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Andrew G Nicholson



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    GR03 - Problem Areas for the Next WHO Classification of Lung Cancers (ID 31)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      GR03.02 - Adenocarcinoma (Now Available) (ID 3310)

      15:45 - 17:15  |  Presenting Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Many of the limitations in the WHO 2004 classification for adenocarcinomas (confusion over the term bronchioalveolar adenocarcinoma, usage of the term “mixed pattern” and no classification for small biopsy/cytology specimens) were addressed in the 2011 IASLC/ATS/ERS multidisciplinary classification,1 and this proposal was adopted by the 2015 WHO classification with minor changes.2

      Adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma have now replaced the term “bronchioloalveolar adenocarcinoma”, with subsequent TNM staging changes to use invasive size for T factor size.3 However there remains significant interobserver variation between pathologists in relation to the point at which invasion starts, indicating that tighter definitions of distinguishing a lepidic pattern from other invasive patterns are needed, especially in areas where these disagreements have a clinical impact.

      Interobserver agreement between pathologists has been shown to be much better for distinction of invasive patterns (acinar, papillary, micropapillary, solid). Accumulating data supports the 2015 WHO proposal that the cribriform pattern be regarded as a pattern with adverse prognostic significance. It is also proposed that micropapillary be expanded to include a filigree, as well as classical, pattern. One of the most important needs is for pathologists to better recognize the morphologic spectrum of the micropapillary pattern which is often underestimated. Several publications suggest prognostic groupings as lepidic, acinar/papillary and solid/micropapillary as a stratification, and these have been shown to predict response to adjuvant therapy.4 This leads into the issue of grading of resected adenocarcinomas and the presence of more aggressive histological patterns as a minor component.

      The histological feature termed “spread through airspaces” or STAS has been shown to be a poor prognostic factor for all major histologic types of lung cancer, including adenocarcinoma where it is frequently seen. There is considerable evidence that the presence of STAS carries prognostic significance,5,6 in particular in relation to non-anatomic resections, but there remains a need to identify where STAS begins and artefactual dissemination of tumour due to handling and processing of specimens ends.7 A tighter definition and evidence of international reproducibility is needed.

      While subtyping of histological patterns is well established in non-mucinous adenocarcinomas, mucinous adenocarcinomas are less well characterised. Various patterns of mucinous differentiation have been proposed, as well as assignment of histologic patterns in similar fashion to non-mucinous ADCs although only invasive mucinous adenocarcinomas (IMA) and colloid adenocarcinomas currently have specific subgroupings.2 This proposal has proved to be well founded given the specific molecular features and behaviour pattern of IMAs,8 although again work is required to refine prognostication. More data is also required tumours with mixed mucinous and non-mucinous areas.

      Resections are increasingly occurring after neoadjuvant therapy, with there is already a need to assess these in a structured fashion.9,10 Work is ongoing within the IASLC Pathology Committee to propose a method for classification in this clinical scenario.

      The 2015 WHO classification saw a seminal change in its structure, in that a classification system was proposed for biopsies and cytology specimens, rather than solely resections. In addition, a major theme utilized in the 2015 WHO classification was a multidisciplinary approach incorporating surgery, imaging, oncologic respiratory medicine, molecular biology as well as pathology. which needs to be maintained into the discussions of future classifications.1 This approach must remain and will likely need to be enhanced, given the revolution in molecular and immunologic characterisation of tumours, especially adenocarcinomas, and all these new clinically relevant findings will need to be part of pathologic reporting for the ensuing decades. The relative importance and structure of morphologic, immunohistochemical, molecular and immunologic data will need to be incorporated into a system that is appropriate not just for the most advanced cancer centres where all data are available but for laboratories and diagnostic services in underserved countries where morphologic features may be the only ones available.

      REFERENCES

      1. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary. Proc Am Thorac Soc 2011;8:381-5.

      2. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyons, France.: International Agency for Research on Cancer (IARC); 2015.

