioma. Expert opinion on medical diagnostics. 2007;1(1):137-42. 11. Pavlou MP, Diamandis EP, Blasutig IM. The long journey of cancer biomarkers from the bench to the clinic. Clin Chem. 2013;59(1):147-57. 12. Andriole GL, Crawford ED, Grubb RL, 3rd, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310-9. 13. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-8. 14. Boudville N, Paul R, Robinson BW, Creaney J. Mesothelin and kidney function--analysis of relationship and implications for mesothelioma screening. Lung Cancer. 2011;73(3):320-4. 15. Davies HE, Sadler RS, Bielsa S, Maskell NA, Rahman NM, Davies RJ, et al. Clinical impact and reliability of pleural fluid mesothelin in undiagnosed pleural effusions. Am J Respir Crit Care Med. 2009;180(5):437-44. 16. Hooper CE, Morley AJ, Virgo P, Harvey JE, Kahan B, Maskell NA. A prospective trial evaluating the role of mesothelin in undiagnosed pleural effusions. Eur Respir J. 2013;41(1):18-24. 17. Canessa PA, Franceschini MC, Ferro P, Battolla E, Dessanti P, Manta C, et al. Evaluation of soluble mesothelin-related peptide as a diagnostic marker of malignant pleural mesothelioma effusions: its contribution to cytology. Cancer Invest. 2013;31(1):43-50. 18. Creaney J, Segal A, Olsen N, Dick IM, Musk AW, Skates SJ, et al. Pleural fluid mesothelin as an adjunct to the diagnosis of pleural malignant mesothelioma. Dis Markers. 2014;2014:413946. 19. Creaney J, Yeoman D, Naumoff LK, Hof M, Segal A, Musk AW, et al. Soluble mesothelin in effusions: a useful tool for the diagnosis of malignant mesothelioma. Thorax. 2007;62(7):569-76. 20. Creaney J, Francis RJ, Dick IM, Musk AW, Robinson BW, Byrne MJ, et al. Serum soluble mesothelin concentrations in malignant pleural mesothelioma: relationship to tumor volume, clinical stage and changes in tumor burden. Clin Cancer Res. 2011;17(5):1181-9. 21. Robinson C, Walsh A, Larma I, O'Halloran S, Nowak AK, Lake RA. MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma. Eur J Cancer. 2011;47(1):151-61. 14
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22. Creaney J, Olsen NJ, Brims F, Dick IM, Musk AW, de Klerk NH, et al. Serum mesothelin for early detection of asbestos-induced cancer malignant mesothelioma. Cancer Epidemiol Biomarkers Prev. 2010;19(9):2238-46. 23. Dick I, Creaney J. Serum biomarkers in malignant pleural mesothelioma. In: Mineo TC, editor. Malignant Pleural Mesothelioma: Present Status and Future Directions: Bentham Sscience Publishers; 2015. p. 251-60. 24. Park EK, Sandrini A, Yates DH, Creaney J, Robinson BW, Thomas PS, et al. Soluble mesothelin-related protein in an asbestos-exposed population: the dust diseases board cohort study. Am J Respir Crit Care Med. 2008;178(8):832-7. 25. Hollevoet K, Van Cleemput J, Thimpont J, De Vuyst P, Bosquee L, Nackaerts K, et al. Serial measurements of mesothelioma serum biomarkers in asbestos-exposed individuals: a prospective longitudinal cohort study. J Thorac Oncol. 2011;6(5):889-95. 26. Gube M, Taeger D, Weber DG, Pesch B, Brand P, Johnen G, et al. Performance of biomarkers SMRP, CA125, and CYFRA 21-1 as potential tumor markers for malignant mesothelioma and lung cancer in a cohort of workers formerly exposed to asbestos. Arch Toxicol. 2011;85(3):185-92. 27. Felten MK, Khatab K, Knoll L, Schettgen T, Muller-Berndorff H, Kraus T. Changes of mesothelin and osteopontin levels over time in formerly asbestos-exposed power industry workers. International archives of occupational and environmental health. 2014;87(2):195-204. 28. Filiberti R, Marroni P, Spigno F, Merlo DF, Mortara V, Caruso P, et al. Is soluble mesothelin-related protein an upfront predictive marker of pleural mesothelioma? A prospective study on Italian workers exposed to asbestos. Oncology. 2014;86(1):33-43. 29. Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brunner N, Chan DW, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008;54(12):e1179. 