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R. Bueno
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 8
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.01 - PD-L1 Is Highly Expressed in Malignant Mesothelioma and PD-1<sup>+ </sup>Lymphocytes within Malignant Effusions Induce PD-L1 Expression (ID 553)
16:45 - 16:56 | Author(s): S. Khanna, A. Thomas, D. Abate Daga, B. Morrow, J. Zhang, S.M. Steinberg, A. Orlandi, P. Ferroni, J. Schlom, F. Guadagni, R. Hassan
- Abstract
- Presentation
Background:
The PD-1 and PD-L1 pathway is an immune checkpoint, which protects normal tissues from immune attack by curbing the effector T-cell response but can also prevent anti-tumor immune response. However their role in mesothelioma is not well understood. The present study aimed to understand the PD-1 and PD-L1 expression levels and their interactions in mesothelioma patients.
Methods:
Sections of formalin-fixed, paraffin-embedded pleural and peritoneal mesothelioma tumor samples from patients who were evaluated for various clinical trials at the NCI Center for Cancer Research were tested for PD-L1 expression (Anti-PD-L1 rabbit monoclonal recombinant primary antibody MKP-1B-196-10; Merck-Serono). PD-L1 expression on primary and established mesothelioma cell lines, malignant pleural effusions and ascites of mesothelioma patients were assessed using a commercial anti-PD-L1 antibody and analyzed by flow cytometry. Paired malignant effusion and peripheral blood samples were tested for PD-1 and PD-L1 expression on immune cells. Co-cultures of autologous tumor cells and T cells grown from malignant effusions of a mesothelioma patient were evaluated to understand the PD-1 and PD-L1 interaction.
Results:
Tumor samples from 65 patients included 44 peritoneal and 21 pleural mesotheliomas; 55 with epithelioid histology and 10 of other subtypes (sarcomatoid 2, biphasic 3, uncategorized 5). 41 of 65 (63%) tumors were positive for PD-L1 expression (defined as >5% PD-L1 expression on tumor cells, of any intensity) with levels of expression ranging from 5% to 80% of tumor cells, and intensities from 1+ to 3+. 24 (37%) were negative including 10 with focal staining. A higher proportion of males had tumor PD-L1 expression than females (73% vs. 46%; p=0.04). There was no association between PD-L1 expression and primary site of disease, age, race, histology and distant metastasis. Patients with PD-L1 positive tumors had a numerically inferior overall survival than patients with PD-L1 negative tumors (23.0 months vs.33.3 months; p=0.35). All 6 primary and 4 established mesothelioma cell lines tested showed basal expression of PD-L1. This was enhanced on treatment with IFN-γ. The fraction of cells expressing PD-L1 in malignant effusions ranged from 17 to 43%. Malignant effusions from 2 of 3 patients had high PD-1 expression on both CD4[+] and CD8[+] T cells. In addition, CD8[+] T cells in malignant effusions had significantly higher levels of PD-L1 expression compared to CD8[+] T cells in peripheral blood (7.47±2.75 % T cells versus 1.97±1.22% T cells; p=0.03). Autologous lymphocytes when co-cultured with tumor cells from malignant effusion, recognized tumor cells and induced IFN-γ mediated PD-L1 expression on their surface.
Conclusion:
High PD-L1 expression in mesothelioma patient tumor samples and tumor cells derived from malignant effusions, as well as presence of PD-1[+] T cells in these effusions indicates the prominent role of PD-1/PD-L1 pathway in maintaining an immunosuppressive milieu in mesothelioma. Thus, inhibiting this pathway could be useful therapeutically.
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ORAL40.02 - Molecular Landscape of Malignant Mesothelioma from Whole Exome Sequencing (ID 2439)
16:56 - 17:07 | Author(s): S.K. Lu, H. Anbunathan, S. Popat, M.E.R. O'Brien, E. Lim, A. Montero Fernandez, A.G. Nicholson, M. Lathrop, A.M. Bowcock, M.F. Moffatt, W.O.C. Cookson
- Abstract
- Presentation
Background:
Whole exome sequencing has revealed key genetic events in several cancer types that have been successfully translated into clinical benefits. These advances are still lacking in malignant mesothelioma (MM), a highly aggressive malignancy with limited effective therapy. Frequent BAP1 mutations occur in a subset of this disease but the full molecular landscape of MM is still poorly characterized.