      3. Travis WD, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol 2016;11:1204-23.

      4. Tsao MS, Marguet S, Le Teuff G, et al. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol 2015;33:3439-46.

      5. Chen D, Mao Y, Wen J, et al. Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: a systematic review and meta-analysis. Ann Thorac Surg 2019.

      6. Kadota K, Nitadori J, Sima CS, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      7. Blaauwgeers H, Flieder D, Warth A, et al. A Prospective Study of Loose Tissue Fragments in Non-Small Cell Lung Cancer Resection Specimens: An Alternative View to "Spread Through Air Spaces". Am J Surg Pathol 2017;41:1226-30.

      8. Fernandez-Cuesta L, Plenker D, Osada H, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 2014;4:415-22.

      9. Qu Y, Emoto K, Eguchi T, et al. Pathologic Assessment After Neoadjuvant Chemotherapy for NSCLC: Importance and Implications of Distinguishing Adenocarcinoma From Squamous Cell Carcinoma. J Thorac Oncol 2019;14:482-93.

      10. Blumenthal GM, Bunn PA, Jr., Chaft JE, et al. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol 2018;13:1818-31.

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    MA05 - Update on Clinical Trials and Treatments (ID 123)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA05.01 - Second or Third Line Anti-PD-1 Therapy After Multimodality Therapy Including Total Pleurectomy in Malignant Pleural Mesothelioma (Now Available) (ID 1955)

      13:30 - 15:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical resection plays an important role in the management of selected patients with malignant pleural mesothelioma (MPM). Early experience with anti-PD-1 immunotherapy showed promise in MPM, but it is yet uncertain if it can improve outcomes when tumour relapses following surgical resection, radiotherapy and chemotherapy. We reviewed our experience in patients who received Pembrolizumab or Nivolumab following multimodality therapy.

      Method

      Retrospective study including patients with histologically-proven MPM having completed multimodality therapy and received anti-PD-1 immunotherapy as 2nd or 3rd line treatment. Data were retrieved from a prospective mesothelioma database. Histopathology, BAP1, MTAP and PD-L1 (22C3) immunohistochemistry were performed on surgical specimens and reported by a senior pathologist. All patients had chest computed tomography and positron emission tomography (PET-CT) as part of their normal follow-up. Response evaluation was determined using RECIST 1.1 criteria.

      Result

      16 patients received anti-PD-1 immunotherapy between August 2015 and March 2019. All patients had total pleurectomy/decortication, prophylactic radiotherapy (21Gy/3) and systemic chemotherapy based on pemetrexed and platinum. Median age was 68.5 years, with male predominance (13/16). 56% had epithelioid type, 44% had biphasic type. Median time to starting immunotherapy was 20 months (range 11-42) following surgery. Median ECOG performance status was 0. Twelve patients received Pembrolizumab and 4 received Nivolumab. Median number of cycles of anti-PD-1 therapy received was 5 (range 1-33). Disease control rate at 12 weeks was 56.2% and 7 (43.7%) patients had disease progression. Adverse events were observed in 6 patients (one Grade 3). Eight patients were alive by 1st April 2019. Median OS from starting immunotherapy was 13.5 months. Three patients received treatment for 14 months or more. Five patients started further therapy after discontinuing immunotherapy.

      Conclusion

      In our cohort, second or third-line anti-PD-1 immunotherapy showed efficacy with DCR comparable to non-surgical setting. Further studies are warranted to validate our preliminary findings.

      wclc 2019 figure 1anti pd1.jpg

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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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      MA12.02 - Growth Patterns in Epithelioid Malignant Pleural Mesothelioma: A Clinicopathological Review of 614 Cases Over 15 Years (Now Available) (ID 1595)

      14:00 - 15:30  |  Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Nuclear grading system has been validated as a powerful prognostic tool for epithelioid malignant pleural mesothelioma (MPM) whilst growth patterns had demonstrated prognostic value in earlier studies. We aim to externally validate the previous findings and evaluate the utility of a composite architecture-nuclear grade scoring system.

