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Clinical Chemistry 53: 666-672, 2007. First published February 8, 2007; 10.1373/clinchem.2006.079327
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(Clinical Chemistry. 2007;53:666-672.)
© 2007 American Association for Clinical Chemistry, Inc.

Cancer Diagnostics

MESOMARKTM: A Potential Test for Malignant Pleural Mesothelioma

Heather L. Beyer, Ryan D. Geschwindt, Curtis L. Glover, Ly Tran, Ingegerd Hellstrom, Karl-Erik Hellstrom, M. Craig Miller, Thorsten Verch, W. Jeffrey Allarda, Harvey I. Pass and Niranjan Y. Sardesai

1 Research and Development Division, Fujirebio Diagnostics, Inc., Malvern, PA.

aAddress correspondence to this author at: Research and Development Division, Fujirebio Diagnostics, Inc., 201 Great Valley Pkwy., Malvern, PA 19355. Fax 610-240-3803; e-mail allardj{at}fdi.com.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Soluble mesothelin-related peptides (SMRP)have been reported to be potential biomarkers for malignant pleural mesothelioma (MPM). We report analytical and preliminary clinical studies of MESOMARKTM, a quantitative assay for SMRP.

Methods: The MESOMARK assay is a 2-step immunoenzymatic assay in an ELISA format with a 6-point calibration curve (0–32 nmol/L). We assessed analytical imprecision, analyte stability, and analytical interferences. We measured SMRP by this assay in 409 apparently healthy individuals (reference interval study), 177 patients with nonmalignant conditions, and 500 cancer patients, including 88 with MPM.

Results: The limit of detection was 0.16 nmol/L. At 2–19 nmol/L, intraassay imprecision (CV) was 1.1%–5.3%, and total imprecision was 4.0%–11.0%. The mean dilution recovery for 5 samples was 109% (range, 99%–113%). No interference was seen from added bilirubin (200 mg/L), hemoglobin (500 mg/L), triglycerides (30 g/L), chemotherapeutic agents, or other tested substances. Recombinant mesothelin was stable in serum upon freeze/thaw at –70 °C and upon storage for at least 7 days at 2–8 °C. The 99th percentile of the reference group was 1.5 nmol/L [95% confidence interval (CI), 1.2–1.6 nmol/L; n = 409], and mean SMRP was significantly higher in sera from patients with MPM (7.5 nmol/L; 95% CI, 2.8–12.1 nmol/L; n = 88). SMRP was increased in 52% and 5% of MPM patients and asbestos-exposed individuals, respectively. Concentrations in other nonmalignant and malignant conditions were similar to those in healthy controls.

Conclusions: The MESOMARK assay is analytically robust and may be useful for the detection and management of mesothelioma.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Malignant mesothelioma is a highly aggressive neoplasm with poor prognosis. Mesothelioma accounted for ~1.5% of the 171 900 total lung and bronchus malignancies in the US in 2003 (1)(2), and epidemiological studies have established exposure to asbestos fibers as the primary cause (3)(4)(5). Although malignant mesothelioma remains a relatively uncommon malignancy in the US, it continues to be an important cause of mortality in numerous areas worldwide, e.g., England, Wales, continental Europe, and Australia.

Because the disease is asymptomatic in early stages and definitive diagnosis is difficult, detection typically occurs at a late stage, and recurrence rates, even in patients with surgically resected tumors, are very high. Treatment efficacy is routinely assessed by clinical symptoms and costly radiologic imaging techniques with limited sensitivity and specificity (6). Thus, there has been an increasing need for a simple diagnostic blood test for screening asbestos-exposed patients as well as for monitoring response to treatment.