30. Morre DJ, Hostetler B, Taggart DJ, Morre DM, Musk AW, Robinson BW, et al. ENOX2based early detection (ONCOblot) of asbestos-induced malignant mesothelioma 4-10 years in advance of clinical symptoms. Clinical proteomics. 2016;13:2. 31. Golfier S, Kopitz C, Kahnert A, Heisler I, Schatz CA, Stelte-Ludwig B, et al. Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther. 2014;13(6):1537-48. 32. Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325-33. 33. Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E, Plotkin J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014;6(261):261ra151. 34. Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, et al. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med. 2013;5(208):208ra147. 35. Dahl IM, Solheim OP, Erikstein B, Muller E. A longitudinal study of the hyaluronan level in the serum of patients with malignant mesothelioma under treatment. Hyaluronan as an indicator of progressive disease. Cancer. 1989;64(1):68-73. 36. Creaney J, Dick IM, Segal A, Musk AW, Robinson BW. Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma. Lung Cancer. 2013;82(3):491-8. 37. Mundt F, Nilsonne G, Arslan S, Csuros K, Hillerdal G, Yildirim H, et al. Hyaluronan and NERC/mesothelin as key biomarkers in a specific two-step model to predict pleural malignant mesothelioma. PLoS One. 2013;8(8):e72030. 38. Hjerpe A, Ascoli V, Bedrossian CW, Boon ME, Creaney J, Davidson B, et al. Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma: Complementary Statement from the International Mesothelioma Interest Group, Also Endorsed by 15
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the International Academy of Cytology and the Papanicolaou Society of Cytopathology. Diagn Cytopathol. 2015;43(7):563-76. 39. Hollevoet K, Nackaerts K, Gosselin R, De Wever W, Bosquee L, De Vuyst P, et al. Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma. J Thorac Oncol. 2011;6(11):1930-7. 40. Hollevoet K, Nackaerts K, Thas O, Thimpont J, Germonpre P, De Vuyst P, et al. The effect of clinical covariates on the diagnostic and prognostic value of soluble mesothelin and megakaryocyte potentiating factor. Chest. 2012;141(2):477-84. 41. Ostroff RM, Mehan MR, Stewart A, Ayers D, Brody EN, Williams SA, et al. Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool. PLoS One. 2012;7(10):e46091. 42. Pass HI, Levin SM, Harbut MR, Melamed J, Chiriboga L, Donington J, et al. Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma. N Engl J Med. 2012;367(15):1417-27. 43. Zhang X, Shen W, Dong X, Fan J, Liu L, Gao X, et al. Identification of novel autoantibodies for detection of malignant mesothelioma. PLoS One. 2013;8(8):e72458. 44. Creaney J, Dick IM, Meniawy TM, Leong SL, Leon JS, Demelker Y, et al. Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma. Thorax. 2014;69(10):895-902. 45. Weber DG, Casjens S, Johnen G, Bryk O, Raiko I, Pesch B, et al. Combination of MiR103a-3p and mesothelin improves the biomarker performance of malignant mesothelioma diagnosis. PLoS One. 2014;9(12):e114483. 46. Grigoriu BD, Chahine B, Vachani A, Gey T, Conti M, Sterman DH, et al. Kinetics of soluble mesothelin in patients with malignant pleural mesothelioma during treatment. Am J Respir Crit Care Med. 2009;179(10):950-4. 47. Wheatley-Price P, Yang B, Patsios D, Patel D, Ma C, Xu W, et al. Soluble mesothelinrelated Peptide and osteopontin as markers of response in malignant mesothelioma. J Clin Oncol. 2010;28(20):3316-22. 48. Nowak AK, Brown C, Millward MJ, Creaney J, Byrne MJ, Hughes B, et al. A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma. Lung Cancer. 2013;81(3):422-7. 49. Hassan R, Sharon E, Thomas A, Zhang J, Ling A, Miettinen M, et al. Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. Cancer. 2014;120(21):3311-9. 50. Hooper CE, Lyburn ID, Searle J, Darby M, Hall T, Hall D, et al. The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication. Br J Cancer. 2015;112(7):1175-82.