      Method

      We retrospectively reviewed 614 consecutive cases of epithelioid MPM diagnosed at our institution over a 15-year period. Clinicopathological information including predominant growth pattern (Solid, Tubulo-papillary, Trabecular, Micropapillary, Microcystic, Discohesive, Pleomorphic) and 2-tier nuclear grade were retrieved from an institutional mesothelioma database. The tumours were categorised into High Grade (Solid, Micropapillary, Score=1) and Low Grade (All others, Score=0). A composite score (0-2) was generated based on growth pattern and 2-tier nuclear grade (0-1). Survival analysis was performed using Kaplan-Meier method.

      Result

      Pleomorphic epithelioid MPM was associated with the worst median overall survival (5.4 months), followed by micropapillary- (6.2 months), solid- (10.5 months), microcystic- (15.3 months), discohesive- (16.1 months), trabecular- (17.6 months) and tubulo-papillary- (18.6 months) patterns. The composite scoring system further improved stratification of overall survival based on 2-tier nuclear grade (19.8 vs. 13.4 vs. 8.1 months, p<0.001).

      growth patterns (except cribriform_wdpm).jpg

      composite architecture-ng score v2.jpg

      Conclusion

      Epithelioid MPM growth patterns predicted survival in our cohort. Composite architecture-nuclear grade scoring system further improved prognostic stratification.

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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: 2
    • Now Available
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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  |  Author(s): Andrew G Nicholson

      • 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  |  Author(s): Andrew G Nicholson

      • 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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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-06 - Integrative Omics Analysis Reveals Important Roles of Adenosine Diphosphate in Haemostasis and Platelet Activation in NSCLC (ID 1273)

      09:45 - 18:00  |  Author(s): Andrew G Nicholson

      • Abstract

      Background

      Lung cancer is the leading cause of cancer-related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non-small cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5-year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms.

      Method

      We hypothesised that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches.

      Result

      We confirmed the presence of previously described metabolic NSCLC pathways, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC.

      Conclusion

      The important roles of adenosine diphosphate (ADP) in promoting cancer metastasis through platelet activation and angiogenesis suggests this metabolite could be a potential therapeutic target.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-63 - Correlation of Mutations in TP53, CDKN2A and PIK3CA with VISTA Expression in Pleomorphic Lung Carcinoma (ID 2248)

      09:45 - 18:00  |  Author(s): Andrew G Nicholson

      • Abstract

      Background

      Pleomorphic Lung Carcinoma (PC) is a rare subtype of NSCLC poorly responsive to systemic therapy. VISTA is an immune checkpoint that negatively regulates T-cells and offers an alternative therapeutic approach to immune checkpoint manipulation. It has increased expression in the tumour microenvironment. We aimed to identify the genomic associations of PC with VISTA immunohistochemistry (IHC) expression and establish its correlation with PD-L1 IHC expression.

      Method

      Histopathological assessment and diagnosis was confirmed for 42 cases of resected PCs from the Royal Brompton Hospital histopathology diagnostic archive. DNA was isolated and a targeted capture panel for next generation sequencing performed. Samples were stained with H&E to confirm diagnosis, VISTA (D1L2G) and PD-L1 (28-8) and scored as the proportion of positively stained cells. Normal lung acted as control.

      Result

      VISTA was increased in tumour infiltrating immune cells compared to background lung and tumour (median: 33% (0-85) vs. 0% (0-15); vs. 0% (0-11); P<0.001). VISTA was upregulated on infiltrating immune cells of cases with variants in TP53 (n=25, median 52.5% vs. 24% P=0.008) and CDKN2A (n=4, median 57.5% vs. 30%; P=0.068) but was reduced in cases with PIK3CA mutations (n=4; median 7% vs. 35%; P=0.029). There was no association of VISTA with PD-L1 expression (spearman rank: -0.19; P=0.22).

      Figure 1: Percent of VISTA staining of immune cells according to tumour mutation

      figure1a.png

      Conclusion

      VISTA is raised in infiltrating immune cells of tumours with TP53 and CDKN2A mutations. This may suggest dampening of the immune reaction to tumours defective in cell cycle control. Conversely, tumours with PIK3CA mutations had reduced VISTA expression by infiltrating immune cells. VISTA and PD-L1 exhibited no association in their levels of expression and therefore offers a therapeutic opportunity.

