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K. Lamote



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    MTE23 - Screening Tools for a High Risk Population - Can We Screen for Early Mesothelioma? (ID 67)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Mesothelioma
    • Presentations: 1
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      MTE23.1 - Screening Tools for a High Risk Population - Can We Screen for Early Mesothelioma? (ID 621)

      07:00 - 08:00  |  Author(s): K. Lamote

      • Abstract
      • Presentation
      • Slides

      Abstract
      Malignant pleural mesothelioma (MPM) is an asbestos-related disease with a very poor prognosis because of late-stage diagnosis due to unspecific imaging techniques and non-specific symptoms resembling pleural effusions such as chest pain and dyspnea. Early diagnosis could improve the disease’s outcome by reducing the diagnostic delay. Serum tumor biomarkers for early MPM screening are attractive because of their non-invasive and low-cost nature. Nevertheless, MPM is a heterogeneous disease suggesting an ideal biomarker should be capable of capturing all the MPM subtypes and to distinguish MPM from benign or metastatic pleural conditions. To have a clinical impact, biomarkers should predict the development of the disease in which a positive test could enrich the at-risk population eligible for further screening and reduce the economical burden of wild screening. In order rule in MPM, a biomarker should have a positive predictive value of minimally 10%, and the low MPM prevalence urges the need for a high test specificity. Many candidate blood biomarkers have been studied such as hyaluronic acid, carcinoembryonic antigen, CYFRA 21.1 and cancer antigen 125. Nonetheless, their accuracy is insufficient and based upon small-sized retrospective studies without further validation. Hence, they are of little use in clinical practice. More recently, the cell adhesion proteins soluble mesothelin (SM), megakaryocyte potentiating factor (MPF) and osteopontin (OPN) were investigated. OPN functions in cancer progression, bone matrix formation and immunologic responses. Despite 78% sensitivity and 88% specificity found by Pass et al., subsequent validation studies revealed contradictory accuracy findings with AUCs ranging from 0.64 to 0.89. Furthermore, OPN lacks specificity because it is overexpressed in other tumor types, limiting its use as a diagnostic mesothelioma marker. SM has been found the best available serum marker for MPM. It is derived from a mesothelin gene-encoded precursor protein, which is cleaved into a soluble fraction (MPF) and a membrane-bound fraction (mesothelin) involved in cancerous growth, proliferation and migration and present on the pleural, peritoneal and pericardial mesothelial cells. SM enters the circulation by shedding of the membrane-bound mesothelin or frameshift mutations and is highly expressed in mesothelioma and other malignancies. The first determined serum MPF levels differentiated MPM from healthy controls with 91% sensitivity and 100% specificity. Subsequent studies resulted in diagnostic accuracies with AUCs between 0.79 and 0.88. MPF and SM are highly correlated and have equal diagnostic performances. SM was elevated in MPM patients compared to controls and had discriminative power with 84% sensitivity and 100% specificity. A commercial MesoMark[TM] ELISA assay for SM was developed and evaluated by different groups gaining diagnostic accuracies with AUCs from 0.72 to 0.81. The use of SM as diagnostic marker is still under debate because of large intergroup inconsistencies. An individual patient data meta-analysis was performed, yielding an AUC of 0.77 representing the overall SM diagnostic performance. When SM was used to rule in or rule out diagnosis, the specificities and sensitivities were respectively 95% and 32% and 22% and 95%. SM has low specificity and is only selective for epithelioid and biphasic MPM, hampering its use as a stand-alone marker and possible replacement of the current gold standard of invasive histopathologic diagnosis. Hence a combination of several tumor markers might improve the diagnostic performance. However, combining SM, OPN and MPF did not outperform the accuracy of SM alone and it is necessary to take GFR, BMI and age into account as confounding effects because they influence the biomarker levels. New markers like HMGB1 and fibulin-3 were investigated and were found upregulated in patients sera compared to sera from healthy controls. Although both are promising, a long and cumbersome validation process will need to be executed comparing the accuracy of both biomarkers with serum SM. In the past, several programs have been conducted to screen asbestos-exposed individuals for lung disease with annual chest X-rays. Besides demonstrating the presence of benign asbestos-related diseases, these modalities have not proven to be effective at detecting early malignancies. CT has a superior sensitivity, and its use in screening has been examined in several large-scale studies (Table). Results predominantly illustrate the low prevalence of mesothelioma, and the high background noise (non-calcified nodules) in asbestos-exposed populations. In addition, the standardization of reading both chest X-ray and CT has proven to be difficult, while the cost and radiation doses represent other problematic issues. PET and MRI are currently not applied in screening, and their cost is likely to be prohibitive. Altogether, it is now generally accepted that the use of imaging has not made any impact on the early detection of mesothelioma, and their use is not recommended by the different (inter)national guidelines. In the future, the ‘Holy Grail’ could be sniffed out thanks to the innovative field of exhaled breath analysis. Volatile organic compounds (VOCs) arise from the cells’ metabolism and are released in exhaled breath, making these promising diagnostic MPM markers obtained via high-throughput non-invasive techniques. Electronic nose (eNose) analysis has shown promising results for diagnosing MPM with diagnostic accuracies ranging from 80.8% to 95% in discriminating MPM patients from asbestos-exposed and healthy individuals. However, eNoses work as blackboxes and do not identify VOCs as possible biomarkers. GC-MS analysis identified cyclohexane to discriminate MPM patients from asbestos-exposed and healthy persons. Although this research field opens new perspectives for biomarker discovery, a lot of small-sized studies were performed in order to identify new biomarkers for screening, urging the need for large-scale validation studies. Although different routes of discovering biomarkers for early screening have been paved, the way to a validated and clinically useful screening biomarker panel still has to be constructed. Table: Prospective screening studies using chest CT in asbestos-exposed cohorts to detect asbestos-related malignancies.