Methods:
We have therefore conducted whole exome sequencing of tumours from the pleura for 36 cases of MM. DNA from matched blood was available for 7 of the cases and was also sequenced. The variants were identified with GATK tools and annotated with ANNOVAR. Variants were filtered with the following criteria: quality score ≤ 50, present in dbSNP138, 1000 genomes variants and NHLBI ESP 6500 variants. Mutations with deleterious functional consequences predicted by Polyphen-2, SIFT and Mutation Taster tools were confirmed by Sanger sequencing.
Results:
A total of 9,064 variants (3,256 somatic) were identified. We confirmed mutations in genes previously described to be mutated in MM in 5 cases: BAP1 (R227C, Q684X, H141P), NF2 (76_76del, R221X) and TP53 (I195N). In BAP1 wt tumours (6 of the 7 cases with matched blood), we confirmed somatic mutations in 5 genes encoding components of either MAPK or WNT signaling pathways. In addition, we validated somatic mutations in 12 genes across 4 of the 6 cases, many of which are novel in MM and are involved in chromatin modification. We also observed these genes to be mutated in BAP1 wt tumours in the 29 additional unmatched MM cases.
Conclusion:
Thus our data suggests that in addition to BAP1, mutations in genes associated with MAPK, WNT signaling and the chromatin remodeling complex may represent a consistent pattern of molecular alterations in MM.
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ORAL40.03 - Combination Therapy with a CD40-Agonist and Dendritic Cell Immunotherapy Has Synergistic Effects in a Murine Mesothelioma Model (ID 2643)
17:07 - 17:18 | Author(s): L. Lievense, F. Dammeijer, M. Lambers-Kaijen, R. Hendriks, M. Van Nimwegen, J. Hegmans, J.G. Aerts
- Abstract
- Presentation
Background:
The potential of immunotherapy in mesothelioma has recently been demonstrated in multiple (pre)clinical studies. The success of immunotherapy relies on the induction of an anti-tumor immune response which has to overcome the local immunosuppressive environment in established tumors. Tumor-associated macrophages (TAMs) are an important part of the suppressive environment in mesothelioma and reprogramming these TAMs towards a more pro-inflammatory phenotype using a CD40-agonist has shown promising results in multiple solid tumors. Dendritic cell (DC) immunotherapy has been shown to elicit anti-tumor T-cell responses and is currently being studied in mesothelioma patients at our institution. We hypothesize that the combination treatment with a CD40-agonist and DC therapy has synergistic effects and the aim of the current study is to investigate the efficacy of this combinatorial approach.
Methods:
Wildtype Balb/c mice were injected intraperitoneally (i.p.) with the AB1 murine mesothelioma cell line. Different treatment regimens were compared as follows: untreated control group (n=6), monotherapy with CD40-agonist (FGK4.5 monoclonal antibody, n=5), monotherapy with DC immunotherapy (n=5) and combination therapy of DC immunotherapy followed by treatment with the CD40-agonist (n=5). Three days after completion of the treatment regimens, blood was drawn and analyzed using flow cytometry to investigate peripheral immune activation. All mice were monitored and sacrificed when showing signs of severe illness. After sacrifice, tumors are investigated using flow cytometry to determine the local immunological composition.
Results:
Blood analysis revealed that peripheral monocytes of the CD40-agonist group and the combination therapy group showed an increase in expression of MHC-II and PD-L1 compared to the mice in the control group and the DC immunotherapy group. In addition, the combination therapy induced a profound increase in effector CD8 T-cells and proliferating CD8 T-cells compared to the monotherapies. The interim survival analysis at day 40 post tumor cell injection demonstrates a 17% survival of the control group, 80% survival of the monotherapies and 100% survival of the combination therapy. The final survival analysis will be presented at the conference.
Conclusion:
Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces synergistic immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. Although the final survival data are awaited, the presented data demonstrate the potential of the combination of cellular immunotherapy and targeting of the local tumor microenvironment in mesothelioma.
