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Ramon Palmero Sánchez

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    MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 12
    • Now Available
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      MA23.01 - Phase II Trial of an Oral FGFR Inhibitor AZD4547 as Second or Third Line Therapy in Malignant Pleural Mesothelioma: Final Results of FRAME Study (Now Available) (ID 2208)

      14:30 - 16:00  |  Presenting Author(s): Wei-Sen Lam  |  Author(s): Anna K Nowak, Fred Chen, Sanjeevan Muruganandan, Sukyana Arunachalam, Melvin Chin, Michael Millward, Cathy Read, Kevin Murray, Jenette Creaney, Y C Gary Lee

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment options are limited after first line platinum-based therapy for malignant pleural mesothelioma (MPM). FGFR-9 is a mitogenic ligand that activates the FGF-receptor (FGFR) family and is overexpressed in pleural fluid and tumour samples from mesothelioma patients. In mesothelioma mouse models, FGF-receptor inhibitors reduce tumour burden. Hence, we examined the efficacy of the FGFR tyrosine kinase inhibitor, AZD4547 as second/third line therapy in MPM.

      Method

      From April 2016 to January 2019, we conducted a single-site, single arm, open-label study of AZD4547 in patients with MPM. Eligible patients had histologically or cytologically confirmed mesothelioma, measurable disease and had progressed after first or second line therapy. Patients received oral 80mg twice-daily AZD4547 with protocol dose reductions as required. The primary end point was 6-month progression free survival (PFS6); key secondary endpoints included PFS, response rate, overall survival, and safety and tolerability. Using a Simons' two-stage design, 26 patients would be recruited to the first stage and the study would be declared negative if fewer than 7 (27%) of 26 patients achieved PFS6.

      Result

      24 patients (21 (87%) male), median age 69.5 (range 53-84) were recruited. Histological subtype was epithelioid (83.3%), biphasic (8.3%), sarcomatoid (8.3%). Most patients had one prior regimen (14; 58%). Common toxicities included grade 1 and 2 hyperphosphataemia, nail changes, stomatitis, and ophthalmological changes, consistent with reported toxicities of this drug class. No adverse events required hospitalisation. There were two partial responses (8%); 17 patients (70%) had stable disease (SD) for at least 6 weeks, and 5 patients (21%) had progressive disease as their best response. Three of 24 patients (12%) were progression free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and was discontinued once the criteria for progressing to stage 2 could not be met. Progression free survival was 3.9 months and overall survival was 9.3 months. One patient remained on study with SD for 16 months, experiencing ongoing grade 2 hyperphosphatemia, alopecia of body and facial hair and grade 2 onycholysis.

      Conclusion

      The FGFR inhibitor AZD4547 was ineffective for patients with MPM who had progressed on first or second line therapy. Continuous grade 2 cutaneous and ocular toxicities were observed with prolonged therapy

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      MA23.02 - CDK4/6 Inhibitors Show Antitumor Effects in Preclinical Models of Malignant Pleural Mesothelioma (Now Available) (ID 1866)

      14:30 - 16:00  |  Presenting Author(s): Elisabeth Aliagas  |  Author(s): Maria Martínez-Iniesta, Miguel Hernández, Ania Alay, David Cordero, Xavier Solé, Francisco Rivas, Anna Ureña, Noelia Vilariño, Cristina Muñoz-Pinedo, Alberto Villanueva, Ernest Nadal

      • Abstract
      • Presentation
      • Slides

      Background

      Novel therapeutic approaches are needed to improve the clinical outcome of patients with malignant pleural mesothelioma (MPM). In the current study, we investigate the antitumor activity of CDK4/6 inhibitors in preclinical models of MPM.

      Method

      MPM cell lines (H28, H226, H2052, H2452, MSTO-211H) and primary cultures (ICO_MPM1, ICO_MPM2, ICO_MPM3) were treated with abemaciclib or palbociclib for 24 and 72 hours. Cell viability was evaluated by cell counting and crystal violet assays. Cell death and cell cycle distribution were analyzed by flow cytometry and senescence was quantified by β-galactosidase expression. For transcriptomic studies, mRNA expression was assessed through RNA sequencing analysis. Gene set enrichment analysis (GSEA) was used to identify signaling pathways deregulated in MSTO-211H cells treated with CDK4/6 inhibitors. MSTO-211H cells were implanted subcutaneously in athymic mice that were randomly assigned to the following cohorts (n=7): i) vehicle; ii) cisplatin + pemetrexed; iii) palbociclib alone and iv) palbociclib + gemcitabine. Tumors’ size and mice weight was monitored during 4 weeks to evaluate efficacy.

