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M. Soeberg
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MTE29 - Advances in Malignant Pleural Mesothelioma (Ticketed Session) (ID 322)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 07:30 - 08:30, Stolz 1
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MTE29.02 - Advances in Malignant Pleural Mesothelioma (ID 6593)
08:00 - 08:30 | Author(s): M. Soeberg
- Abstract
- Presentation
Abstract:
Epidemiology: MPM, representing around 90% of all mesothelioma cases diagnosed, is an aggressive tumour with a poor prognosis, and relatively few treatment options. The association of mesothelioma with asbestos exposure is well established. The latency period, the interval between first asbestos exposure to the diagnosis is long (around 40 years), and explains why in many instances the effect of banning asbestos from the workplace has yet to be seen. At the same time there is evidence accumulating that non-occupational asbestos exposure may significantly contribute to mesothelioma incidence [1] and it is most worrying that unrestricted use of this carcinogen is allowed in Russia and most Asian, African and South American countries. Unfortunately the multilateral treaty to promote shared responsibilities in relation hazardous chemicals (Rotterdam convention) has become paralyzed by the veto of asbestos producers and considering the rapid surge of asbestos consumption in developing countries the end of the mesothelioma epidemic is not in sight [2]. Molecular biology: Major efforts have been undertaken to explore the genomic alterations responsible for the development of malignant pleural mesothelioma. Recent next-generation sequencing efforts have confirmed the frequent loss of tumour suppressor genes identified in earlier studies. Deletion and loss of function mutation of CDKN2A, NF2 and BAP1 are common molecular events in MPM, but the overall mutational load tends to be lower in MPM than in lung cancer. Mutation, aberrant splicing, and gene fusions occur in additional genes such as SF3B1, TRAF7 and SETD2, but at lower frequency [3]. Expression analyses suggest that there are subgroups of tumours both within and between the traditional histopathological subtypes of MPM [3, 4], and this has potential implication for prognosis. Although still to be published, the results from a TCGA mesothelioma study paint a similar picture of the mutational and transcriptional landscape. Investigation of microRNA expression reveals a general downregulation of microRNAs with tumour suppressor activities. In addition to miR-31, frequently co-deleted with CDKN2A, the miR-15/16 family is consistently downregulated in MPM tumours. This family controls expression of targets such Bcl-2, CCND1 and VEGF, and thus plays a role in the regulation of proliferation, apoptosis and angiogenesis. Recent data suggest that these microRNAs also play role in controlling the levels of PD-L1 expression in MPM cells [5], targeted by immune checkpoint inhibitors. Treatment Options: MPM is notoriously refractory to localized and systemic treatment. Meta-analyses (multivariate analyses) of large series of patients confirm that the prognosis of the select group of patients able to undergo radical surgery is significantly better than without surgery [6]The debate about the extent of radical surgery has for some time been governed by the significant risks associated with radical surgery as noted in the MARS trial. Therefore, when radical multimodality treatment approaches are considered, it seems prudent to involve an experienced team at a high volume centre. While the important palliative role of radiotherapy in MPM has been accepted by the oncological community, consolidation radiotherapy after radical surgery [7] has not been shown to provide major benefits in terms of local control. To define the role of (intensity modulated) accelerated radiotherapy in MPM comparative studies are needed. The impressive data (median overall survival of 51 months) from the SMART study [8] combining pre-operative intensity modulated radiation therapy (IMRT) immediately followed by extra-pleural pneumonectomy in 62 patients MPM patients with epithelial histology suggests that such an approach may have the potential to become an alternative for induction chemotherapy followed by radical surgery. Almost every chemotherapy agent has been tested in MPM. Cisplatin, methotrexate, pemetrexed and the anthracyclines doxorubicin and daunorubiucin were most active, but single agent activity seldomly exceeded a 20% response rate. A systematic review of the chemotherapy literature carried out in the early 2000s concluded that combination therapy was likely to be more effective than single agent therapy [9]and shortly thereafter Vogelzang’s randomized comparison between