Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
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 3rd 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
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Keywords: combined modality treatment, malignant mesothelioma,
chemotherapy, Immunotherapy
S94 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017