      Result

      Treatment with abemaciclib or palbociclib at 100nM induced a significant decrease in cell proliferation (mean 50.9% ± 7.6; mean 47.3% ± 9.9, respectively) in distinct MPM cell models, including cells derived from patients who progressed to prior cisplatin and pemetrexed. Both CDK4/6 inhibitors induced G1-phase cell cycle arrest, while cell death was slightly affected (up to 1-5%). At concentrations ranging from 250 to 500nM, the percentage of senescent cells was increased after abemaciclib (15-26%) and palbociclib (18-25%) treatment in all the analyzed cell models. GSEA revealed that CDK4/6 inhibitors promote interferon signaling pathway and MHC presentation. In the in vivo experiment, a significant reduction in tumor growth was observed in response to palbociclib alone or combined with gemcitabine for 4 weeks (vehicle = 1335.8±586.4 mm3; cisplatin + pemetrexed= 726±573.5 mm3; palbociclib = 479±235.7 mm3; palbociclib + gemcitabine = 517±487.4 mm3; p< 0.05).

      Conclusion

      CDK4/6 inhibitors reduce cell proliferation in culture models of MPM mainly by blocking cell proliferation at G1 and by inducing senescence. Palbociclib alone or combined with gemcitabine reduces in vivo tumor growth of subcutaneously implanted MSTO-211H cells compared to chemotherapy.

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      MA23.03 - BAP1 Loss Induces Genome Instability Through BRCA1-Dependent and Independent Mechanisms in Mesothelioma (Now Available) (ID 1133)

      14:30 - 16:00  |  Presenting Author(s): Anita Singh

      • Abstract
      • Presentation
      • Slides

      Background

      Background

      BRCA1 associated protein 1 (BAP1) is a tumor suppressor that is the most frequently mutated in the majority of mesotheliomas. We have previously reported that loss of BRCA1 expression in mesothelioma is a common event, and mediates resistance to spindle checkpoint activator vinorelbine, a drug with relevance to treatment of mesothelioma. However, the loss of BRCA1 is unknown in mesothelioma. The aim of this study is to determine the functional relationship between BAP1 and BRCA1 and examine their role in vinorelbine resistance in mesothelioma cells.

      Method

      We conducted functional genetic analysis of BAP1 and BRCA1 in two MPM cell lines, MSTO and H2452, the latter carrying an inactivating A95D mutation in the UCH domain of BAP1. BAP1 knockdown was achieved by siRNA transfection, while BRCA1 knockdown was achieved by doxycycline induction of an integrated shRNA. Patient samples were processed for BAP1 and BRCA1 immunohistochemistry from MEDUSA cohort.

      Result

      Loss of BAP1 expression led to reduced expression of BRCA1, whereas knockdown of BRCA1 did not affect BAP1 expression. Treatment with the proteasome inhibitor, MG132, restored BRCA1 expression in the absence of BAP1 indicating that BAP1 contributes to post-translational stabilization of BRCA1 protein and the stabilization of BRCA1 by BAP1 is independent of its de-ubiquitination activity. Knockdown of BAP1 induced SAC deficiency and vinorelbine resistance concurrent with reduced expression of BRCA1 and the SAC component, MAD2L1. We also identified a positive and significant correlation between BAP1 and BRCA1 expressionin patient samples.

      Conclusion

      Our data demonstrates that BAP1 regulates BRCA1 expression through regulating its protein stability. Our findings suggest that BAP1 inactivation dysregulates the spindle assembly checkpoint via BRCA1 dependent and independent mechanisms, conferring resistance to vinorelbine. As such BAP1 may have potential as a predictive biomarker for spindle poisons, to underpin chemotherapy stratification. A hypothesis that would be tested in a multicentre randomised phase II VIM trial.

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      MA23.04 - Discussant - MA23.01, MA23.02, MA23.03 (Now Available) (ID 3817)

      14:30 - 16:00  |  Presenting Author(s): Nobukazu Fujimoto

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA23.05 - A Phase II Trial of Nintedanib in Recurrent Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 943)

      14:30 - 16:00  |  Presenting Author(s): Antoinette Josephine Wozniak  |  Author(s): Bryan J. Schneider, Gregory Kalemkerian, Robert Daly, Wei Chen, Jaclyn Ventimiglia, Misako Nagasaka, Marjorie Zauderer

      • Abstract
      • Presentation
      • Slides

      Background

      Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGF, FGF, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy.

