American Journal of Respiratory and Critical Care Medicine

Rationale: Previous data suggested that serum levels of soluble mesothelin (SM) are related to tumor size and may have prognostic significance in malignant pleural mesothelioma (MPM).

Objectives: We tested the hypothesis that this marker could also be useful for monitoring response to treatment.

Methods: Serial measurements of SM were determined in 40 patients diagnosed with MPM and subjected to gene-transfer therapy using intrapleural infusion of an adenoviral vector expressing human IFN-β or conventional treatment (mainly chemotherapy).

Measurements and Main Results: In patients with baseline SM levels greater than 1 nM/L and disease progression after therapy, SM levels increased by 2.1 nM/L at two, 5.2 nM/L at four and 1.3 nM/L at 6 months. Patients with initial SM below 1 nM/L had a similar but more moderate increase of SM over time. Patients who responded to treatment or were considered stable had an initial small decrease of SM followed by a return to baseline values after 6 months of follow-up. In patients with baseline SM levels greater than 1 nM/L, increasing levels were associated with a significantly shorter median survival than in patients with stable or decreasing SM levels (4.4 vs. 27.7 months; P = 0.012).

Conclusions: Increasing serum levels of SM were associated with disease progression and worse outcome, whereas stable or decreasing values suggested response to treatment. If confirmed in larger series, SM could be used to monitor patients with malignant pleural mesothelioma under treatment.

Scientific Knowledge on the Subject

There are no published data (except in some limited abstracts) on the utility of mesothelin for monitoring response to treatment in malignant pleural mesothelioma.

What This Study Adds to the Field

We show that serum mesothelin measurement could be useful in monitoring the evolution of patients with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a severe disease whose incidence is increasing due to previous asbestos exposure. Patient outcome is dismal despite current therapeutic modalities that include surgery, chemotherapy, and irradiation of the thoracic drainage sites. In early stages, surgery may offer a chance for a prolonged survival, but patients need to be carefully selected; less than 10% of the patients are eligible for this therapy (1, 2). In advanced stages, chemotherapy with the new antifolates combined with cisplatin offers a small but significant survival advantage (3). Other chemotherapeutic treatment options may include gemcitabine or in the future, gene therapy, proapoptotic agents (such as inhibitors of histone desacetylases), or antiangiogenic therapies.

The evaluation of the response to treatment can be difficult for a number of reasons: (1) MPM does not often present as a single tumor, but rather as multiple pleural foci that are difficult to assess even using the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria; (2) the presence of pleural effusions that are often loculated and chronic can be difficult to differentiate from tumor; (3) the flattened shape (rather than round tumor nodules seen with lung cancer) make the assessment of tumor volume by conventional imaging such as CT scan difficult (4); and (4) MPM is often very fibrotic, resulting in small changes in the size of the tumor despite effective tumor cell killing. New potential tools may include the use of computerized algorithms for tumor evaluation and [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) scans, which can quantify the amount of metabolically active tissue and may provide information on prognosis and tumor response (5, 6). Data on these methods are under investigation. Therefore, the availability of a soluble tumor marker which could reflect the tumor burden would be of importance in clinical practice.

Soluble mesothelin (SM) (also called soluble mesothelin-related peptides) (79) and osteopontin (10) have been proposed as diagnostic markers in mesothelioma. SM is expressed primarily by the epithelioid subtype of MPM (11), and previous data suggested that serum SM levels increase with tumor growth (7) and iare related patient survival (9). Thus, SM may be useful to monitor the patient response to therapy. Recently, the FDA has approved SM (the MESOMARK enzyme-linked immunoabsorbent assay) as a test for monitoring patients treated for MPM, but, to our best knowledge, data about the usefulness of this test are limited and have been not published. Therefore, we conducted a multicenter retrospective study of the kinetics of SM in MPM patients treated by conventional therapies (i.e., chemotherapy ± radiotherapy and surgery) or evaluated in a clinical trial of gene-transfer therapy using intrapleural infusion of adenoviral vector expressing human interferon-β (Ad.huIFN-β). Some of these results have been published in abstract form (12).

Patients

Patients were recruited in two locations: in the United States (Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania) and in France (Thoracic Oncology Department, CHRU of Lille).