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    P1.06 - Mesothelioma (ID 169)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.06-08 - WDPM-Like but Not Cribriform as Secondary Growth Patterns Modify Survival in Epithelioid Malignant Pleural Mesothelioma (ID 1609)

      09:45 - 18:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      The presence of well differentiated papillary mesothelioma (WDPM)- like and cribriform growth patterns in otherwise unequivocally invasive, tubulo-papillary-predominant epithelioid malignant pleural mesothelioma (MPM) is recognised in clinical practice, but their prognostic impact is largely uncertain. We hypothesise they modify prognosis as secondary patterns.

      Method

      We retrospectively reviewed the tubulo-papillary-predominant, invasive epithelioid MPM (n=269) as a subset of 614 consecutive epithelioid MPM diagnosed at our institution over a 15-year period. The diagnostic criteria for WDPM-like and cribriform patterns were inferred from those of canonical WDPM and lung adenocarcinoma. Survival analysis was performed using Kaplan-Meier method.

      Result

      We identified 10 cases of tubulo-papillary-predominant epithelioid exhibiting WDPM-like pattern, and one case being predominantly WDPM-like (Estimated incidence 4.1%). They are associated with significantly prolonged median overall survival (78.7 months vs. 18.0 months, p=0.001). On the other hand cribriform neither as predominant (n=9, 3.3%, p=0.672) or secondary growth patterns (n=46, 17.1%, p=0.952) achieved statistical significance in univariate setting compared with tubulo-papillary epithelioid MPM without such pattern.

      wdpm-like.jpg

      cribriform pattern (predominant and secondary).jpg

      Conclusion

      We propose tubulo-papillary-predominant epithelioid MPM with WDPM-like features as a rare and favourable prognostic group. Further molecular analysis is planned. Cribriform pattern does not appear to be prognostically relevant. We recommend external validation of our findings for both growth patterns.

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    P1.11 - Screening and Early Detection (ID 177)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.11-30 - Very Rapid Growth of Small Pulmonary Nodules Predicts Benignity (ID 704)

      09:45 - 18:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      Growth of pulmonary nodules on repeat CT is used to identify malignant lesions, although very rapid growth is thought to imply an inflammatory process. Few data exist examining the optimum threshold at which rate of growth predicts a benign aetiology.

      Method

      Using an institutional CT database of small (<15mm) solid pulmonary nodules (n=784), we identified patients with antecedent (≥30 days prior) thin section (≤2mm) CT imaging and a final diagnosis of primary lung malignancy or a definite benign diagnosis based on pathology or longitudinal CT follow up data (n=137). Enlarging nodules (volume growth >25%) were identified (n=63) using semi-automated volumetry, and the volume doubling time (VDT) calculated. In cases where no nodule existed on the antecedent CT, a volume of 5mm3 was assigned, permitting the calculation of a ‘virtual’ VDT. Comparison of volume doubling time between benign and malignant nodules was made using Wilcoxon signed rank test. A receiver operator curve was constructed, and the optimum threshold of nodule growth rate predictive of benignity was calculated using the methods of Miller.

      Result

      The final study population consisted of 63 nodules in 57 patients [32/62 (50.8%) malignant, median age 67 years (range 34–85 years), male = 30/57 (52.6%)]. There was no difference in patient age nor in smoking status between groups, although patients with malignant diagnoses significantly more likely to be female (p < 0.001).

      The median time between baseline (T1) and antecedent (T0) scans was 260 days (interquartile range 343 days). At baseline (T1), benign lesions (median diameter 10mm, median volume 380 mm3, range 10-4300mm3) were significantly smaller than malignant nodules (median diameter 13mm, median volume 890mm3, range 60-4250 mm3); p = 0.001.