16
S0012-3692(16)62593-X
DOI:
10.1016/j.chest.2016.12.004
Reference:
CHEST 870
To appear in:
CHEST
Received Date: 30 August 2016 Revised Date:
22 November 2016
Accepted Date: 8 December 2016
Please cite this article as: Creaney J, Robinson BWS, Malignant mesothelioma biomarkers – from discovery to use in clinical practise for diagnosis, monitoring, screening and treatment, CHEST (2017), doi: 10.1016/j.chest.2016.12.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Malignant mesothelioma biomarkers – from discovery to use in clinical practise for diagnosis, monitoring, screening and treatment.
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Jenette Creaney, PhD, [email protected], National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western
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Australia, Australia and Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
Bruce W. S. Robinson, MBBS, FRACP, MD, [email protected], National Centre for
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Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia and Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
Corresponding Author: Prof. Jenette Creaney, [email protected]; School of Medicine
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Australia.
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and Pharmacology, M503, QQ Block, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009,
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The authors have no conflict of interest to disclose.
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Abstract
Malignant pleural mesothelioma is a highly aggressive tumour associated with asbestos exposure. There are few effective treatment options for mesothelioma and patients have a very poor prognosis with a median survival of less than 12 months from diagnosis. Biomarkers have been proposed as a
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cost-effective means of cancer management and the search for a mesothelioma biomarker has been on-going for the past thirty years. Many traditional soluble (glyco)-protein biomarkers have been evaluated over this time and an ever increasing list of new biomarkers, including mRNA, DNA,
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miRNA and antibodies, are being reported from biomarker discovery projects. To date, soluble mesothelin is the only tumour biomarker to receive FDA approval for clinical use in mesothelioma.
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Mesothelin is a glycoprotein normally expressed on the surface of mesothelial cells, and in the cancerous state can be present in the circulation. Mesothelin has a limited expression on normal, non-malignant tissue and is thus an attractive therapeutic target for mesothelin-positive tumours. In this review we will focus on the discovery and clinical usages of mesothelin and provide an update on other mesothelioma biomarkers and show how such biomarker studies might impact on the
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management of this deadly tumour in the future.
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Introduction
Malignant pleural mesothelioma is a highly aggressive tumour commonly associated with asbestos exposure. There are >15,000 cases worldwide and there is real concern that unregulated asbestos use in Asia will see the number of cases significantly increase (1). Clinical management of
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mesothelioma for the majority of patients is largely palliative and based on combination cisplatin and pemetrexed chemotherapy. Recent randomized trial results suggest that bevacizumab may be considered an alternative first line treatment option, but as yet this not been routinely clinically
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adopted (2). A selective, subset of patients with good performance indicators may undergo cytoreductive procedures with curative intent as part of a multimodality approach with
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chemotherapy and radiotherapy, although debulking pleurectomy is sometimes performed with palliative intent for symptom control (2). New therapies are currently being actively explored for this cancer including immunotherapeutic approaches.
Biomarkers, have been proposed as a cost-effective means of cancer management and the search for
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a mesothelioma biomarker has been on-going for the past thirty years. In an appropriate clinical setting tumour biomarkers can play a meaningful role in diagnosis, prognosis, predicting treatment
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responses, monitoring response, as well as screening for the early detection of disease. Many traditional, soluble (glyco)-protein biomarkers have been evaluated in mesothelioma over this time,
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mostly in a case:control setting as diagnostic or screening markers. More recently, through highthroughput biomarker discovery programmes, an ever increasing list of new biomarkers, including mRNA, DNA, miRNA and antibody targets, are being proposed for mesothelioma. This list in general requires further follow-up studies. In the current review we will focus on the discovery and clinical usages of soluble mesothelin which is one of the few blood-based biomarkers to receive US Food and Drug Administration (FDA) approval for clinical use in cancer (3). With the advent of targeted therapy, based on a patient’s individual tumour characteristics, as well as the rapid progress in immunotherapy for mesothelioma treatment, there will be a requirement to extend biomarker 3
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discovery and validation in the future to an individualized approach in order to assess a patient’s suitability to these treatments.