The MESOMARKTM assay measures soluble molecules that are related to the mesothelin/megakaryocyte potentiating factor (MPF)1 family of proteins and recognized by the monoclonal antibody OV569 (7). Mesothelin and MPF are synthesized together as a 69-kDa precursor from which an N-terminal 31-kDa fragment is released as MPF, and mesothelin is the 40-kDa C-terminal membrane-bound fragment. Immunohistochemical studies revealed tissue expression of mesothelin in a variety of tissues, most notably in mesothelioma, lung, ovarian, endometrial, and pancreatic tumors (8). At least 3 known variants of the mesothelin family have been reported in the literature (9)(10). Although early studies indicated that mesothelin was not soluble (11), recent work demonstrated variants 1 and 3 to be soluble, with variant 1 being the predominant form detected in serum (10)(12). Variant 3 contains a 3' frameshift leading to an extended C-terminus, and variant 2 contains a 24-bp insertion and can be detected only at the mRNA level.

Despite the expression of membrane-bound mesothelin in different tumors, these soluble mesothelin-related peptides (SMRP) have proven to be a promising cancer biomarker in the sera of patients with tumors of mesothelial origin (7)(10). We report here analytical validation studies of the MESOMARK assay, establishing assay performance and its potential utility in a clinical patient population.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
mesomark assay
The MESOMARK assay (Fujirebio Diagnostics, Inc.) uses antibody 4H3, which binds to mesothelin variants 1, 2, and 3, and antibody 569, which binds to variant 1 and 3 (12). We performed the assay according to the manufacturer’s instructions. Briefly, patient serum samples were diluted 1:101 with the assay diluent provided and applied in duplicate to a microwell plate precoated with antibody 4H3. After incubation for 1 h at room temperature, plates were washed, and antibody OV569-HRP conjugate was added for 1 h. After a wash step, TMB substrate was added to the reaction wells for 15 min, and then 100 µL of stop solution was added. The absorbance at 450 nm was used to quantify the SMRP concentrations by comparison with a 6-point calibration curve established by a 4-parameter logistic fit using Softmax Pro software (Molecular Devices). Unless otherwise noted, all studies were performed with representative reagent sets from 2 independent lots. Four operators were trained during a 5-day, 10-run training study before the start of analytical MESOMARK tests.

primary antigen and assay standardization
MESOMARK values are expressed as nmol/L and are related to a reference preparation maintained by Fujirebio Diagnostics, Inc. The reference preparation is a recombinant antigen (reactive with both OV569 and 4H3) produced with a stably transfected cell line, OV569-, immunoaffinity purified, and quantified by amino acid analysis. This cell line has been described in detail elsewhere (10). Antigen concentrations were measured in nanomoles per liter. Primary calibrators and controls were referenced to this preparation and ranged from 0 to 32 nmol/L to cover the majority of the expected range in patient populations. Subsequent lots of antigen (used to manufacture the reagent set calibrators and controls) were matched against the primary calibrators and controls based on absorbance measurement in the MESOMARK assay, allowing for traceability to the reference preparation.

samples
Serum samples for use in analytical studies were supplemented with recombinant OV569-reactive antigen, whereas serum samples for use in the clinical studies were not supplemented. The latter were collected from apparently healthy volunteers (n = 409), as well as from patients with several malignant and nonmalignant conditions. Malignant conditions included mesothelioma (n = 88), ovarian cancer (n = 111), lung cancer (n = 174), colon cancer (n = 50), pancreatic cancer (n = 52), and endometrial cancer (n = 25). Nonmalignant conditions included hypertension (defined as a blood pressure >150/90 mmHg; n = 100), exposure to asbestos (n = 61), and endometriosis (n = 16). Clinical samples were collected retrospectively based on reported diagnosis and blinded to the operator. Invalid results were addressed by retests of the sample in question. These samples were obtained from commercial sources (Biochemed) in 2004 except for samples from mesothelioma patients and asbestos-exposed individuals, which were kindly supplied by Dr. Harvey Pass (Karmanos Cancer Institute, Wayne State University, Detroit, MI). Patients with a histologically confirmed diagnosis of mesothelioma seen at the Karmanos Cancer Institute gave informed consent to have serum, plasma, and normal and tumor tissue samples taken on the day of operative intervention for their tumors. These cases were performed both at the Karmanos Cancer Institute and the National Cancer Institute in Bethesda, Maryland, between 1995 and 2003. All blood samples were drawn before anesthesia or before surgery in the clinic, when the patient was examined by the physician. The asbestos-exposed population consisted of patients seen at the Center for Environmental Medicine in Southfield, Michigan, who, after giving informed consent, donated urine and serum. These asbestos-exposed patients also filled out a demographics questionnaire and gave permission for analysis of their pulmonary function tests and radiographic images. All patients provided informed consent, and all procedures and protocols were approved by the institutional review board.

analytical methods
Analytical Sensitivity.
Calibrator A (the assay diluent) was assayed in replicates of 25 for each reagent set lot, and the mean absorbance plus 2 SD was determined and compared with a calibration curve (prepared in duplicate). The detection limit (also called the limit of the blank) was calculated based on the linear segment connecting the A and B calibrators.

