Investigating phenotypic and genomic heterogeneity in malignant pleural mesothelioma.

Background: Phenotypic and genomic heterogeneity may contribute to the pathogenesis of Malignant Mesothelioma (MM). We have implemented a novel clinical study in which multiple samples of tumor and normal pleura are obtained from individual patients undergoing surgery for the management of MM. Method(s): Patients undergoing routine video-assisted thoracoscopic surgery (VATS) undergo a baseline FDGPET scan. Extra samples are taken from both PET positive and PET negative areas of pleura, along with normal pleural samples. Corresponding fresh and formalin fixed tissue samples are obtained. Patients are subsequently treated as per standard of care practice, along with detailed clinical follow up and serial PET imaging. Standard H&E will be performed on formalin fixed samples to look for morphological heterogeneity in tumor cells and stroma and the findings will be correlated with PET imaging. Result(s): Six (6) patients (4 epithelioid, 1 sarcomatoid and 1 biphasic subtype) with median age of 70 (62-81) have been recruited into the project so far. All patients underwent an FGD-PET scan prior to VATS procedure. Multiple samples from PET avid and PET non-avid areas were collected and stored from 5 out of 6 patients. Preliminary results show that high quality samples were obtained. The H&E analysis shows that tumors from PET avid area are morphologically different to PET not avid areas (Figure 1). Further IHC analysis of various MM specific markers is underway. Conclusion(s): This preliminary data demonstrate the feasibility of our clinical approach. We therefore propose to create a unique research platform in which MM samples from multiple sites from each patient will be integrated with clinical, imaging and therapeutic response. Further proof-of-principle studies will explore: (i) regional heterogeneity and the response to therapies; (ii) variability in the detection of predictive biomarkers within the same patient; (iii) genomic heterogeneity within MM, and its relations