      24/31 benign lesions and 3/32 malignant lesions were not visible on the T0 scan, and were assigned a volume of 5mm3. The median benign lesion VDT was 70 days (interquartile range 270 days), malignant median VDT was 188 days (interquartile range 170 days); p = 0.2. The majority of lesions with very rapid growth (VDT < 90 days) were benign diagnoses (n= 17/24 [70.8%]). When examining these rapidly growing nodules, the optimal cut-point of the receiver-operator was a VDT of 50 days, AUC = 0.735. This provided 100% specificity for benign disease.

      Conclusion

      Our results confirm that very rapid nodule growth predicts benignity; a VDT of <50 days was 100% specific for benignity. Further work is required to validate these findings in other cohorts.

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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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      P1.13-11 - An Audit on IASLC Compliance of Lymph Nodes Dissection and Impact on Survival After Surgery for Non-Small Cell Lung Cancer (ID 196)

      09:45 - 18:00  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      The IASLC proposed minimal criteria for 6 nodes / stations to ascertain certainty status of complete (R0) resection after lung cancer surgery and in 2017, Edwards et al presented that failure of compliance leading to R0 (un) status was associated with poorer survival.

      The aims of this audit are to assess compliance of the IASLC recommendations on lymph node staging and determine the impact of R0 (un) status on prognosis in an independent cohort.

      Method

      We included patients who underwent lobectomy or pneumonectomy for primary lung cancer. Data was obtained from electronic records and survival status obtained from NHS Spine.

      Result

      From January 2010 to December 2017, 2,521 patients underwent lung resection for primary lung cancer staged using TNM7. The mean age (SD) was 67 (10) and 1,235 (49%) were men, the primary diagnoses were either adenocarcinoma or squamous carcinoma in 2,057 (82%).

      The IASLC compliance with 6 node / stations was 627 (25%) and when sub-carinal station was mandatory it was 608 (24%). After exclusions, we were left with 1,859 patients and on adjustment of T and N category, there was no difference between IASLC non-compliance R0 (un) on overall survival with a hazard ratio of 0.95 (95% CI 0.74 to 1.21; P=0.657) compared to R0 compliant.

      After adjusting for T and N category there was no significant difference in total lymph nodes stations harvested with a HR 1.01 (0.97 to 1.04, P=0.712) or number of positive stations HR 1.04 (0.92 to 1.16; P=0.543) in survival.

      lymph node.png

      Conclusion

      Independent validation of R0 (un) status did not concur with poorer survival. The designation carries uncertainty and likely to be influenced by the extent of N2 dissection. When adjusted for stage, there was no difference on number of stations harvested nor the total number of positive stations on survival.

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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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      P2.03-10 - Comprehensive Molecular Profiling and Comparison of Common and Rarer Subtypes of Lung Cancer (ID 1870)

      10:15 - 18:15  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      Genomic profiling of tumours has become a crucial component of precision cancer medicine. In order to comprehensively characterize molecular alterations in different lung cancer subtypes, we analysed a total number of 327 samples by using Whole-Exome Sequencing (WES) and SNP genotyping arrays. Additionally, we used Targeted Capture Sequencing (TCS) for scanning a selected panel of genes (n=52) at high sequencing depth.

      Method

      We WES (McGill University Innovation Centre in Montreal) 153 paired tumour-normal samples, with a further 174 paired tumour-normal samples undergoing TCS. Sequencing data were processed and mutations identified using BWA (v.0.7.15), Picard (v.2.17.11), GATK (v.3.7), VarScan (v.2.4.2) and VEP (v. 92) softwares. Illumina OmniExpressExome (v1.6) arrays were used for genotyping all samples and copy number alterations (CNAs) were identified using ASCAT (v.2.5.2), DNACopy (v.1.56.0) and GISTIC (v.2.0) softwares.

      Result

      The analysed samples had a tumour content varying from 20 to 90%. The age range of patients was between 28 to 89 years. Out of 159 lung cancer patients, 89 patients had lung adenocarcinoma (LUAD), 36 squamous cell carcinoma (LUSC) and 34 lung neuroendocrine (NET), of which 22 were subclassified as lung carcinoid (LC), 6 small cell carcinoma (LSCLC), 5 large cell carcinoma (LCNEC) and 1 combined NET subtype.