Imprecision.
Within-run and total imprecision values were evaluated according to NCCLS Protocol EP5-A (13). Two replicates each of 3 panels were assayed in 2 separate runs on each of 20 days, at 2 separate clinical sites. The low-end imprecision was evaluated at a single clinical site by assaying low-end panels (40 runs in 20 days). Panels consisted of defibrinated human plasma supplemented with OV569-reactive antigen (range, 1.26–19.02 nmol/L). Data from the study were analyzed with the Analyze-It software package (Analyze-it Software, Ltd.).

Dilution Linearity.
Dilution linearity was assessed with a single reagent set lot and modeled after the NCCLS protocol EP6-A (13). Five serum samples from apparently healthy individuals were supplemented with OV569-reactive antigen to >25 nmol/L, followed by dilutions ranging from 1:1.1 to 1:20. Expected and observed SMRP values were compared for each dilution.

Recovery.
To each of 5 sera we added OV569-reactive antigen at concentrations covering the range of the calibration curve. Using the same reagent set lot, we compared observed and expected sample values.

Interference Studies.
All interference studies were performed using 1 reagent set lot. Potentially interfering compounds were added at final concentrations ~10-fold higher than the expected peak plasma concentrations (Cmax) to aliquots of 5 independent serum samples containing OV569-reactive antigen, whereas control samples were treated with the appropriate vehicle solution.

Chemotherapeutics included Gemzar (gemcitabine-HCl) and Alimta, both purchased from Eli Lilly and Company, and carboplatin and cisplatin (cis-diammineplatinum dichloride), both purchased from Sigma Chemical.

Naturally occurring serum components included hemoglobin (5 g/L), triglycerides (Liposyn, Abbott Diagnostic Division; 30 g/L), bilirubin (Sigma; 200 mg/L), and added protein (1.5% bovine serum albumin and 0.5% bovine gamma globulin, Sigma). Human hemoglobin was isolated from whole blood cellular pellets that were lysed with an equivalent volume of water followed by centrifugation to remove cellular debris.

To assess human antimouse antibody (HAMA) and rheumatoid factor (RF) interference, 1 serum specimen collected from an otherwise healthy volunteer, 10 specimens that were positive for HAMA, and 5 specimens that were positive for RF were supplemented with 3 different concentrations of OV569-reactive antigen. All samples were assayed, and the observed values of the supplemented samples were compared with the nonsupplemented samples.

A potential prozone/hook effect was tested by adding high concentrations of recombinant antigen to 3 serum samples (5991, 7881, and 10 291 nmol/L) followed by 2-fold serial dilutions to 1:1024.

antigen stability studies
Serum Processing.
We tested 30 serum samples supplemented with 2 different concentrations of OV569-reactive antigen and 20 nonsupplemented samples on days 0, 3, and 7 (intermediate storage at 2–8 °C). Values were compared over the time course. Two different collection procedures were also compared (red top tubes vs serum separator tubes; Becton Dickinson)

Sample Freeze/Thaw.
Aliquots from 12 of the above samples and 1 mesothelioma patient sample were subjected to 1–10 freeze/thaw cycles at –70 °C, and SMRP values for the frozen/thawed samples were compared with the fresh sample values.

