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Andrea Bille



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    IBS06 - Multimodality Treatment - Realtime Data from National Registries (Ticketed Session) (ID 37)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      IBS06.01 - Realtime Data from Europe ETOP / ESTS Database (Now Available) (ID 3331)

      07:00 - 08:00  |  Author(s): Andrea Bille

      • Abstract
      • Presentation
      • Slides

      Abstract

      Title: Mesothelioma Realtime Data from Europe - ETOP Mesoscape / ESTS Database

      Introduction:

      Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. Despite a still increase in incidence, it remains an orphan disease and studying limited numbers of MPM cases hampers the derivation of solid conclusions.

      The combination of two databases including clinical as well as pathological information will allow researchers to improve the knowledge and facilitate decision-making in patients with MPM.

      The European Thoracic Oncology Platform (ETOP) Mesoscape project and the European Society of Thoracic Surgeons’ (ESTS) database are designed to address clinical, pathological, and molecular characteristics of mesothelioma patients and their impact on outcome. The joined analysis of both databases is a unique approach to real-time data reflecting the reality of mesothelioma characteristics, treatment and prognosis in Europe.

      Materials and Methods:

      A decentralized biobank with fully annotated tissue samples is established for ETOP Mesoscape. Selection criteria for participating centers included sufficient number of cases, and documented ethical approval. Patient selection is based on availability of comprehensive clinical data with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue.
      The ESTS database is a clinical database with pre-operative, intra-operative and post-operative data. A minimum set of data is captured, including demographic, histology, treatment, staging and follow up data.

      The characteristics between the two databases are compared using the Fisher’s exact test (for categorical variables) and Mann-Whitney test (for continuous variables), while Kaplan-Meier method (with log-rank test).

      Results:

      Up to 29 May 2019, the ETOP Mesoscape included information on 497 patients from 10 centers, diagnosed between 1999-2018. In the ESTS database, as of April 2019, 2269 patients are included, diagnosed between 1989-2019.

      Patients in both databases are primarily men (84% in the ETOP, 71% in the ESTS), of 0/1 ECOG Performance status (46/46% and 59/29% in ETOP and ESTS respectively), with known previous exposure to asbestos (75% and 93%) and median ages 64 and 67 years old.

      Significant differences are detected between the two data sources with respect to gender, exposure to asbestos and age (p-value <0.001).

      The primary histology of patients is epithelioid (72% in ETOP and 70% in ESTS), followed by biphasic (22%; 17%) and sarcomatoid (6%; 9%) (not significantly different between the two databases).

      Clinical staging is available for 77% of the patients in ETOP, but only for the 28% in the ESTS database. The stage distribution (I/II/III/IV) is 14/29/42/15% in the ETOP and 23/21/41/16% in the ESTS (significantly difference p<0.001).

      Among the biomarkers common in both data sources, Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97% in both cases; WT1: 89% and 87% in the ETOP and ESTS database respectively).

      For the ETOP cases 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive.

      Palliative treatment has been administered in 41% of the ETOP cases. Among them, 84% received palliative chemotherapy (with the vast majority 92%, using multiple agents). Palliative surgery was undertaken in 32% (62 of 194 patients with available information) and palliative radiotherapy for 13% of the patients.

      Complete resection has been performed in 59% of the ETOP Mesoscape patients. This was combined with induction chemotherapy (81%), while adjuvant chemotherapy and radiotherapy was administered in 4% and 37% respectively.

      The surgical approach adopted for the ESTS patients was either video-assisted thoracoscopic surgery (VATS) (59%) or thoracotomy (41%) based on a subset of 887 patients with available information. Post-operation treatment information is available for 620 ESTS patients. Among them, 71% received chemotherapy, 54% underwent surgery and 15% radiotherapy.

      Conclusion:

      We present the combined results from the ETOP Mesoscape and the ESTS database, one of the largest databases. These two series allow us to report on mesothelioma epidemiology and treatment.

      Up to now, the comparison of the baseline characteristics of the patients of the two data sources revealed some statistically significant differences with respect to gender, age, exposure to asbestos and clinical stage.

      As tissue from all ETOP Mesoscape patients is preserved locally and is available for detailed molecular investigations, Mesoscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome, besides providing an overview of the molecular landscape.

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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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      MA12.05 - Genomic Analysis of Long Term Malignant Pleura Mesothelioma Patients Treated with Palliative Chemotherapy (Now Available) (ID 2750)

      14:00 - 15:30  |  Presenting Author(s): Andrea Bille

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is an aggressive tumor related to asbestos exposure with a median survival of 9 months from diagnosis. The aim of this study was to evaluate correlation between genetic mutations and survival in patients who received only palliative chemotherapy.