Patients Recruited at the University of Pennsylvania Medical Center

Sixteen patients were enrolled in one of two Phase 1 immunogene transfer trials conducted between August 2003 and June 2007, using intrapleural infusion of an adenoviral vector expressing human IFN-β (Ad.huIFN-β). Eighth subjects were enrolled in a single dose trial (reported in Reference 13), whereas eight subjects were enrolled in a two-dose trial, with infusions separated by 2 weeks. Patients were eligible if they had a histologically proven diagnosis of malignant pleural mesothelioma, were not candidates for resection, had an Eastern Cooperative Oncology Group performance status ≤ 2, and had a residual pleural space. Exclusion criteria included prior surgical resection, pleurodesis, chemotherapy, or radiotherapy or the presence of significant cardiac, hepatic, or renal disease. All subjects had serum collected at baseline and at 1, 2, 4, and 6 months after infusion.

Patients Recruited in Lille (France)

Patients were recruited from a series of 167 mesothelioma cases from our prospective regional MPM surveillance program which started in 2003 and involved 20 different pulmonary or thoracic surgery departments from the North and West of France (details in Reference 8). In 24 cases, we had at least two serum samples and a thoracic CT scan available, enabling us to evaluate tumor evolution and soluble mesothelin kinetics. Four patients received only supportive therapy due to rapid disease progression and the rest were subjected to chemotherapy (mainly pemetrexed with cisplatin, but one received carboplatin with pemetrexed, one was treated by cisplatin and gemcitabine, and a last one by another regimen). Exclusion criteria were any concomitant infectious disease or patient refusal. Irradiation of chest wall drainage points (21 Gy in seven fractions) was done for all patients. The 24 recruited patients had similar characteristics as the whole group concerning the age, percentage of epithelioid subtype, or median mesothelin at diagnosis.

Serum samples collected from patients were stored at −80°C until analyzed. Clinical data and outcome of the patients were also collected every 4 weeks. A chest CT scan was performed within 1 week of the serum collection (before delivering the treatment) and afterward every three cycles of chemotherapy. Patients treated with gene therapy had chest CT evaluations at 2 and 6 months after vector instillation.

Evaluation of the tumor volume and of the response to treatment was done using modified RECIST criteria (14). These criteria use unidimensional measurement of tumor thickness perpendicular to the chest wall or mediastinum, measured in two sites at three different levels on a CT scan.

ELISA Assays

The soluble mesothelin was assayed by ELISA using the MESOMARK kit (Fujirebio, Malvern, PA or CISbio International, Gif/Yvette, France) according to the manufacturers' instructions.

Statistical Analysis

Kaplan-Meier curves and the log-rank test statistic was used to compare differences in survival between groups. A two-sided P value of < 0.05 was considered significant. Statistical calculations were performed with SPSS statistical package (version 12.0F; SPSS, Chicago, IL).

The protocol was approved by local ethical committee of both sites. Some of these data have been published in abstract form (12).

The analyzed series include a total of 40 patients (n = 16 from the United States recruited between August 2003 and June 2007 and n = 24 from France recruited between May 2003 and November 2006). Serum samples were collected before treatment and when possible after 2, 4, and 6 months of treatment. Serum samples were available at two time points in 23 patients, at three time points in nine patients, and at four time points in eight patients. The mean age of the patients was 66.1 years (SD 10.3 years). There were 11 women and 29 men (Table 1).

TABLE 1. DEMOGRAPHIC DATA OF RECRUITED PATIENTS


Description

n

Age (mean ± SD)

M/F (n)

Treatment Received (Chemotherapy/BSC/Gene Therapy)
All patients4066.0 ± 10.329/1119/5/16
Patients recruited from
 U.S.1668.6 ± 11.312/40/0/16
 Europe2464.3 ± 9.317/719/5/0
Low initial serum mesothelin level (at diagnosis)1570.2 ± 7.311/4
 Progressive disease1171.5 ± 7.18/35/2/4
 Stable disease466.7 ± 1.73/10/0/4
High initial serum mesothelin level2563,5 ± 11.118/7
 Progressive disease1665.7 ± 11.112/46/3/7
 Stable or response to treatment
9
59.5 ± 10.4
6/3
8/0/1

Definition of abbreviation: BSC = best supportive care; F = female; M = male.