Storage Temperature.
Five serum separator tubes of blood were collected from each of 20 healthy volunteers. One tube of each set was processed on the day of collection, and the serum was stored at –70 °C as the comparison (presumably stable) material. The remaining blood tubes were stored unprocessed at 2–8 °C or at 37 °C and processed on days 1, 2, 4, and 7 followed by storage at –70 °C until further analysis. All samples were analyzed in 1 batch.

statistical analyses of clinical samples
Nonparametric ROC analyses were performed comparing the MESOMARK results in the mesothelioma patients to those of the healthy volunteers alone and to the benign and other nonmalignant conditions combined, and the areas under the curves (AUCs) were calculated. The 95% confidence interval (CI) was also determined for the AUCs. Equality of the median MESOMARK assay values in the healthy volunteers and the different stages and histological subtypes of the mesothelioma patients were compared using a nonparametric k-sample test and the {chi}2 statistic.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
analytical studies
Within-run imprecision (CV) of the MESOMARK assay ranged from 1.1% to 6.4% between the 2 clinical sites tested (total imprecision, ≤11.0%; see Table 1 in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol53/issue4), and the limit of detection (limit of the blank) was 0.16 nmol/L for both lots tested (see Table 2 in the online Data Supplement). Dilution linearity was demonstrated across 1–27 nmol/L, and linear regression analysis resulted in the following: observed = 0.99(expected) + 0.77; R2 = 0.986. The total mean percent recovery of added antigen in serum samples (see Table 3 in the online Data Supplement) across all of the dilutions tested was 107%, and individual recoveries ranged from 94% to 127%.

After addition of potential interferents, mean results were 96%–101% of expected (Table 1 ).


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  		Table 1. Interfering substances.1

None of the 3 serum samples tested exhibited this effect (data not shown). Most importantly, the highest concentration of analyte tested for the prozone effect (10 291 nmol/L) was >60-fold greater than the highest measured value in a mesothelioma patient sample (170 nmol/L) to date.

antigen stability
Freeze/thaw studies (12 samples) yielded mean values of 89%–98% of the "fresh control" samples (–70 °C sample) across 10 freeze/thaw cycles, with no trends observed (see Table 4 in the online Data Supplement). For samples stored at 2–8 °C for up to 7 days, mean recoveries across all samples tested (n = 51) were 94% and 92% on days 3 and 7 of testing, respectively (data not shown).

Neither a storage temperature of 37 °C nor hemolysis resulting from storing unprocessed blood samples over extended periods of time (at 2–8 °C and 37 °C) had a significant effect on measured SMRP. For the 10 samples in each set at 2–8 °C (37 °C), mean recoveries were as follows, as a percentage of the initial values: day 1, 99% (96%); day 2, 99% (87%); day 4, 101% (80%); day 7, 95% (103%). No trends were observed, and the variations in recoveries were within the imprecision profile for the assay.

clinical validation
SMRP was higher in 88 mesothelioma patients than in other patient groups and controls, including 61 asbestos-exposed individuals (Fig. 1 ). Median MESOMARK values in the preoperative samples from mesothelioma patients were significantly higher than values in samples from healthy individuals (Table 2 ; P values ≤0.0001). In MPM, results showed no clear relationship to stage of MPM or its histologic type (Tables 2 and 3 ).


Figure 1
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  		Figure 1. MESOMARK values across a cross-section of samples.

Samples from patients with different diagnosed cancers were tested for SMRP concentrations using the MESOMARK assay. Ca, cancer; Exp, exposure; Pre-op mesos, preoperative mesothelioma samples.


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  		Table 2. SMRP concentrations in healthy controls and mesothelioma patients.1


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  		Table 3. Demographic data for healthy controls and preoperative mesothelioma patients.

ROC curves (Fig. 2 ) comparing normal individuals with preoperative mesothelioma samples yielded an AUC of 87.4% (95% CI, 82.8%–92.0%), whereas a comparison of asbestos-exposed patients with preoperative mesothelioma samples yielded an AUC of 80.6% (95% CI, 73.7%–87.4%). An ROC curve comparing preoperative mesotheliomas vs all nonmesothelioma samples (healthy, benign, and other cancers) yielded an AUC of 81.0% (95% CI, 75.5%–86.5%; data not shown).


Figure 2
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  		Figure 2. ROC curve for healthy vs preoperative (pre-op) mesotheliomas.