      Method

      From 2005 to 2015, 720 patients underwent a surgical pleural biopsy and were diagnosed with malignant pleural mesothelioma. Among these, 27 patients survived longer than 30 months (long survival) from diagnosis and 113 survived less than 30 months. The pleural biopsy of the long term survival patients were reviewed and 12 FFPE samples were considered suitable and matched with 12 FFPE biopsy samples from patients who survived less than 12 months.

      Result

      The DNA of 24 patients was sequenced. One sample did not reach quality to be further considered and was excluded. The mean age of total population was 71.6±8.8 and 15 patients were males (table 1). Eleven patients had a mean overall survival of 5.5 months while 12 patients lived more than 30 months. The mutational analysis identified a total of 428 alterations of which 148, classified as somatic and functional, were further considered. Among these, 85% were missense variants, 8% were variants causing a stop gain, 6% were splice variants. UQCRC1 was significantly associated with a reduced survival of MPM patients (p=0.027); figure 1. Positive trend of correlation was observed between mutations in ACTR1 and CUL1 and short MPM survival. By contrast, no significant correlation was observed between gene mutations and long survival.

      Figure 1.

      figure 1 updated.jpg

      Table 1. patient characteristics.

      Variable

      Long survival

      n=12 (%)

      Short Survival

      n=11 (%)

      		 P value
      Age (median) 67 72 0.216
      Sex 0.193
      Female 6 (50) 2 (18.2)
      Male 6 (50) 9 (81.8)
      Side 0.684
      Right 7 (58.3) 5 (45.5)
      Left 5 (41.7) 6 (54.5)

      Conclusion

      This is the first study that focusing on MPM patients not suitable for multimodality treatment investigated differences in mutational profile between short and long survivors. Our results suggest a possible role of mitochondria metabolism in mesothelioma aggressiveness.

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    P1.13 - Staging (ID 181)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Staging
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.13-06 - Impact of Lymph Node Involvement and Tumor Location on Survival Following Resection for pN1/pN2 Non-Small Cell Lung Cancer (ID 848)

      09:45 - 18:00  |  Presenting Author(s): Andrea Bille

      • Abstract

      Background

      The aim of this analysis is to validate the proposal for the new N staging system for non-small cell lung cancer and evaluate the impact of cancer location on N disease

      Method

      Between January 2011 and December 2015 2,531 anatomical lung cancer resections were performed. Retrospective analysis of the database identified 449 patients with pathological N1 / N2 disease. Patients with N0 disease, carcinoid, small cell lung cancer or secondary cancer were excluded. Patients with M1a (n=5) were excluded as well.

      Result

      449 patients were enrolled in the analysis. Median age was 68 years (range 37 - 87). There were 197(43.9%) female patients. 63.3% (n=284) of the patients were dead at the time of the analysis. Median overall survival of the population was 36.4 months (range 0.4 – 116 months). N1 disease had a median OS of 41.8 months (range 33 -50 months) and N2 26.9 months (range 19 - 34 months) (p=0.004). Dividing single N1 (N1a), multiple N1 (N1b), single N2 with skip metastases (N2a1), single N2 metastasis with N1 disease (N2a2) and multiple N2 (N2b) there was a statistical significant difference in survival (p=0.048): 41.7 months (range 32 - 51), 39.2 months (range 17 - 61), 33.3 months (range 14 - 52), 25 months (range 10 - 39) and 24.6 motnhs (range 19 -30) respectively.

      Analyzing multiple N2 disease (N2b) with single N1 station involved vs multiple N2 the OS was 18.9 months (range 12-25 ) vs 31.8 months (range 13-49) respectively. Seventy one patients had skip metastasis, the presence or not of skip metastasis alone did not correlate with OS: 32.2 months (range 16 - 47) vs 37.3 mo (range 32.5 – 42 mo) (p=0.7). Analyzing factors related to the N subclassification sex (p=0.24), side (p=0.17) and histology (p=0.26) were not correlated with the N status. The tumor location was instead related with N status (p=0.05)

      Lymph node involvement per tumor location for N1/N2 subgroups
      N1a N1b

      N2a1

      ('skip')

      		 N2a2 N2b Total
      Left Hilum 24 0 2 4 5 35
      Left upper lobe 63 2 20 23 10 118
      Left lower lobe 30 3 6 12 5 56
      Right hilum 32 3 2 3 11 51
      Right upper lobe 59 6 10 22 15 113
      Middle lobe 6 0 3 4 3 16
      Right lower lobe 25 4 13 9 9 60