      Reference Total (n) Lung cancer (n) Mesothelioma (n)
      Tiitola et al. 602 5 1 peritoneal
      Vierikko et al. 633 5 1 pleural
      Fasola et al. 1045 9 -
      Mastrangelo et al. 1119 5 -
      Roberts et al. 516 6 2 pleural/2 peritoneal
      Total 3915 30 (0.7%) 6 (0.2%)

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    P3.14 - Poster Session 3 - Mesothelioma (ID 197)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P3.14-003 - Volatile Organic Compounds as diagnostic tool for Malignant Pleural Mesothelioma. (ID 709)

      09:30 - 09:30  |  Author(s): K. Lamote

      • Abstract

      Background
      Early diagnosis of malignant pleural mesothelioma (MPM) can improve patients’ outcome but is hampered by non-specific symptoms and investigations, which delay diagnosis and result in advanced stage disease [van Meerbeeck JP, 2011]. An accurate non-invasive test allowing early stage diagnosis in asbestos-exposed persons is lacking. Breathomics aims at a non-invasive analysis of volatile organic compounds (VOCs) reflecting the cells’ metabolism. The breathogram obtained by the electronic nose does however, not allow identification of MPM-related VOCs [Chapman EA 2009, Dragonieri S 2011]. Ion mobility spectrometry (IMS) combines the advantages of online direct sampling with the possibility of VOC identification and linking to MPM pathogenesis [Baumbach JI 2009]. We investigated which VOCs could play a role in MPM pathogenesis in order to build a possible diagnostic MPM tool.

      Methods
      10 MPM patients and 10 healthy asbestos-exposed individuals (mean asbestos fiberyear count 14,6 (5,5) fibre.years/cc) were included after refraining from eating, drinking and smoking for at least 2 hours before sampling. They breathed tidally for 3 minutes through a mouthpiece connected to a bacteria filter. Ten ml alveolar air was sampled via a CO~2-~controlled ultrasonic sensor and analyzed using the BioScout Multicapillary Column/Ion Mobility Spectrometer (MCC/IMS, B&S Analytik, Dortmund, Germany) [Westhoff M 2009], by using N~2~ as a carrier gas. Per subject a background sample was taken. Peaks of interest were visually selected and their intensity (V) was analyzed and compared between background and breath samples via on-board VisualNow 3.2 software and SPSS v21 (IBM) using Mann-Whitney-U tests.

      Results
      Out of 41 peaks of interest, three show a significantly higher intensity in the exhaled breath of MPM patients than healthy controls [Table]. The high AUC~ROC~ of resp. P12 (0.877) and P24 (0.863) suggests a possible role of these associated VOCs in MPM pathogenesis and as a diagnostic marker in discriminating MPM patients from asbestos-exposed healthy controls. Figure 1

      Conclusion
      Several VOCs of interest were obtained in the breath of MPM patients. Two peaks were significantly discriminating between both populations. GC-MS analysis and further large cohort studies are ongoing in order to validate the accuracy of IMS as a diagnostic tool for MPM.