Discovery of mesothelin
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Mesothelin was identified as an antigen on the surface of ovarian cancer cells through an elegant series of experiments in the early 1990’s (reviewed in (4)). The mesothelin gene, MSLN, encodes a precursor protein that is subsequently processed into two proteins, mesothelin and megakaryocyte
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potentiating factor (MPF). Mesothelin is a ~40kDa glycoprotein that is attached to the cell surface by a glycosylphosphatidylinositol anchor and is expressed on mesothelioma, ovarian, pancreatic
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and other cancers, with limited expression on normal tissues. Regulation of mesothelin expression is not fully understood, though a role for the wnt/β-catenin pathway has been suggested (5) and promoter methylation has been demonstrated to be one means of controlling expression (6). In some situations mesothelin can be shed from the cell surface through the actions of TNF-α converting
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enzyme and can be detected in the blood (4).
Mesothelin as a biomarker for malignant mesothelioma
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In 1999, the Hellstrom laboratory reported elevated levels of a soluble serum mesothelin related protein (SMRP) in 23 of 30 ovarian cancer patients using a double determinant ELISA assay they
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had developed with antibodies directed against ovarian cancer antigens (7). As mesothelioma is a mesothelin-positive tumour we performed a collaborative study with them and found that 37 out of 44 (87%) mesothelioma patients also had significantly elevated levels of this protein in the serum compared to apparently healthy asbestos-exposed, non-asbestos-exposed controls and clinically relevant controls (8). Subsequent case:control studies from many centres around the world have confirmed that mesothelin is preferentially elevated in the serum of mesothelioma patients with high specificity for mesothelioma (9).
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The assay to quantitate soluble mesothelin was commercialised by Fujirebio Diagnostics and marketed under the name MESOMARK. In 2007, the MESOMARK assay was approved as a Humanitarian Use Device by the US Food and Drug Administration (10) for the monitoring of epithelioid and biphasic mesothelioma using serum as an analyte. The assay was also approved or
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licenced for use in this setting in many other countries including Australia.
Diagnostics
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None of the FDA approved circulating protein cancer biomarkers are recommended in practise guidelines for cancer diagnosis (11). However, some are used as diagnostic aids in symptomatic
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individuals whereby an elevated level increases the level of suspicion of disease and the need for invasive tissue acquisition steps at an earlier time than otherwise indicated. Prostate specific antigen (PSA), for instance, is a well-known biomarker for prostate cancer, though considerable controversy surrounds its use. PSA can be elevated in individuals with benign prostate enlargement and prostate inflammation and thus lacks specificity for the malignant condition, which has been
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reported to lead to unnecessary biopsies or other invasive procedures (12, 13). This is not the case for mesothelin, which exhibits a high level of specificity relative to benign pleural and pulmonary
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conditions (8), although renal impairment has been shown to elevate serum mesothelin in the absence of malignancy (14). Thus in the absence of renal disease an elevated mesothelin finding
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raises the suspicion of malignancy.
Elevated pleural fluid levels of mesothelin can also be useful in the clinical setting of an individual who is at risk of mesothelioma who presents with a pleural effusion. Elevated soluble mesothelin is more sensitive when measured in the effusion, rather than the serum. In several studies on consecutive series of patients presenting with pleural effusions being investigated for malignancy by cytological examination, it was shown that effusion mesothelin could be clinically useful (1518). In the context of an effusion being reported as being either suspicious of malignancy, atypical, 5
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non-malignant or non-diagnostic, elevated mesothelin had a positive predictive value of over 57% (Table 1), which should prompt further clinical investigation of the patient rather than observation alone. Curiously, effusion mesothelin appears to have specificity for malignancy in general, rarely being positive in benign conditions. This is not the case for other markers such as CA125 which has
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previously been proposed as a marker for effusions. Thus effusion mesothelin has a clinical management role in patients with pleural effusion where malignancy is one of the differential
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diagnoses.