      Method

      Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and >4 pts had to have a PFS of ≥4 months to proceed to the second stage.

      Result

      Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS=1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea.

      Conclusion

      Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for >4 months thus potentially deriving some clinical benefit from treatment.

      Supported by Boehringer Ingelheim.

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      MA23.06 - Development of a Novel Genetically Engineered Mouse Model of Malignant Pleural Mesothelioma (Now Available) (ID 2506)

      14:30 - 16:00  |  Presenting Author(s): Katarina Gyuraszova  |  Author(s): Tiziana Monteverde, Tatyana Chernova, Rodger Duffin, Kevin Blyth, Anton Berns, Marion Macfarlane, Daniel J. Murphy

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive neoplasm strongly associated with inhalation of asbestos. MPM is difficult to diagnose and typically occurs after long latency period. Most of the studies are restricted to the end-stage disease and little is known about pre-malignant disease. Efforts to develop targeted therapeutic strategies based on cell culture have largely failed. Our aim was to develop a novel genetically engineered mouse model that combines deletion of the major tumour suppressors lost in human MPM with intra-pleural injection of asbestos. This model will allow us to investigate how mutagenesis combines with fibre-induced inflammation to drive disease evolution.

      Method

      We used genetic engineering to develop an accelerated mesothelioma mouse model combining pleural-restricted, CRE-mediated deletion of NF2, Tp53 (Tp53 is lost in c.10% of human MPM) and full-body knock-out of Cdkn2a with intra-pleural injection of asbestos recapitulating the disease-relevant inflammatory microenvironment. We used immunohistochemistry to analyse the tissue and the lesions.

      Result

      Intra-pleural injection of asbestos dramatically accelerates mesothelioma development in mice triple deleted for NF2, Cdkn2a and Tp53, with all such mice succumbing to malignant disease within 3-4 months (Figure 1). These mice develop malignant lesions in the mesothelial lining of the thoracic cavity accompanied with pleural effusion showing high similarity with human malignant mesothelioma. IHC analysis showes positive staining for mesothelioma markers, e.g. pancytokeratin, vimentin and WT-1. Positive macrophage staining (F4/80) strongly indicates involvement of inflamatory component.sc_pic.png

      Conclusion

      In our model, we combined conditional mouse genetics with dose-defined exposure to asbestos to mimic development of human MPM. Our system provides unique insights into the critical transition from pre-malignancy to MPM and will allow us to test emerging therapeutic interventions in the most physiologically relevant pre-clinical setting possible.

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      MA23.07 - Loss of Expression of BAP1 and/or MTAP Aids in the Diagnosis of Malignant Mesothelioma Metastatic to Lymph Nodes (Now Available) (ID 1121)

      14:30 - 16:00  |  Presenting Author(s): Anja C. Roden  |  Author(s): Tobias Peikert, Julie Vrana, Angela Hudson, Dennis Wigle, Marie Christine Aubry, Aaron S. Mansfield

      • Abstract
      • Presentation
      • Slides

      Background

      Stage and histology are the strongest prognostic parameters in malignant pleural mesothelioma and aid management of patients. However, the distinction between reactive intranodal mesothelial cells and metastatic malignant mesothelioma (MM) can be challenging. Loss of BRCA1 associated protein-1 (BAP1) and/or methylthioadenosine phosphorylase (MTAP) expression has been identified in a subset of MM but not in reactive mesothelial proliferation. We investigated the value of these markers in the distinction between reactive mesothelial cells and metastatic MM in lymph nodes.

      Method

      Surgical files of Mayo Clinic Rochester (1996-2018) were searched for metastatic MM in lymph nodes. All cases and if available corresponding primary MM were reviewed by a thoracic pathologist (ACR) to confirm the diagnosis. Primary MM and lymph nodes were stained with BAP1 (clone C-4) and MTAP (2G4). Absence of nuclear staining of BAP1 and absence of nuclear and cytoplasmic staining of MTAP in essentially all tumor cells was considered as loss of expression.