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ORAL40.04 - Discussant for ORAL40.01, ORAL40.02, ORAL40.03 (ID 3466)
17:18 - 17:28 | Author(s): Y. Sekido
- Abstract
- Presentation
Abstract not provided
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ORAL40.05 - The Cancer Stem Cell Inhibitors VS-6063 and VS-5584 Exhibit Synergistic Anticancer Activity in Pre-Clinical Models of Mesothelioma (ID 2753)
17:28 - 17:39 | Author(s): D. Weaver, V. Kolev, Y. Wang, J. Testa, J. Pachter
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum usually resulting from prior exposure to asbestos. Median overall survival with standard of care (SOC) chemotherapy is only 12 months from diagnosis. This poor prognosis may be attributable at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. VS-6063 (defactinib) is an oral small molecule that targets cancer stem cells through the inhibition of focal adhesion kinase (FAK). VS-6063 has demonstrated tolerability, target inhibition, and preliminary signs of clinical activity as a single agent and in combination with paclitaxel in Phase 1 clinical trials (Jones et al., J Clin Oncol 29: 2011 (suppl; abstr 3002); Patel et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 5521)). Currently, VS-6063 is being tested in a randomized, double-blind, placebo-controlled trial in malignant pleural mesothelioma immediately following front-line therapy (COMMAND Trial, NCT01870609). In an effort to identify additional mesothelioma patients who may benefit from a CSC targeting agent, we sought to identify compounds that show synergistic anticancer activity with VS-6063. PI3K/mTOR inhibitors were previously demonstrated to show activity in mesothelioma. VS-5584 is a potent oral small molecule that selectively kills CSCs by targeting multiple PI3K isoforms and mTORC1/2 (Kolev et al, Cancer Res; 75:1, 2014). VS-5584 is currently being investigated as a single agent in a Phase 1 clinical trial, (NCT01991938).
Methods:
The synergy between VS-6063 and VS-5584 was demonstrated in vitro using cell viability assays analyzed by CalcuSyn, HSA and Loewe models. CSCs from mesothelioma cell lines were assessed by the Aldefluor+ flow cytometric assays. The anti-tumor activity of the VS-6063 and VS-5584 combination treatment was tested with in vivo mouse mesothelioma xenograft models.
Results:
A dual PI3K/mTOR inhibitor VS-5584 showed synergistic activity with a FAK inhibitor, VS-6063. VS-5584 further enhanced reduction of mesothelioma CSCs by VS-6063 measured by the Aldefluor+ assay in Mero-14 mesothelioma cells. In a 3D matrigel cell viability assay, the combination of VS-6063 and VS-5584 displayed synergistic reduction in cell viability based on multiple combination analysis models. In a MM87 mesothelioma xenograft model in vivo, the single agent treatment with either VS-6063 or VS-5584 was active in inhibiting mesothelioma tumor growth. Combination treatment further enhanced the antitumor efficacy of either agent alone (p <0.0001).
Conclusion:
VS-6063 (defactinib) and VS-5584 exhibit synergistic anticancer activity in preclinical models of mesothelioma. These data provide a strong preclinical rationale for the open dose-escalation Phase I clinical trial of VS-6063 and VS-5584 in patients with relapsed mesothelioma (NCT02372227).
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ORAL40.06 - Sarcomatoid Differentiation During Progression of Malignant Pleural Mesothelioma (ID 1161)
17:39 - 17:50 | Author(s): B. Vrugt, E. Felley-Bosco, S. Simmler, M. Storz, M. Friess, M. Meerang, A. Soltermann, H. Moch, R. Stahel, W. Weder, I. Opitz
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive tumour with a high local recurrence rate and often a poor prognosis despite multimodal treatment. We evaluated the prognostic impact of morphological and immunohistochemical changes in sequential biopsies obtained from patients with MPM during disease progression.
Methods:
Tissue microarrays were constructed from paraffin-embedded tissue samples of 36 MPM patients (26 epithelioid, 6 biphasic and 4 sarcomatoid) taken before induction-chemotherapy, during surgery and at the time point of tumour recurrence. Immunohistochemical staining for calretinin, cytokeratin 5/6 (CK5/6) and Wilm’s tumor-1 (WT-1) as well as the biomarkers mesothelin, osteopontin, and fibulin-3 was performed, and staining intensity and percentage of positively stained tumour cells scored semi-quantitatively. The results were correlated with clinico-pathological characteristics of the patients including overall survival (OS). To determine the prognostic value of the markers at the different time points, a multivariate analysis including all factors that were significant in univariate analysis was performed.