ROC curve for the ability of the MESOMARK assay to differentiate between healthy volunteers (n = 409) and patients with mesothelioma (n = 88). The table shows the threshold value required for the MESOMARK assay and the sensitivity (and the 95% CI for the sensitivity) at the 5 different specificity levels.

As shown in Table 4 , 99% of serum collected from apparently healthy individuals demonstrated SMRP values ≤1.5 nmol/L, whereas SMRP values were >1.5 nmol/L in 52% of mesothelioma patients. In other cancers (ovarian, pancreatic, colon, and endometrial), MESOMARK values were increased in <10% of the samples tested. In 83% of samples from lung cancer patients and 95% of samples from asbestos-exposed individuals, SMRP was ≤1.5 nmol/L. Statistical performance of MESOMARK at the chosen cutoff was determined in comparison with different patient groups (Table 4 ).


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  		Table 4. Concentrations and diagnostic accuracy of SMRP in subgroups of patients and controls.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our analytical studies indicate that the MESOMARK assay is robust, with freedom from interference from a range of potential interferents; an analyte that is stable (e.g., with freeze/thaw cycles and processing); assay imprecision (total CV) ≤11%; detection limit (0.16 nmol/L) well below the upper limit of the reference interval; linearity to a concentration (27 mmol/L) nearly 20 times the upper limit of the reference interval; and essentially quantitative recovery of added analyte.

The clinical findings in our study are similar to those reported by others using different assays (7)(14)(15). In our study, 83% of lung cancer patients and 95% of asbestos-exposed individuals exhibited serum SMRP concentrations below the upper limit of the reference interval (defined as the 99th percentile value of a distribution of normal healthy individuals). In contrast, 52% of mesothelioma patients had SMRP values above the same cutpoint. For example, increased SMRP concentrations were reported in an Australian mesothelioma patient population, which included patients who had been occupationally exposed to asbestos (7). Interestingly, of 7 patients with increased SMRP values, 3 were later diagnosed with mesothelioma, and 1 was found to have lung cancer (7). Increased SMRP concentrations were found in sera from patients with mesothelioma of the epithelial subtype, but not in sera from patients with sarcomatoid mesothelioma in this study and in studies by other groups (7)(16). In addition, in longitudinal studies increased SMRP concentrations were detected 12–48 months before detection of mesothelioma by conventional means (2 of 8 patients; unpublished data). Although these longitudinal studies included only a limited number of patients, our results might indicate the potential of SMRP as a marker for monitoring response to treatment. Such a biomarker would be beneficial because current imaging methods have limited sensitivity (6) and are costly. There were no reports of established biomarkers for mesothelioma published at the time of the study. Additional studies, however, are ongoing to compare SMRP with other serologic markers such as osteopontin, CYFRA21-1, or CA125. Preliminary data are presented elsewhere (17).

In summary, serum concentrations of SMRP are higher in patients with mesothelioma than in healthy persons, and can be reliably measured by the MESOMARK assay. Data are remarkably consistent across different patient populations and different laboratories and indicate potentially important clinical utility of the SMRP assay in mesothelioma diagnostics. Limitations of SMRP include its increase in patients with renal failure, hypertension, and certain other tumors such as ovarian cancer. Although additional tests and demographic information may be needed to address some of these shortcomings, SMRP does have potential as a biomarker for detection of mesothelioma in a high-risk, asbestos-exposed population.

Because mesothelioma is a rare disease, the use of SMRP as a screening assay may also require the addition of other markers to increase specificity, for example in an asbestos-exposed population. Candidate markers include osteopontin, which was recently reported to be increased in mesothelioma patients (18), the absence of increased carcinoembryonic antigen (6), or a combination with CYFRA21–1, which could aid in differential diagnosis (19). A marker panel requires further studies that are currently ongoing. Other studies are under way to confirm diagnostic accuracy as established in this preliminary study.


   Footnotes
 
1 Nonstandard abbreviations: MPF, megakaryocyte potentiating factor; SMRP, soluble mesothelin-related peptides; HAMA, human antimouse antibody; RF, rheumatoid factor; AUC, area under the curve; CI, confidence interval.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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