      Result

      Forty-four patients (25 males, 56.8%) had a median age of 64 years (range, 24-75) at time of surgery. Tissue was available from nodal metastases in all cases, either paired with the primary MM at time of nodal sampling (N=37) or at a different time (N=4) (time between tissue collections, range, 1day- 4 years, respectively), or without paired primary MM (N=3). Thirty-seven pleural, 6 peritoneal and 1 pericardial MM were of epithelioid (N=39) or biphasic (N=5) subtype. Patients underwent extrapleural pneumonectomy (N=17), pleurectomy (N=7), resection (N=9), debulking (N=2), biopsy (N=8), or autopsy (N=1). In nodal metastases, BAP1 and/or MTAP expression was lost in 29 (of 43, 67.4%) cases; specifically, BAP1 expression was lost in 28 (of 44, 63.6%), MTAP was lost in 14 (of 43, 32.6%), and both were lost in 12 (of 43, 27.9%) cases. Agreement in expression/loss of expression of BAP1 and/or MTAP in primary and metastatic MM occurred in all cases. During a median follow up of patients who underwent extrapleural pneumonectomy or pleurectomy (available in N=23) of 14.8 months (range, 1-119) 17 patients died within a median time of 16 months.

      Conclusion

      BAP1 and MTAP immunostains are helpful in the distinction between metastatic MM and reactive mesothelial cells in lymph nodes when one or both markers lost expression in the mesothelial cells. Expression of both markers does not exclude the possibility of metastatic MM.

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      MA23.08 - Discussant - MA23.05, MA23.06, MA23.07 (Now Available) (ID 3818)

      14:30 - 16:00  |  Presenting Author(s): Kemp Kernstine

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA23.09 - Fusion Genes Identified from Whole Genome and Whole Transcriptome Sequencing of Malignant Pleural Mesothelioma Tumours (Now Available) (ID 2014)

      14:30 - 16:00  |  Presenting Author(s): Tian Mun Chee  |  Author(s): Harald Oey, Kwun M Fong, Ian Yang, Lutz Krause, Rayleen Bowman

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is an asbestos-related cancer without curative treatment. Fusion genes result from structural chromosomal rearrangements such as translocation, inversion, amplification and deletions, leading to erroneous apposition of components of two or more genes. Consequences include abolition of gene functions that protect against tumourigenesis, or increased activation of genes that promote cell proliferation. To identify fusion genes in MPM genomes, we executed whole genome sequencing (WGS) on eight MPM tumours, and validated the expression of putative fusion genes identified from WGS by whole transcriptome analysis (RNA-Seq).

      Method

      Histology of eight MPM tumours was confirmed by two qualified anatomical pathologists, prior to extraction of genomic DNA and RNA. Whole genome and whole transcriptome sequencing were performed using Illumina HiSeq platforms. Following stringent data processing and filtration, putative fusion variants were called using an in-house bioinformatics pipeline. Fusion events with potential functional consequences were then validated by whole transcriptome analysis, and annotated using TCGA Fusion Gene Data Portal and The Gene Ontology Resource.

      Result

      A total of 592 and 321 putative fusion variants were called respectively from WGS data using Delly, and from RNA-Seq using STAR-Fusion computational tools. Expression of WGS putative fusion variants was confirmed in RNA-Seq data, resulting in twelve fusion genes being identified. Among 24 genes involved in fusion events, twenty-two were listed in TCGA Fusion Gene Data Portal with gene partners that were not identified in our cases. Two genes were novel to that database. Multiple functional processes that may lead to tumour development were attributable to these genes including protein polyubiquitination, protein deubiquitination, antioxidant activity, DNA repair, immune response, integrin-mediated signalling pathway, chromatin organization, transcription coactivator activity, angiogenesis, natural killer cell proliferation and DNA-binding transcription factor activity.

      Conclusion

      In combination, WGS and RNA-Seq data analysis revealed several fusion genes that warrant further investigation as possible drivers of malignant mesothelioma, and which may serve as diagnostic and therapeutic targets.

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      MA23.10 - Low Number of Mutations and Frequent Co-Deletions of CDKN2A and IFN Type I Characterize Malignant Pleural Mesothelioma (Now Available) (ID 1627)

      14:30 - 16:00  |  Presenting Author(s): Anca Mihaela Nastase  |  Author(s): Amit Mandal, Shir Kiong Lu, Spyridon Gennatas, Hima Anbunathan, Matthew Edwards, Deborah Morris-Rosendahl, Anthony Newman Taylor, Robert C Rintoul, Eric Lim, Sanjay Popat, Andrew G Nicholson, Mark Lathrop, Anne M Bowcock, Miriam F Moffatt, William O.C Cookson

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive tumour with dismal prognosis and overall survival.