Results:
In 28% of patients with epithelioid or biphasic MPM, a transition towards biphasic or sarcomatoid growth pattern during disease progression was observed (Figure 1). This dedifferentiation was associated with significantly decreased immunoreactivity for WT-1 (p=0.03), calretinin (p=0.005), mesothelin (p=0.01) as well as a shorter OS (p=0.04). Figure 1 Overall, patients with epithelioid or biphasic MPM in the diagnostic biopsy had a significantly better OS (29 months; 95% confidence interval (CI): range 27-32 months) in comparison to patients with sarcomatoid MPM (5 months; 95% CI: 3-7 months) (p<0.0005). On multivariate analysis, male gender (p=0.04) and high fibulin-3 (p=0.02) in the pre-chemotherapy samples were found to be associated independently with shorter OS.
Conclusion:
In patients with epithelioid or biphasic MPM, high fibulin-3 expression in pretreatment samples and gender are independent predictors of shorter OS. In up to one third of patients disease progression is accompanied by sarcomatoid differentiation, suggesting that factors such as molecular alterations involved in epithelial-to-mesenchymal transition (EMT) are contributing to disease course and clinical outcome. Alternatively, induction chemotherapy might contribute to this transition by promoting selection and outgrowth of therapy resistant tumor cells. Eventually, the different tumor biology of this subgroup of patients may be taken into account for the consideration of alternative patient handling.
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ORAL40.07 - Xpo1 Inhibition: A Promising Therapeutic Strategy in Thymic Epithelial Tumors (ID 1230)
17:50 - 18:01 | Author(s): F. Conforti, T. De Pas, A.T. Alberobello, G. Rao, Y. Wang, G. Giaccone
- Abstract
- Presentation
Background:
Growing evidence suggests that nuclear–cytoplasmic transport is frequently dysregulated in cancer cells, and is involved in promoting carcinogenesis, cell survival, drug resistance and tumor progression. In particular, enhanced nuclear export is one mechanism by which malignant cells inactivate tumor suppressor proteins (TSPs). Inhibition of XPO1 (CRM1), the main karyopherin involved in the nuclear export of TSPs, restores nuclear localization and function of TSPs in several preclinical models. Selinexor(KPT-330) is an XPO1 inhibitor being tested clinically in solid tumors and hematological malignancies that showed some activity in patients with thymic epithelial tumors (TETs). Here, we describe the activity of selinexor in preclinical models of TETs.
Methods:
Thymoma (IU-Tab1, T1682), thymic carcinoma (Ty82, T1889, MP57) and immortalized normal thymic epithelial cells (TEC84) treated with selinexor or vehicle were assayed by CellTiter-Glo and flow cytometry. Western blot analysis of nuclear and cytoplasmic protein fractions and immunofluorescence assays were used to study the cellular sublocalization of XPO1 cargoes before and after treatment. The effect of selinexor on cell migration was determined using a wound-healing assay. A selixinor-resistant cell line was generated by growing selinexor-sensitive IU-Tab1 cells at increasing concentrations of the drug. Mutational status and copy number of the XPO1 gene was assessed by Q- PCR and Sanger sequencing.
Results:
All TET cell lines were sensitive to selinexor (IC~50~ 90-250 nM) with the exception of T1682 (thymoma type B), which showed intrinsic drug resistance (IC~50~ > 1000 nM). In the sensitive cell lines, selinexor treatment induced G1 (MP57) or G2 (IU-Tab1, Ty82) cell-cycle arrest at 24 hours, and induced apoptosis 2-5 fold over untreated cells by 72 hours. The cytotoxic effects of selinexor were not observed in immortalized normal TEC84 cells at nanomolar concentrations, and required higher concentrations (IC~50 ~800nM) to induce a cytostatic effect. Drug treatment led to increased nuclear concentrations of several TSPs involved in cell cycle regulation (e.g. p21, p27), genomic stability (p53) and induction of apoptosis (FOXO3a) and also reduced the total cellular expression of the oncogenic protein NF-kB. These results were confirmed with siRNA knockdown of XPO1. In addition,selinexor treatment impaired tumor cell migration and had cytotoxic synergistic effect in combination with doxorubicin or etoposide in T1889 and IU-Tab1 cell lines, increasing nuclear accumulation of the XPO1 cargo protein, Topoisomerase IIα. Furthermore, we demonstrated that selinexor-resistant cell line has similar growth rates to their parental cells, however overexpress XPO1 due to gene amplification, confirming the importance of aberrant XPO1 activity in TET survival.