      Conclusion

      N staging has a significant impact on survival. The new proposed N staging system better stratifies the survival of lung cancer patients with lymph node involvement. Within the N2 category single or multiple N1 and skip N2 metastasis do not have a statistically significant impact on survival.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-05 - A Retrospective Evaluation of PD-L1 Expression Heterogeneity on Primary Non-Small Cell Lung Cancer and Metastatic Lymph Nodes (REPLICA) (ID 2686)

      10:15 - 18:15  |  Presenting Author(s): Andrea Bille

      • Abstract

      Background

      Immunotherapies have changed the treatment landscape in lung cancer. Programmed death ligand (PD-L1) protein which is defined as membranous PD-L1 expression on tumour cells regardless of staining intensity represents a reliable biomarker. The heterogeneity of PD-L1 expression in different sites of disease is unknown; this may have implications on biopsy, staging and potentially treatment choice. The primary objective of this study is to evaluate the relationship between PD-L1 expression in the primary site (lung) and metastatic lymph node LNs N1 and/or N2, in NSCLC.

      Method

      Paired samples (lung tumour and hilar/mediastinal LNs) from 300 patients who underwent lung resection and lymphadenectomy for NSCLC, between January 2013 and October 2018, have been collected and analysed for PD-L1 immunohistochemistry expression using the 22C3 pharmDx Agilent assay. PD-L1 stained slides have been reviewed by two pathologists independently, using Tumour Proportion Score in the categories of <1%, 1-49% and >=50%. The agreement between the pathologists was assessed using Kappa statistic, while cross tabulation was used to compare PD-L1 expression and assess association between the primary tumour and involved LNs.

      Result

      Of the 300 paired samples 285 have been assessed by pathologist 1 and 300 by pathologist 2. The median age of the patients is 69; 55% were males, 92% had a positive smoking history and 65% had an adenocarcinoma; 50% had hilar involvement only. There was moderate agreement between the two pathologists in PD-L1 assessment in both primary tumour [k=0.40 (95%CI 0.34-0.47)] and LNs [k=0.51(95%CI 0.47-0.59)]. Pathologist 1 and 2 reported 80% and 81% overall agreement between PD-L1 expression classification in the primary tumour and involved LNs respectively. When the primary tumour showed no PD-L1 expression, both pathologists reported no PD-L1 expression in 95% of the paired LNs. When the primary tumour expressed PD-L1 >=50%, pathologist 1 reported 30% of involved LNs showed <1% and 30% showed 1-49% staining, whilst pathologist 2 reported 4 % of involved LN showed PD-L1 <1% and 39% showed 1-49% PD-L1 staining.

      Conclusion

      The majority of cases show similar PD-L1 expression between the primary tumour and involved LNs while heterogeneity is present in 20% of cases. Where the PD-L1staining was >=50 in the primary tumour, the majority of involved LNs showed only 1-49% or <1% for PD-L1 expression. These findings may have implications on site of biopsy and management.

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    WS05 - Staging Workshop Part 2: The Importance of Invasive Nodal Staging in Thoracic Malignancies (ID 106)

    • Event: WCLC 2019
    • Type: Workshop
    • Track: Staging
    • Presentations: 1
    • Now Available
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      WS05.04 - Particularities of Lymphadenectomy in Malignant Pleural Mesothelioma (Now Available) (ID 3687)

      15:45 - 17:15  |  Presenting Author(s): Andrea Bille

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant Pleural Mesothelioma (MPM) is an aggressive disease with a poor prognosis. Patients treated with multimodality approach have a survival of 20 to 30 months. Survival is worse in patients with nodal disease1. Lymph node involvement is reported in 35 to 50% of patients undergone surgery. The lymph node staging system and the nodal categories (N0–N3) in the mesothelioma TNM staging are based on the lung cancer TNM. There are significant anatomic differences between the lymphatic drainage pathways of the pleura and the lung parenchyma2. The parietal and visceral pleura have two distinct and separate lymphatic drainage probably. The MPM arises from the parietal pleura and the intrapulmonary lymph node may not be the first lymph nodes to be involved, but they may be involved in a later phase. The lymph drainage of the parietal pleura flows initially through intercostal lymphatic channels, anteriorly to the internal thoracic artery nodes or posteriorly to the internal intercostal lymph nodes (Figure 1). Drainage can also be directly into axillary or cervical lymph nodes. Diaphragmatic lymphatic drainage can flow into mediastinal, internal thoracic, or abdominal nodes3.