      To expand our understanding of molecular background of MPM and to identify novel targetable aberrations we report an integrated genomic analysis of 121 tumour samples.

      Method

      Fresh-frozen tumour samples (obtained from Mesobank UK,the BLF funded Mick Knighton Mesothelioma Tissue Bank, Respiratory BRU Biobank Diagnostic Archive, Royal Brompton Hospital and an Imperial College London prospective study) were analysed by whole exome sequencing (WES, n=50), SNP genotyping (n=118) and targeted capture sequencing (n=119) for 57 genes.

      Sequencing libraries were prepared using Target Enrichment Systems for the Illumina Multiplexed Sequencing platform. Somatic mutations were called using VarScan after recalibration of alignments by Genome Analysis Toolkit (GATK). SNP genotyping was performed with the Human Infinium Omni-Express-Exome v1.3/1.4 Bead Chips arrays. Segmentation and copy number calling was performed using a combination of Allelic specific copy number analysis of tumour (ASCAT), DNACopy and GISTIC softwares.

      Result

      Analysis of WES paired samples revealed a median of 31 non-synonymous somatic mutations per tumour, lower than melanoma (315 somatic mutations) or lung cancer (187.5 for squamous and 158 for adenocarcinoma), two types of tumours linked to known carcinogen exposure.

      Investigation of copy number showed significant frequent deletion (q-value>0.05) of 9p21 locus where CDKN2A, MTAP and IFN type I genes are located. Deletion of CDKN2A was seen in 71/121 patients with homozygous deletion in 58/71 patients. Homozygous co-deletion of CDKN2A and IFN type I was seen in 38/58 patients, homozygous codeletion with MTAP in 49/58 patients while 37 patients showed all three as homozygous co-deleted.

      Patients with CDKN2A and IFN type I deletions had worse overall survival compared with the CDKN2A wild type and patients CDKN2A only deleted patients (median 8.3 months vs 13.1 months, p-value=0.016).

      Deletion of 3p21.1 locus and mutations in BAP1 were detected in 54.5% of the patients, making BAP1 the second most commonly altered gene. RB1 (13q14.2) was commonly altered mainly by deletion in 25.6% of the patients. NF2 and TP53 were affected by mutations in 19.8% and 7.4% of the patients, repectively. Patients with mutations in TP53 had worse overall survival compared with TP53 wild type patients (p-value=0.0005).

      Conclusion

      Co-deletion of CDKN2A, MTAP and IFN type I genes could have therapeutic implications for the patients. Deletion of IFN type I may have direct implications for patient responses to immunotherapy. In the contex of multiple vulnerabilities, the presence of both CDKN2A and RB1 loss might define an important group of patients susceptible to CDK4/6i targeted therapies.

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      MA23.11 - Analysis of Immune Phenotype Composition in Malignant Pleural Mesothelioma (MPM) Using Bulk RNA Sequencing (Now Available) (ID 2326)

      14:30 - 16:00  |  Presenting Author(s): Amit Mandal  |  Author(s): Anca Mihaela Nastase, Shir Kiong Lu, Spyridon Gennatas, Hima Anbunathan, Matthew Edwards, Deborah Morris-Rosendahl, Anthony Newman Taylor, Robert C Rintoul, Eric Lim, Sanjay Popat, Andrew G Nicholson, Anne M Bowcock, Mark Lathrop, Miriam F Moffatt, William O.C Cookson

      • Abstract
      • Presentation
      • Slides

      Background

      Exploiting the immune status of the tumour microenvironment (TME) is increasingly being adopted for many cancer types. Investigation into immune phenotype composition of the TME is at present lacking for malignant pleural mesothelioma (MPM) but critically important in light of the cancer’s overall poor prognosis and lack of targeted therapy as clinical standard of care. In this study, CD8+ve tumour infiltrating lymphocyte (TIL) level has been used as a starting point to compare differences in mutational patterns, histology and survival in MPM.