Conclusion:
Our data show the importance of XPO1 in TETs biology and demonstrate activity of selinexor in preclinical models, further supporting the planned Phase II trial in patients with TETs.
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ORAL40.08 - Discussant for ORAL40.05, ORAL40.06, ORAL40.07 (ID 3467)
18:01 - 18:11 | Author(s): T.M. Jahan
- Abstract
- Presentation
Abstract not provided
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.01 - Risk of Lung Cancer in Female Non-Smokers Requires Extended Screening Guidelines (ID 2137)
16:45 - 16:50 | Author(s): R. Bueno
- Abstract
- Presentation
Background:
The National Lung Screening Trial (NLST) established a 20% reduction in lung cancer-specific mortality with low-dose computed tomography (LDCT) in 30 pack year smokers. However, approximately 25% of all lung cancers occur in non-smokers, and screening guidelines are needed for this large cohort. Pre-test probability of lung cancer can be estimated in this group using a validated risk prediction model [Liverpool Lung Project, LLP]. The LLP compares risk in 579 lung cancer cases with 1157 age and sex matched controls.
Methods:
We used the LLP model to illustrate risk profiles for non-smoking females compared to 30 pack year smokers [the NLST target population]. This tool revealed the individual and cumulative effect of risk factors in non-smoking females. The LLP estimates the probability of developing lung cancer within 5 years based on age, sex, smoking history, family history of lung cancer, infectious and occupational exposures, and prior diagnosis of a malignant tumor other than lung cancer. This tool has been validated in a Caucasian population including never and ever smokers up to 79 years of age (cross validation of tool: AUC=0.70).
Results:
We generated risk profiles for female non-smokers between 65-79 years old and no other co-morbidity, and compared the risk against those for women in the same age bracket with 30-pack year smoking history or additional non-tobacco risk factors (i.e. previous pneumonia, asbestos exposure, having a relative with lung cancer < 60years, and the combination of all factors listed). Significant risk with increasing age was predicted by the LLP model for women with 30 pack year smoking history (peak risk at age 75 years 2.2% over next 5 years). This is less than the risk of 6.7% over the next 5 years (at age 75 years) for non-smoking women with the combination of all mentioned risk factors. Relative risk of lung cancer of non-smoking women with all noted risk factors was 3.5 compared to women with no other risk factors other than 30 pack-years smoking history. Relative risk of smoking women compared to non-smoking without other risk factors was 4, while relative risk of non-smoking women with cumulative risk factors was 14 compared to non-smoking women with no other risk factors. Figure 1
Conclusion:
Therefore, the development of lung cancer risk prediction models is a key advance in the assessment of patients at risk. Individual risk assessment can be judged using the LLP model and could encourage refinement of screening recommendations.
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.01 - FAK Inhibitor VS-6063 Targets Mesothelioma Cancer Stem Cells: Rationale for Maintenance Therapy after Conventional Chemotherapy (ID 2710)
18:30 - 18:35 | Author(s): R. Bueno
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung and peritoneum with median overall survival with standard of care (SOC) chemotherapy only 12 months from diagnosis. This poor prognosis may be attributed at least in part to cancer stem cells (CSCs) that are resistant to chemotherapy and can mediate cancer recurrence and progression. Focal adhesion kinase (FAK) plays an essential role in the survival, self-renewal and tumor-initiating capability of CSCs. The FAK inhibitor VS-6063 (defactinib) is currently being tested in patients with MPM following disease control on standard pemetrexed/platinum chemotherapy (COMMAND, ClinicalTrials.gov NCT01870609).
Methods:
An Aldefluor assay, previously validated as a CSC assay (Shapiro et al., 2014), was used to assess the effects of chemotherapy or VS-6063 on CSCs in vitro. Tumor initiating potential of MPM cells after treatment with SOC agents, and VS-6063 alone or in combination with pemetrexed was measured in vivo. CSC marker expression in MPM patient tumor samples was measured by IHC, Q-PCR and RNASeq analysis. Novel CSC markers were validated in an in vivo limiting dilution assay.