cisplatin and cisplatin/pemetrexed confirmed cisplatin/pemetrexed as the new therapy standard. Thirteen years later this standard has been augmented by a large comparative French intergroup study revealing that the addition of bevacizumab to the cisplatin/pemetrexed standard is associated with a 2.7 months advantage in median overall survival [10]. However, it important to note that a not insignificant number of negative phase II and III studies with a range of inhibitors of growth factors including EGFR, VEGF and PDGF had preceded this positive result. Other targeted agents investigated in phase II and III studies including bortezomib, vorinostat, everolimus, and defactinib, the inhibitor of the NF2/mTOR/FAK pathway, have also failed to show notable activity in pre-treated MPM patients [11]. It has become clear that MPM is an immunogenic tumour type and the preliminary data showing responses after immune checkpoint (PD-L1) inhibition [12] seem to indicate that reversing the immunosuppression induced by advancing disease is likely to represent a major step forward. However, monotherapy with Tremelimumab, inhibitor of CTLA-4 and considered active in phase II studies, failed to produce a survival benefit over placebo in 2[nd] and 3[rd] line, underlining the importance of comparative studies [13]. Independent research groups have reported ‘spontaneous’ regression of MPM, revealed a relation between infiltrating lymphocytes and plasma cells and prognosis and presented promising early clinical results with mesothelin-targeting antibodies [11]. Most recently dendritic cell vaccination combined with pulsed (metronomic) cyclophosphamide to deplete regulatory T cells resulted in prolonged tumour control in a limited group of MPM patients [14]. It is not excluded that targeting multiple compartments involved in immune surveillance will lead to increased efficacy. Early signs of efficacy of experimental treatment with tumour suppressive microRNAs packaged in minicells [15, 16] and the interaction between the microRNA 15/16 family and PD-L1 expression point to the complexity of immune checkpoint regulation and underlines the need for additional translational studies to unravel the resilient drug resistance mechanisms operable in MPM. 1. Marinaccio, A., et al., Malignant mesothelioma due to non-occupational asbestos exposure from the Italian national surveillance system (ReNaM): epidemiology and public health issues. Occup Environ Med, 2015. 72(9): p. 648-55. 2. Takahashi, K., P.J. Landrigan, and R. Collegium, The Global Health Dimensions of Asbestos and Asbestos-Related Diseases. Ann Glob Health, 2016. 82(1): p. 209-13. 3. Bueno, R., et al., Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet, 2016. 48(4): p. 407-16. 4. de Reynies, A., et al., Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition. Clin Cancer Res, 2014. 20(5): p. 1323-34. 5. Williams, M., et al., Tumour suppressor microRNAs regulate PD-L1 expression in malignant pleural mesothelioma., in International Mesothelioma Interest Group (iMig) 2016. 2016: Birmingham 6. Linton, A., et al., Factors associated with survival in a large series of patients with malignant pleural mesothelioma in New South Wales. Br J Cancer, 2014. 111(9): p. 1860-9. 7. Stahel, R.A., et al., Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol, 2015. 16(16): p. 1651-8. 8. de Perrot, M., et al., Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg, 2016. 151(2): p. 468-73. 9. Berghmans, T., et al., Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis. Lung Cancer, 2002. 38(2): p. 111-121. 10. Zalcman, G., et al., Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet, 2016. 387(10026): p. 1405-14. 11. Schunselaar, L.M., et al., A catalogue of treatment and technologies for malignant pleural mesothelioma. Expert Rev Anticancer Ther, 2016. 16(4): p. 455-63. 12. Alley, E.W., et al., Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028. Cancer Research, 2015. 76(18): p. CT 103. 13. Kindler, H.L., et al., Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): Results from the global, double-blind, placebo-controlled DETERMINE study. Journal of Clinical Oncology, 2016. 34(15 (May Suppl)): p. #8502. 14. Cornelissen, R., et al., Extended Tumor Control after Dendritic Cell Vaccination with Low-Dose Cyclophosphamide as Adjuvant Treatment in Patients with Malignant Pleural Mesothelioma. Am J Respir Crit Care Med, 2016. 193(9): p. 1023-31. 15. Reid, G., et al., Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer. Epigenomics, 2016. 8(8): p. 1079-85. 16. Kao, S.C., et al., A Significant Metabolic and Radiological Response after a Novel Targeted MicroRNA-based Treatment Approach in Malignant Pleural Mesothelioma. Am J Respir Crit Care Med, 2015. 191(12): p. 1467-9.
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