      Method

      Bulk RNA sequencing of tumour tissue from 35 MPM patients (in-house cohort) was performed. Sequencing read alignment and gene count estimation were performed using STAR (v.2.5.2b). To increase the sample size, raw data from Bueno et al. (n=211 subjects) was accessed and gene count estimations performed. In addition, the TCGA-MESO cohort (n=86 subjects) count data was included from the GDC (Genomic Data Commons) website. All count data were normalized cohort-wise using the ‘voom’ method implemented in limma package. Deconvolution of constituent immune phenotypes in the TME from the bulk RNA-sequencing data was performed by applying CIBERSORT (v.1.04) on normalized count data sets. For assessing the genetic context of observed immune phenotypes, somatic mutations were profiled using targeted sequencing of a custom gene panel for the in-house cohort. For the Bueno et al. and the TCGA-MESO cohorts, somatic mutations were either available from an overlap of whole-exome sequencing (WES) and targeted gene panel, or from WES only.

      Result

      A total of 27 samples (3 of 35 (8.6%), 21 of 211 (9.9%) and 3 of 86 (3.5%) from the in-house, Bueno et al. and TCGA-MESO cohorts respectively) were identified with immune phenotype enriched for CD8+ve TIL. Histological subtype distribution in the CD8+ve enriched samples was seen to be almost equivalently split between Epithelioid and Biphasic subtypes (51.85% and 48.15% respectively). Interestingly, BAP1 mutation was found to be present in only 7.7% of the samples. Considering in addition the genes NF2, SETD2, SETD6, SETDB1, TP53 and LATS1/2, mutations were only found to be present in 57.7% of the samples in total. As such >40% of samples with CD8+ve TIL do not have any mutations detected in known hotspot genes for MPM. Histological subtype is not significantly different between these ‘wild-type’ and hotspot gene(s) mutated samples. Median survival for the groups was found to be 1.85 and 0.73 years respectively.

      Conclusion

      In the present study, approximately 3-10% of MPM samples were found to have enrichment for CD8+ve TIL. Nonetheless on closer examination of the genetic context, mutation patterns emerge that warrant further investigation. For samples that have TP53 (n=3) mutation or mutations in multiple hotspot genes (BAP1, NF2, SETD2, LATS2; n=1), survival understandably is lowest (0.27 years average). This raises a number of further questions including what sustains a tumour despite high CD8+ve TIL population? And more importantly with lack of tumour mutational burden what other TME signals draw effector immune cells? Further investigations, by comparing additional immune markers with copy number changes that might be present in hotspot genes, are therefore required.

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      MA23.12 - Discussant - MA23.09, MA23.10, MA23.11 (Now Available) (ID 3819)

      14:30 - 16:00  |  Presenting Author(s): Kenneth John O’Byrne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)

      14:00 - 15:30  |  Author(s): Ramon Palmero Sánchez

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.

      Method

      Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.

      Result

      T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).

      kaplanmeier_immunegroups.png

      IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.

      Conclusion

      Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.

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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA13.03 - Retrospective Study of Intrathecal Therapy for Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Carcinomatosis (Now Available) (ID 2086)

      14:00 - 15:30  |  Author(s): Ramon Palmero Sánchez

      • Abstract
      • Presentation
      • Slides

      Background

      Leptomeningeal carcinomatosis (LMC) is a devastating cancer-related neurological complication with poor prognosis. In EGFR-mutant (mut) NSCLC patients (pts), osimertinib achieves high penetration into cerebral-spinal fluid (CSF) and promising efficacy. However, for EGFR-mut T790M-negative pts treated with prior 1st- and 2nd-generation tyrosine kinase inhibitors (TKI) and for driver negative NSCLC pts, a combination of intrathecal therapy (IT) and systemic therapy (ST) seems to be an appropriate approach. Our purpose is to explore the clinical outcome of IT combined with ST among NSCLC with LMC depending on EGFR status.

      Method

      NSCLC pts with LMC treated with IT in our institution between 2010 and 2018 were retrospectively studied. After LMC diagnosis, intrathecal methotrexate (scheduled: 12mg twice weekly for 4 weeks, then 12mg weekly for 4 weeks) was given in combination with ST. A Kaplan-Meier survival analysis was performed for overall survival (OS) and progression free survival (PFS).