Approximately 10% of mesothelioma cases can occur in the peritoneal cavity, such cases are
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frequently associated with production of serous effusion. To date, only a limited number of studies have examined biomarkers in malignant peritoneal mesothelioma, and most of those have consisted of a small number of peritoneal cases within a larger cohort of pleural cases. From the limited data available it appears that elevated mesothelin concentration in ascites of mesothelioma patients are
Monitoring
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also indicative of malignancy (19).
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Most FDA approved circulating cancer biomarkers are used for monitoring therapeutic response to treatment, particularly for early detection of relapse so that a new treatment strategy can be pursued.
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Several studies have indicated that mesothelin is useful as a monitoring biomarker. Various treatments have resulted in a decrease in serum mesothelin level that was associated with treatment response, tumour shrinkage, or survival (Table 2). Our own study found that, in addition to treatment related reduction in mesothelin level being predictive of survival, a greater number of patients could be evaluated using the biomarker than could be evaluated by radiological methods (20). Unfortunately, clinical utility is not universal because even with advanced stage disease there are mesothelioma patients in whom serum mesothelin is not detectable. The clinical reality of mesothelioma’s progression and the limited treatment options available has meant that mesothelin 6
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has not been widely adopted as a monitoring tool, with clinicians relying primarily upon imaging such as computed tomography (CT) and positron emission tomography (PET). However, the characteristic morphology of mesothelioma, which usually forms a rind surrounding the lung rather than having a classical spheroid shape, presents significant quantitative difficulties for tumour
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treatment response measurement. Furthermore, quantitating response to immunotherapies by imaging can be confounded by the infiltration of tumour by immune cells, which appears as ‘pseudo-progression’ before effective tumour reduction can be observed. Clinical adoption of
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tumour biomarkers for mesothelioma, including mesothelin, warrants further study in order to extend their usefulness. For example, monitoring the response of mesothelioma to therapies and
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guiding therapeutic decisions, including identification of ineffective toxic therapies much earlier and identification of effective therapies warrants further study.
Screening
Great interest in biomarker research centres on their potential use in screening for the early
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detection of cancer. In principal, mesothelioma is a cancer that is amenable to early screening for a number of reasons. Firstly, high risk individuals can be readily identified as a result of their level of
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asbestos exposure and individuals can therefore be identified as being at risk from, for example, their occupational asbestos exposure history. Mesothelioma is a localised, non-metastatic cancer in
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its early stages and is therefore potentially curable if detected at an early stage. It is therefore logical to search for a suitable biomarker so that early intervention therapeutic strategies can be tested. Whilst retrospective studies have been encouraging (22), several prospective studies have shown that monitoring serum mesothelin levels in asbestos exposed cohorts shows false positive rates above 90% and thus does not assist in the early detection of mesothelioma (23). The combination of a low sensitivity and low pre-test probability is likely to result in a falsely high positive rate (2428), with associated unnecessary procedures and subjective anxiety, as previously seen when CA125 was used alone in screening for ovarian cancer (29). 7
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four to ten years prior to clinical diagnosis of mesothelioma (30). This is an exciting preliminary finding that, in common with all new potential biomarkers at the discovery stage, requires extensive validation. If the potential of ENOX2 as an early mesothelioma biomarker is realized and a suitable
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high-throughput screening assay becomes available, the ability to diagnose mesothelioma before clinical symptoms are present in at-risk individuals will be realized. This will have the potential to
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increase the efficacy of the treatment options for mesothelioma that are available, or may become available, in the future.
Treatment
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The limited expression of mesothelin on normal tissues has provided the impetus to test mesothelin as a target for immune-based therapies in mesothelioma and other tumour types with high mesothelin expression such as pancreatic and ovarian cancers. Several Phase I clinical studies have been performed to determine safety and dose of the anti-mesothelin immunotoxin, SS1P and also of
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a chimeric anti-mesothelin antibody construct, MORAb-009 (amatuximab) (4). Issues arose with both strategies with patients developing anti-SS1P or anti-MORAb009 neutralising antibodies that
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may have limited efficacy. Currently, strategies are being trialled to mitigate these autoantibody responses.