Results:
Treatment of a human MPM cell line with pemetrexed or cisplatin, the SOC therapy for mesothelioma, resulted in a 6-fold enrichment of ALDH-positive CSCs. In direct contrast, the FAK inhibitor VS-6063 markedly reduced the proportion of CSCs. Control and pemetrexed-treated MPM cells showed robust tumor initiation in vivo, while cells treated with VS-6063 alone or VS-6063 plus pemetrexed had decreased tumor initiating capacity. FAK inhibitor was found to selectively induce apoptosis in CSCs, indicating that the mechanism of their elimination is cell death. In addition to ALDH, several new mesothelioma CSC markers were validated in in vivo limiting dilution assay and their clinical utility was assessed. An increase in CSC markers, including ALDH1, CD133 and CXCR2, was observed in tumor samples from 11 patients following first line pemetrexed-cisplatin chemotherapy. In tumor biopsies from MPM patients treated for 12 days with VS-6063, tumor pFAK (Y397) and expression of CSC markers was reduced. Interestingly, gene expression analysis of these samples revealed an inhibition of CSC pathways after VS-6063 administration. VS-6063 maintained the effect of chemotherapy in patient-derived xenograft (PDX) mouse model. Treatment with pemetrexed/cisplatin resulted in tumor growth inhibition followed by rapid tumor re-growth upon cessation of the treatment. Tumor re-growth was substantially delayed when FAK inhibitor was administered after chemotherapy.
Conclusion:
These data provide a strong rationale for the current clinical testing of VS-6063 following treatment with pemetrexed plus platinum to potentially prolong time to progression in patients with mesothelioma.
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MTE 33 - (Debate on) Prognostic Biomarkers in Mesothelioma (Ticketed Session) (ID 85)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 07:00 - 08:00, 201+203
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MTE33.01 - (Debate on) Prognostic Biomarkers in Mesothelioma (ID 2024)
07:00 - 07:30 | Author(s): R. Bueno
- Abstract
- Presentation
Abstract not provided
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ORAL 14 - Biology 2 (ID 112)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:T. Nakano, P. Baas
- Coordinates: 9/07/2015, 16:45 - 18:15, 702+704+706
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ORAL14.03 - Integrin Linked Kinase Pathway: A Potential Driver of Tumorigenesis of Malignant Pleural Mesothelioma (ID 2135)
17:07 - 17:18 | Author(s): R. Bueno
- Abstract
Background:
Identifying driver mutations assists with understanding molecular aspects of cancer and development of novel drugs. The genetics of malignant pleural mesothelioma (MPM) has primarily been to date described in terms of deletions of specific chromosomal regions with CDKN2A and NF2 most commonly mutated, and more recently, evidence for a role of BAP1. The current work suggests that activation of the Integrin Linked Kinase (ILK) pathway may be oncogenic in a subset of MPM.
Methods:
Whole-genome sequencing was accomplished for 10 tumor and matched normal genomic DNA samples using a Complete Genomics platform. Tumor and normal genomes were sequenced to at least 30-fold haploid coverage, with corresponding diploid coverage of at least 99.5%. Selected candidates single nucleotide variations (SNVs) were further characterized using PCR and Sanger sequencing to identify tumor-specific single nucleotide mutations. Potential driver genes were investigated in 147 additional MPM cases by targeted resequencing. Levels of transcripts were examined in an available expression data set (Affymetrix® Human Gene 1.1 ST Array). Association of mutation status and gene expression to clinicopathologic variables was explored statistically.
Results:
Among 146 single nucleotide variants (SNVs) mapping in amino acid coding regions of annotated exons and generating non-synonymous amino acid changes, 85 were confirmed to be tumor specific. Functional enrichments of genes affected by point mutations were performed utilizing Ingenuity Pathway Analysis to identify clusters of genes annotated in pathways potentially relevant to the biology of MPM. Mutations affecting genes involved in the Integrin Linked Kinase (ILK) pathway were the most significantly (p = 4.9e-5) enriched. Specifically, 5 of 10 sequenced MPM samples showed point mutations in at least one of 6 genes of this pathway (MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A). Re-sequencing analysis of 147 MPM tumors identified 40 SNVs in these genes among 31 MPM samples (21%). Thirty-five (88%) SNVs were present in both tumor and matching normal DNA samples. In 4 samples, tumor specific mutations were identified, 3 in MYH9 (1.4%) and 2 in RHOA (1.4%) both recently proposed as genes involved in tumorigenesis. Non-epithelioid tumors expressed significantly higher levels of MYH9 (p<0.001), RHOA (p<0.001), and MYH10 (p=0.001) compared to epithelioid tumors. RHOA was more highly expressed in men than women (p=0.001). The highest quartile of MYH9 and of RHOA expression was associated with higher gender-adjusted risk of death (HR=2.23 and HR=1.95, respectively) compared to the lower three quartiles (p<0.001) by multivariate analysis.