      Result

      A total of 39 pts were included. Patient’s clinical characteristics are summarized in table 1. EGFR status was 17 mut (del19: 11pts); 11 wild-type (wt) and 11 unknown (unk). LMC and NSCLC diagnosis were more likely to be synchronous in EGFR wt compared with EGFR mut. The median follow-up from LCM diagnosis was 10.2 months. At the time of this analysis, only 6 pts were alive. Thirty-two pts received ST in combination with IT, 18 (46%) pts chemotherapy (6wt/ 3mut/ 9unk), while 14 (36%) pts an EGFR TKI (1wt/ 13mut). Clinical response (improvement of neurological symptoms and/or KPS) was seen in 11 (65%) EGFR mut pts vs 2 (18%) wt pts (p=0.033). Median OS and PFS for the whole cohort were 23 weeks (95%CI, 8.1 to 37.9) and 10 weeks (95%CI, 7.1 to 12.8) respectively. Median OS was higher for EGFR mut pts compared to wt pts, 38 weeks (95%IC 13.6-62.4) and 19 weeks (95%IC, 4.06-33.9) respectively, however this difference was not statistically significant (p=0.36) probably due to lack of statistical power.

      table1_lmc.jpg

      Conclusion

      Methotrexate-based IT given concurrently with systemic TKI may confer a higher clinical benefit and a trend toward OS benefit in NSCLC patients with LCM and EGFR activating mutations.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-54 - Somatic Genome Alterations in Lung Cancer Patients Diagnosed with Li Fraumeni Syndrome (Now Available) (ID 1014)

      09:45 - 18:00  |  Author(s): Ramon Palmero Sánchez

      • Abstract
      • Slides

      Background

      Li-Fraumeni syndrome (LFS) is a rare hereditary condition that consists of TP53 mutations inherited in autosomal dominant manner that confer high risk of developing cancer, including lung adenocarcinoma (LUAD). EGFR-mutated LUAD were reported in the context of LFS but there is no systematic description of somatic mutations and characteristics of lung cancer (LC) patients with LFS.

      Method

      We present a retrospective analysis of clinical and molecular characteristics of patients with LFS diagnosed with LC at the Catalan Institute of Oncology from 1999 to 2019. We collected demographical and clinicopathological features, germline and somatic mutational alterations, treatment and progression-free survival (PFS) and overall survival (OS).

      Result

      A total of 7 patients with LC and LFS were identified in the Genetic Counseling Unit database. They were carriers of germline mutations in TP53. Five of them were classified as pathogenic: c.638G>A; p.(Arg213Gln), c.725G>A; p.(Cys242Tyr), c.742C>T; p.(Arg248Trp), c.844C>T; p.(Arg282Trp) and c.1010G>A; p.(Arg337His) and two of them as likely pathogenic: c.374C>T; p.(Thr125Met) and c.473G>A; p.(Arg158His). Six out of 7 patients were female and 5 out of 7 never smoker. Median age at diagnosis was 38 year-old (range: 29-74). Five patients had stage IV at diagnosis and the most common histologic subtype was LUAD (5). Six patients had first grade family history of cancer with a median of 2 family members (range: 1-4) and 2 patients had prior history of cancer. Tumor somatic profile in LC was obtained in 6 patients, consisting on a ROS-1 rearrangement in one patient and EGFR mutations in 5 patients (exon 19 deletion in 3 patients and missense mutations in 2 patients, p.(Gly719Ala) at exon 18 and p.(Leu858Arg) at exon 21) and in 1 patient was unknown. All patients with mutant EGFR received EGFR tyrosine kinase inhibitors (TKI) with a median PFS of 29 months (95% CI 0-67). Four had partial response and one a complete response to TKI treatment. At disease progression, one patient had small cell transformation and another acquired EGFR T790M mutation. Median lines of treatment were 4 (range 1-6). Two patients are alive at data cut off. Median OS is 47 months (95% CI 32-62).

      Conclusion

      Patients diagnosed with LC and LFS are enriched with actionable genomic alterations and have an earlier onset of the disease. Clinical outcome of patients with EGFR mutations and LFS did not differ from EGFR mutated LC patients who do not carry TP53 germline mutations.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-03 - How to Predict High Grade Radiation Pneumonitis in Non-Small Cell Lung Cancer Patients Treated with Thoracic Radiotherapy (Now Available) (ID 835)

      09:45 - 18:00  |  Author(s): Ramon Palmero Sánchez

      • Abstract
      • Slides

      Background

      Predictive factors of radiation pneumonitis (RP) have been studied without conclusive results. The aim of this retrospective study was to identify clinical, inflammatory or dosimetric factors that could predict the development of high grade RP (HGRP).