The efficacy of several other mesothelin-directed treatment approaches are being investigated including of mesothelin antibody-drug conjugates (anetumab ravtansine), vaccines and chimeric antigen receptors (CAR) (4). Anetumab ravtansine consists of a human anti-mesothelin antibody coupled to a microtubule-targeting esterified maytansinol (DM4); in preclinical studies efficacy has been demonstrated in mesothelioma, pancreatic and ovarian cancer patient-derived xenografts (31). A phase II trial is underway comparing antumab ravansine against vinorelbine in a second line setting in mesothelioma patients. A live-attenuated strain of Listeria which expresses human mesothelin has been developed as a vaccine. So far minimal toxicity has been reported (32) and the 8
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results of a clinical trial of the vaccine in mesothelioma patients used in combination with standard of care chemotherapy are expected by early next year. Another approach being investigated is the adoptive transfer of anti-mesothelin CAR T cells as a means of directly targeting mesothelinexpressing tumour cells. Efficacy has been demonstrated in preclinical in vitro and in vivo studies (33). Several clinical trials are reportedly ongoing that are examining various different preparations of mesothelin targeted T cells at clinicaltrials.gov (accessed 1/8/2016). Several dramatic clinical
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responses have been demonstrated in patients with advanced mesothelioma using these approaches (34) and the results of current trials are eagerly awaited.
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Other biomarkers
Hyaluronic acid has been shown in studies going back to the 1980’s to be elevated in mesothelioma
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associated pleural effusions (35). The technical expertise previously required to measure hyaluronic acid by high performance liquid chromatography may have limited the number of follow-up studies into this biomarker. However, recent studies using a more user-friendly assay system have shown that mesothelin and hyaluronic acid levels in effusion have similar diagnostic accuracy (36) and that by combining the two markers in a two-step model diagnostic accuracy can be improved (37).
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Guidelines for cytological diagnosis of mesothelioma recommend the use of ancillary tests in addition to traditional morphology analysis which may include hyaluronic acid and mesothelin
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effusion biomarkers (38).
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MPF, the N-terminal fragment of the mesothelin gene product (also referred to as NERC/mesothelin) appears to have a similar profile of expression to mesothelin. And several studies have reported similar diagnostic accuracy and monitoring results with the two markers (39, 40). However, it is unlikely from a commercial point of view that, with the presently available data, MPF would be pursued as a clinical biomarker for mesothelioma.
Various other potential biomarkers have been reported for mesothelioma, some with very high reported diagnostic accuracy including a 13-component aptamer panel (41), fibulin-3 (42) and an 9
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autoantibody biomarker panel (43). Unfortunately, the high diagnostic accuracy of fibulin-3 has not been subsequently validated in independent studies (44), and independent validation studies for the aptamer and autoantibody panel have not been reported. Other studies have explored the use of biomarker panels, particularly combining different markers with mesothelin as a means of
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improving disease predictive power in a diagnostic setting. One promising study found combining mesothelin with mir103a-3p increases diagnostic performance and the authors suggest that this improvement may be due in part to the combination of different molecular classes of biomarkers
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(45).
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Several studies have evaluated the clinical utility of osteopontin as a mesothelioma biomarker. Osteopontin lacks the specificity to be a diagnostic aid, but levels may reflect inflammatory and wound healing status. Indeed several studies have shown that osteopontin levels have prognostic and/or predictive value, but as yet this work has not seen significant clinical translation.
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These and other reported biomarkers offer promise for future mesothelioma screening, diagnosis, and monitoring, however further investigations are needed to support the original findings and
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Conclusion
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demonstrate clinical utility.