Patients Exhibiting Initial Low Levels of Serum Mesothelin

We separated the patients based on their SM levels at the time of the first determination. Our first group included patients with initial SM values lower than 1 nM/L, a level considered as normal or “nondiagnostic” for MPM (15, 16). In this group of 15 patients (13 with epithelioid mesothelioma, 1 with a sarcomatoid subtype, and 1 with mixed subtype), the median value of serum SM at the time of diagnosis was 0.58 nM/L (interquartile range [IQR], 0.33–0.82 nM/L). Eleven patients had progressive disease: the median SM value of these patients increased progressively from 0.58 nM/L (IQR, 0.33–0.82) at diagnosis to 0.73 nM/L (IQR, 0.56–1.5), 1.3 nM/L (IQR, 0.87–1.45), and 3.75 nM/L at 2 months, 4 months, and 6 months after diagnosis, respectively (Figure 1A). The median increase of SM after 2, 4, and 6 months of follow-up were, respectively, 0.15 nm/L (IQR, 0.11−0.6), 0.6 nM/L (IQR, 0.29–0.87), and 3.2 nm/L (two cases only) (Figure 1B).

The remaining four patients (all treated by gene therapy) had stable disease on the chest CT scan 2 months after vector instillation. Their median SM level showed a modest initial decrease followed by a much more slowly increase: 0.65 nM/L (IQR, 0.5–0.75) at diagnosis, 0.4 nM/L (IQR, 0.27–0.5) at 2 months, 0.7 nM/L (IQR, 0.5–0.8) at 4 months, and 0.85 nM/L (IQR, 0.6–1.02) at 6 months, with a mean change of, respectively, −0.25 nM/L (IQR, −0.32 to 0.15), 0.1 nM/L (IQR, −0.05 to 0.15), and 0.25 nM/L (IQR, 0.02–0.4 nM/L) (Figure 2).

Patients with Initial Serum Mesothelin Greater than 1 nM/L

Our second group of patients included those with SM levels greater than 1 nM/L. In this group of 25 patients, there were 22 epithelioid MPM, one case of mixed MPM and two cases of MPM classified as sarcomatoid. Sixteen patients had progressive disease despite treatment (gene therapy: n = 7; chemotherapy: n = 6 and best supportive care: n = 3). SM values increased by more than 10% of baseline value in 12 patients, decreased in one (20% decline), and were stable (within ± 10% of baseline value) in three patients. The median increase over baseline (first diagnostic time) of SM was 2.1 nM/L at 2 months (IQR, 1.15–4.08), 5.2 nM/L at 4 months (IQR, 0.05–13.9), and 1.3 nM/L (IQR, 0.8–1.99) at 3 months. Thus, in this group of patients with progressive disease, the majority demonstrated an increase in SM levels, which mirrored the tumor growth seen on CT imaging (Figures 3A and 3B).

From the remaining patients (one receiving gene therapy and eight receiving chemotherapy), three were considered to have an objective response, four had stable disease, and two had progression at 2 months but stable disease at the 6-month evaluation. These nine patients exhibited a clear decrease of SM level, except one patient considered to be stable (Figure 4A). The SM decrease was greatest at the 4-month evaluation and after 6 months the serum values tend to return toward the baseline values (Figure 4B).

Relationship of SM Levels and Overall Survival

A second way to evaluate the value of SM levels, independently of the CT scan data, was to examine the correlation between SM levels and overall survival. In the subgroup of 17 patients with high initial mesothelin values recruited from France, the change in SM was measured and overall survival was determined during long-term follow-up of these patients. An increasing level of SM was defined as an increase of at least 10% in the first available serum sample at the end of the treatment compared with the pretreatment value.

The difference in overall survival between the two groups was significant, with a median survival of 27.7 months in the group with stable mesothelin values (n = 7) compared with 4.4 months in the group (n = 10) with increasing values (P = 0.012; log-rank test) (Figure 5).

The survival of patients with MPM is short, despite efforts to develop better therapeutic strategies; however, a number of new therapeutic approaches are being developed and studied (17, 18). There are some prognostic factors proposed for MPM in the literature, such as the histologic subtype, the tumor stage according to the IMIG staging system, the completeness of resection after surgery, and some basic markers proposed by EORTC/CALGB and recently updated (e.g., platelet count, hemoglobin, performance status, etc.) (1922). These parameters are not validated at an individual level but rather are used to assess the homogeneity of groups of patients with MPM in a clinical study or trial (18). Hyaluronic acid level in the pleural fluid may be of interest, but definitive data are lacking (23). PET scanning is also being investigated (5, 24); however, evaluation of patients treated for MPM relies mostly on physical examination and CT scan (using modified RECIST criteria). This is often difficult and suboptimal.