      Method

      A retrospective analysis was conducted in patients with non-small cell lung cancer (NSCLC) treated with concurrent chemo- radiotherapy, secuential chemo-radiotherapy or radiotherapy (RT) alone at the Catalan Institute of Oncology from 2012 to 2016 who developed symptomatic RP. Collected variables were: anthropometric values, Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio, lung function, tumor features (histology, localization, staging) and treatment characteristics. RP was classified using RTOG scale. Patients were divided in 2 groups (low-grade [G1-G2], and HGRP [G3-G5]). Multivariate and regression tree analysis were performed.

      Result

      Sixty-seven patients were identified: 61% had low-grade RP and 39% HGRP. Development of HGRP was only associated with RT total dose (p=0.045). The most relevant predictive factors of HGRP were tumor location in lower lobes, high NLR values and the presence of peripheral vasculopathy. Figure 1 shows, when tumor is located in lower lobes and NLR is > 2.75, the probability of HGRP was 70% vs 50% when NLR <2.75. In other locations with NLR >4.56 the probability to develop a HGRP was 62%. But, when NLR<4.56, the presence of peripheral vasculopathy and its treatment determine the development of HGRP. When vasculopathy was not treated the probability to develop HGRP was 36% vs 0% when it was treated.61% had low-grade RP and 39% HGRP. Development of HGRP was only associated with RT total dose (p=0.045). When cancer is localized in lower lobes and NLR is > 2.75 the probability to develop HGRP was 70% vs 50% when NLR <2.75. In other locations with NLR >4.56 the probability to develop a HGRP was 62%. But, when NLR<4.56, the presence of vasculopathy and its treatment determine the development of HGRP. When vasculopathy was not treated the probability to develop HGRP was 36% vs 0% when it was treated.

      Figure 1. Probability to develop HGRP (G3 –G5)

      probability to develop hgrp (giv –gv).png

      Conclusion

      The probability of develop HGRP has been associated with RT dose and the association of cancer location, NLR, presence of vasculopathy and its treatment.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-03 - Landscape of Gene Fusions in Lung Adenocarcinoma Patients with Minimal Cigarette Exposure Identified on Malignant Pleural Effusions (ID 575)

      10:15 - 18:15  |  Author(s): Ramon Palmero Sánchez

      • Abstract
      • Slides

      Background

      Gene fusions in lung adenocarcinoma (LuAD) involving tyrosine kinase receptors such as ROS1, ALK or RET are recurrent oncogenic drivers (~10%), enriched in light or never-smokers. Some of them represent emerging and predictive biomarkers for targeted therapies. Here we report the fusions detected in a cohort of metastatic LuAD patients with low tobacco exposure (never or former-smokers).

      Method

      Patient-derived cancer cell lines (PDC) were successfully established from malignant pleural effusions from 11 patients diagnosed with LuAD. We assessed the genetic and molecular profile by whole-exome sequencing (WES) and RNA sequencing (RNA-seq) in each cell line.

      Result

      Patients’ characteristics: median age, 58 (39-86); 9 were female. Eight of eleven were never-smokers and three, former-smokers. Seven patients were treatment naïve when pleural effusion samples were collected. A cytological examination of pleural fluid was performed by a lung pathologist and all samples were positive for malignant cells. Known driver mutations in lung primary tumours included one ALK translocation detected by FISH and three EGFR Del19 mutations by targeted sequencing. The three EGFR-mutant LuAD patients progressed to first or second-generation EGFR-TKI and we were able to stablish paired PDC after progressing to tyrosine kinase inhibitors (TKI) in two of them. We identified an acquired FGFR3-TACC3 fusion in one paired PDC after gefitinib progression (T790M-negative), that led to overexpression of FGFR3 concurrent with an enrichment of squamous cell lineage transcripts (e.g. TP63, SOX2) and MDM2 amplification. Among EGFR wild type (wt) patients, two RET rearrangements, CCDC6-RET and KIF5B-RET, and one EML4-ALK fusion -also detected in the primary tumour- were identified in PDC models. In addition, in two of the samples we discovered novel gene fusions that will be described in detail, involving proteins that are not kinases, and thus, their potential role in cancer is still unknown.

      Conclusion

      In this cohort enriched with never-smoking LuAD patients presenting pleural effusions at diagnosis, the presence of known driver fusions during the disease’s course detected by RNA-Seq was 36% (4/11), including a FGFR3-TACC3 fusion as an acquired resistance mechanism to EGFR-TKI. Further study is ongoing in our PDC models to test the functional role of these fusions in order to facilitate precision medicine.

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