Mesothelin remains one of the most promising biomarkers for malignant mesothelioma diagnosis and monitoring, however, low sensitivity limits its utility as a screening tool. If results from clinical trials targeting tumours expressing mesothelin bear fruit then the promise, in terms of the sought after precision medicine goal, of having a diagnostic test to guide therapy could be soon realised. New biomarkers for mesothelioma are being actively investigated, but without validation studies clinical adoption is unlikely in the near future. Many new mesothelioma biomarker candidates that are reported are not evaluated beyond the discovery phase, therefore the potential of these 10
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biomarkers as diagnostic or monitoring tools remains unfulfilled. However, the promise of new therapeutic approaches that could significantly improve treatment outcomes for mesothelioma may
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spur a resurgence of interest in the use of biomarkers in this disease.
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Table 1:
Davies et al. 2009 (15)
Oxford Centre for Respiratory Medicine, Oxford, UK North Bristol Lung Centre, Bristol, UK Division of Pneumology, La Spezia, Italy PathWest diagnostic laboratory, Perth Australia
166 consecutive patients with possible malignant PE Non diagnostic/ non-malignant 206 consecutive Atypical patients with a new undiagnosed PE Non-diagnostic 275 consecutive Undiagnosed patients with undiagnosed PE 1331 consecutive Atypical/ patients with possible suspicious malignant PE Non-diagnostic/ non-malignant
Hooper et al. 2013 (16) Canessa et al. 2013 (17)
a
Total No. 11 94
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Creaney et al. 2014 (18)
Cytological analysis Atypical
No. MM 8
Sensa % 63
Spec %
NPV %
PPV %
100
50
100
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Study cohort
7
57
97
97
57
26
13
73
70
70
73
148 NRb
15 NR
64 76
96 94
96 NR
69 NR
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Study setting
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Study
81
34
62
98
78
95
855
43
44
99
97
65
Sensitivity, specificity negative predictive value (NPV) and positive predictive value as reported by authors, note that different threshold cut-off
NR – not reported
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b
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values were used in different studies. Davies et al, Hooper et al., and Creaney et al., used a 20nM cut-off, whilst Canessa et al. used a 9.3 nM cut off.
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Table 2: Studies reporting the use of mesothelin for monitoring response in treated patients Study
Treatmenta
Grigoriu et al., 2009 (46)
various (CT ± RT and surgery; or BSC; or clinical trial with gene transfer Ad.huIFN-β)
Wheatley-Price et al., 2010 (47)
various (CT; surgery; or BSC; or clinical trial with biological therapy) various (CT; RT; surgery; or BSC)
41
A 10% change in mesothelin correlated with radiological response (n=21) (p<0.001)
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Change in mesothelin correlated with radiological response in chemotherapy treated patients (n=55) (p=0.023)
Hollevoet et al., 2011 (39)
various (CT; or multimodality)
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Significant association between best overall response to chemotherapy (n=57) and 15% change in mesothelin (p<0.001).
Nowak et al., 2013 (48)
clinical trial (biological agent)
30
Hassan et al., 2014 (49) Hooper et al., 2015 (50)
clinical trial (biological agent) CT
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Significant correlation between change in tumour measurement (n=27) and change in mesothelin (p=0.012). Radiological response significantly associated with reduction in mesothelin (n=20; p=0.003) not reported
Correlation of change in mesothelin levels with survival * Subgroup analysis Significantly shorter survival for patients with 10% increase in baseline mesothelin levels: median survival -increasing mesothelin group - 4.4 months (n=10) -decreasing group - 28 months (n=7) (p=0.012) not reported
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* In majority of cases with progressive disease (n=16) mesothelin increases over time; * In majority of cases with stable disease or a partial response (n=9) mesothelin decreases
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Summary results with response to treatment
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Creaney et al., 2011 (20)
Study cohort 40
a – CT – chemotherapy; RT – radiotherapy; BSC – best supportive care * for cases where baseline mesothelin levels >1nM
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Significantly longer median survival for patients with reduction in mesothelin following chemotherapy (19 months) compare to patients with increased mesothelin (5 months; p<0.001) not reported
not reported
not reported significant longer median survival for patients with reduction mesothelin following chemotherapy (481 days) compared to increased mesothelin (293 days) (p=0.031)
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