Conclusion:
Tumor specific mutations in MYH9 or RHOA were found in six of 157 (3.8%) MPM patients. Interestingly, both MYH9 (22q13.1) and RHOA (3p21.3) reside in two chromosomal regions frequently deleted in MPM. Additional analysis is in progress to investigate the role of ILK pathway activation in MPM. These observations suggest that a sub-class of MPM may respond to therapy targeting the ILK pathway.
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ORAL 26 - Clinical Trials 2 (ID 127)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A. Scherpereel, C. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 702+704+706
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ORAL26.03 - Predictive and Prognostic Value of Clinical TNM Staging for Patients with Malignant Pleural Mesothelioma Undergoing Surgery (ID 3127)
11:07 - 11:18 | Author(s): R. Bueno
- Abstract
- Presentation
Background:
Clinical staging of malignant pleural mesothelioma (MPM) is challenging due to the unique morphology of the tumor, macroscopic resolution and lack of radiographic contrast between tumor and adjacent structures and the number and complexity of anatomic features comprised by the descriptors. Recent analysis of a large IASLC MPM database revealed discrepancy between clinical (cTNM) and pathological (pTNM) staging (J Thorac Oncol 2012;7: 1631–1639). The current study examined in a retrospective cohort the concordance between cTNM and pTNM stage, the accuracy of individual clinical T and N features in predicting corresponding pathological features, and the prognostic significance of each feature.
Methods:
An IRB approved MPM registry was queried to identify patients who had undergone extrapleural pneumonectomy with complete pathological evaluation and who had preoperative CT or PET-CT scans available for review. All scans were assigned binary scores at the level of individual features by a single chest radiologist (R.G.) with significant experience with MPM. Corresponding scores for pathological features were obtained from the registry database along with histological subtype and overall survival (OS). cTNM and pTNM stage were assigned according to AJCC/UICC 7[th] edition criteria. Taking pTNM as gold standard, each case was scored as concordant, understaged or overstaged by cTNM. Sensitivity, specificity and univariate hazard ratio (HR) for death were determined for individual cT and cN features.
Results:
Inclusion requirements were met for 390 patients. Available preoperative imaging comprised CT scan for 240 (62%) and integrated PET-CT for 150 (38%) patients. MPM was left-sided in 196 (50%) cases. Histology was epithelioid in 234 (60%), biphasic in 141 (36%), sarcomatoid in 13 (3%) and desmoplastic in 2 (<1%) cases. Staging by pTNM was: I, 7 (2%); II, 33 (8%); III, 225 (58%); IV, 125 (32%). Staging by cTNM was: I, 30 (8%); II, 39 (10%); III, 250 (64%); IV, 71 (18%). cTNM was concordant with pTNM staging in 188 (48%), overstaged in 139 (36%), and understaged in 63 (16%) cases. Concordance rate was not substantially modulated by type of scan, use of contrast, prior sclerosis or presence of pleural effusion. The most predictive and prognostic features included (N, sensitivity, specificity, HR, p-value): T2: Interlobar fissures (297, 85%, 71%, 1.4, 0.02); T3: Endothoracic fascia (158, 48%, 64%, 1.4, 0.004), Mediastinal fat (105, 28%, 73%, 1.8, <0.0001); T4: Diffuse/multifocal chest wall (21, 12%, 96%, 1.8, 0.01).
Conclusion:
Data-driven modification of cTNM criteria may improve concordance between cTNM and pTNM staging. Despite inherent sensitivity limitations of cTNM, improved prognostic performance may be achievable by 1) incorporating a size criterion (e.g. radiographic tumor volume), and 2) emphasizing features with high specificity and significant prognostic value when defining T descriptors.
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