      The MPM may involve also the endothoracic fascia, the chest wall, the mediastinal adipose tissue, the pericardium and the diaphragm, making the lymphatic drainage more complex. The intercostal space lymph nodes, the paraspinal lymph nodes, the peri diaphragmatic lymph nodes and the internal mammary chain lymph nodes may be the first lymphatic stations to be involved rather than the intrapulmonary lymph nodes.

      It was reported that extrapleural and the mediastinal nodes (N2) may in fact be the initial site of nodal metastases in patients with mesothelioma, with N1 nodes becoming secondarily involved only when invasion of lung parenchyma occur4.

      Data from several single-institutional retrospective series have yielded conflicting evidence as to whether there is indeed a prognostic difference between patients with pathologic N1 (pN1) and pN2 pleural mesothelioma. Those data are based on the lymph node mapped derived from lung cancer staging system. The IALSC TNM collected data from 29 institution and specifically analysed the impact of pathological nodal status on survival5,6. 851 cases were eligible for the pathological N status analysis. According to the analysis for the revision of the N descriptor the survival of pN1 and pN2 was 16.9 and 17.4 months (p=0.28)5. Interestingly 54% had skip metastases based on the lung cancer staging map. Based on this evidence in the 8th TNN edition N1 and N2 were grouped together3 and N3 disease was re classified as N2 disease.

      Like for other tumours, such as breast or melanoma, few papers tried to identified a sentinel lymph node in MPM with no success7. In the paper of Edwards et al8 there is no mention of the intercostal lymph nodes sampling, reflecting how limited the data on lymph node mapping are and how variable is the sampling technique between surgeons.

      During the operation an extensive nodal sampling should be performed. The intercostal lymph node at different levels, the mediastinal and intrapulmonary stations, the peri diaphragmatic and the internal mammary lymph nodes should be sampled. Specifically, the peri diaphragmatic lymph node should be categorized in above and below the diaphragm if the diaphragm is removed. All these lymph node stations should be sampled to collect more data on the lymph node drainage and spread of the disease according to the parietal and visceral pleura involvement.

      In conclusion, there is variability in the lymphatic drainage in mesothelioma. The lymph node map we used for mesothelioma is inadequate and a different lymph node map specific for mesothelioma should be created based on the different lymphatic drainage of the parietal and visceral pleura compared to the lung. There are no guidelines in how to perform lymph node sampling in mesothelioma. A routine lymphadenectomy should be performed at the time of surgery considering extrapleural, mediastinal and intrapulmonary lymph node stations according to the different lymphatic drainage of the parietal and visceral pleura.

      References

      Flores RM, Routledge T, Seshan VE, et al. The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: implications for revision of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg. 2008 Sep; 136:605–610

      Okiemy G, Foucault C, Avisse C, et al. Lymphatic drainage of the diaphragmatic pleura to the peritracheobronchial lymph nodes. Surg Radiol Anat. 2003; 25:32–35.

      John G. Edwards, PhD, FRCS,a D. J. Stewart, FRCS,a Antonio Martin-Ucar, FRCS,a Salli Muller, Cathy Richards, FRCPath,b and David A. Waller, The pattern of lymph node involvement influences outcome after extrapleural pneumonectomy for malignant mesothelioma. J Thorac Cardiovasc Surg 2006;131:981-7

      Abdel Rahman AR, Gaafar RM, Baki HA, et al. Prevalence and pattern of lymph node metastasis in malignant pleural mesothelioma. Ann Thorac Surg. 2008;86: 391–395.

      Rice D, Chansky K, Nowak A, Pass H, Kindler H, Shemanski L, Opitz I, Call S, Hasegawa S, Kernstine K, Atinkaya C, Rea F, Nafteux P, Rusch VW; The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. Mesothelioma Domain of the IASLC Staging and Prognostic Factors Committee, advisory boards and participating institutions.J Thorac Oncol. 2016 Dec;11(12):2100-2111

      Rusch VW, Giroux D, Kennedy C, et al. Initial analysis of the International Association for the Study of Lung Cancer mesothelioma database. J Thorac Oncol. 2012; 7:1631–1639

      Cherie P. Parungo, Yolonda L. Colson, MD, PhD, Sang-Wook Kim, PhD, Sungjee Kim,
      PhD, Lawrence H. Cohn, MD, Moungi G. Bawendi, PhD, and John V. Frangioni, MD, PhD. Sentinel Lymph Node Mapping of the Pleural Space. Chest. 2005 May ; 127(5): 1799–1804

      Edwards JG, Stewart DJ, Martin-Ucar A, Muller S, Richards C, Waller DA.

      The pattern of lymph node involvement influences outcome after extrapleural pneumonectomy for malignant mesothelioma. J Thorac Cardiovasc Surg. 2006 May;131(5):981-7.

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