Serum soluble mesothelin measured at the time of diagnosis has been shown to be correlated with tumor volume (7) and survival (9). Until now, these potential biological markers have been evaluated as prognostic factors at diagnosis rather than as predictive markers to monitor the response of MPM to treatment. The goal of this study was to specifically examine SM levels in relation to therapeutic response. To study this question we used two approaches. The first was to compare SM levels with CT and PET scans. Although this is the standard of care, it may be inaccurate and thus represent a “tarnished gold standard.” Accordingly, in a relatively large and uniform subgroup (i.e., the French patients undergoing chemotherapy), we applied an independent and more objective standard (survival). For the first time, we show here that patients with MPM having an objective response after chemotherapy exhibited decreasing, or at least stable, serum SM levels, whereas patients having progressive disease exhibited increasing SM values. We considered that a significant change in SM level should exceed 10% of baseline value because the coefficient of variation of the assay is between 4 and 11%, according to the manufacturer-supplied data. We also showed that the survival of patients with decreasing/stable values of SM during follow-up is significantly greater than in patients with increasing SM.

Even in the group of patients with “normal” values of SM at the time of diagnosis, we observed an increase of SM exceeding 10% over baseline as the result of a progressive disease in almost all cases. In contrast, patients from this group exhibiting stable disease had a modest absolute initial decrease in serum SM levels in three out of four cases.

In patients with SM levels greater than 1 nM/L, progression of the disease was associated with a progressive increase of SM in 12 out of 16 patients (75%), while an increase of less than 10% was encountered in three cases (18.7%). The median increase in serum mesothelin is paradoxically smaller at 6 months than after 4 months of follow-up. We feel this is likely due to the death of the patients, with the most important increases corresponding with the most rapid progression of the disease. Conversely, in patients with an objective response or stable disease, an initial decrease of serum mesothelin level was observed, followed by a return to near baseline values 6 months later, due to disease relapse.

Another interesting finding of this investigation was the progressive increase of SM in some patients with nonepithelioid subtype of MPM and a low SM level at diagnosis. One possible explanation could be that these patients had a mixed type MPM with a low epithelial component, and, due to an insufficient number of pleural biopsies, they were wrongly classified as having a nonepithelioid mesothelioma (25). Later, the tumor growth resulted in an increase of the epithelioid component of the MPM with a subsequent elevation of SM level. Thus, serum mesothelin seems to be an interesting marker for monitoring the response to treatment in patients with MPM, suggesting that SM blood level could reflect the tumor burden. Mesothelin is produced by the tumor itself and expressed at the cell membrane of mesothelial tumor cells (26, 27). The mechanism of mesothelin release from the cell surface into the circulation is unknown, but the available data are in favor of a proteolitic cleavage (2729). Factors modulating this enzymatic pathway may strongly influence serum mesothelin level and the kinetics of the marker from one patient to another even if both patients would have a similar clinical and radiologic pattern or the same outcome. Moreover, it is unknown if the therapy may influence this process of mesothelin release. However, because there is a strong relationship between the kinetics of serum SM and patient survival, our conclusion that serum mesothelin mirrors the tumor evolution under treatment is sustained.

Another important finding was that the relationship between the kinetics of serum SM and the response to treatment held true no matter which therapy was used (chemotherapy, gene therapy, or multimodal treatment). This confirmed the reproducibility of these findings and may allow using SM as a predictive serum marker in all MPM cases.

One potential pitfall of this marker is that it will likely be useful only for epithelioid or mixed-type tumors (which account for the majority of cases). In mixed-type tumors with a low or very low epithelioid component, the usefulness of this marker may also be limited, being possibly less sensitive than current imaging investigations or clinical examination.

In conclusion, we demonstrated for the first time that SM may be a useful predictive and prognostic tumor marker in patients with MPM. These results support the use of serum mesothelin in monitoring treated patients with MPM. However, our findings should be interpreted with caution because the number of recruited patients was limited, as were the data derived from the survival analysis. Further prospective investigations (from larger clinical therapeutic trials in MPM, for example) are needed to establish the use of serum mesothelin levels as a predictive and prognostic marker in patients with MPM.

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Correspondence and requests for reprints should be addressed to Arnaud Scherpereel, M.D., Ph.D., Pulmonary and Thoracic Oncology Department, Hopital Calmette, CHRU of Lille, 59037 Lille cedex, France. E-mail:

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