      TP53 appeared as the most mutated gene in LUSCs (82%), non-carcinoid NETs (58%) and LUADs (47%), but not in the LC subtype, while the chromatin remodelling gene ARID1A was altered across all subtypes (9%). Other mutated genes in LUAD were KRAS (31%), STK11 (22%), RBM10 (15%), EGFR (14%) and KEAP1 (14%); in LUSC were PTEN (26%), CDKN2A (21%), KEAP1 (21%) and NF1 (15%); in NET, non-carcinoid top mutated genes included RB1 (42%), ENPP2 (33%), ERBB4 and STK11 (17% for each), while ARID1A and ACKR3 were each present in 9.5 % of LC.

      In LUADs, mutations in EGFR and KRAS appeared as mutually-exclusive (P=0.007), while gene pairs NFE2L2 - AKT1 (P=0.012) and STK11- ALK (P=0.029) were co-mutated in LUAD and LUSC, respectively. Deletions in exons 19 and 20 of EGFR correlated with longer survival time compared to patients with wild-type EGFR (P=0.058). In NET, patients with mutated RB1 showed lower survival time compared to patients with wild-type RB1 (P=0.022).

      Examination of CNAs showed TERT amplifications (5p15.33 cytoband) were commonly found at high frequencies across all subtypes, especially in non-carcinoid NET (71.4%). Other recurrent CNAs included amplifications in MYC in 37% of LUAD and 40% of LUSC, and in EGFR in 33% of LUAD and 14% of LUSC. Deletions in the CDKN2A locus were seen at frequencies of 31% and 28% in LUAD and LUSC, respectively.

      LC patients showed longer survival time compared to other tumours (P=0.015). COSMIC mutational signatures 18 (of unknown aetiology) and 24 (associated with exposure to aflatoxin) were exclusively found in LC.

      Conclusion

      The results confirm that lung cancer is a group of heterogenous diseases. In addition to the known effects of EFGR mutations, possible therapeutic avenues could be suggested for TERT amplifications, for which nucleoside analogues have shown to promote cancer cell death or EZH2 inhibitors for ARID1A-mutated cancers.

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-05 - Multimodality Therapy Using Total Pleurectomy in Malignant Pleural Mesothelioma: Long-Term Outcomes in 150 Consecutive Cases (Now Available) (ID 1441)

      10:15 - 18:15  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      We wished to evaluate the long-term outcomes of patients receiving multimodality therapy including total pleurectomy/decortication, radiotherapy and systemic chemotherapy for malignant pleural mesothelioma.

      Method

      Retrospective analysis of patients treated between September 2004 and April 2019 by a specialised thoracic multidisciplinary team. Treatment involved total pleurectomy and decortication of lung, prophylactic radiotherapy (21 Gy in 3 fractions) and systemic chemotherapy based on pemetrexed and platinum. PET-CT was used routinely to diagnose disease recurrence or progression. Second or third-line therapies were administered when appropriate. Survival and prognostic factors were analysed by the Kaplan-Meier method and Cox regression analysis.

      Result

      150 patients had multimodality therapy over a 15-year period. Median age at operation was 62 years (range 32-82) and the male/female ratio was 122/28. Thirty-one patients (20.6%) had received chemotherapy before surgery. Thirty-three patients (22%) had extended resections. Sixty-two patients suffered a postoperative complication and 90-day mortality was nil. Eleven patients (7.3%) had reoperation within 30 days. Histological types were epithelioid in 105 patients and non-epithelioid in 45. Pathological stages were: I:86, II: 9, III: 54, and IV:1 (8th TNM classification). All patients but one received prophylactic radiotherapy. Six patients (4%) did not received systemic chemotherapy. Sixty-five patients (43.3%) received second-line or further systemic therapies. Five patients received stereotactic radiotherapy and three patients had late reoperation for focal tumour recurrence. Median survival was 30.5 months overall (95% CI 25.4-35.6), 34 months for epithelioid type (95% CI 25.8-42.2) and 18.3 months for non-epithelioid type (95% CI 14.2-22.4). Histological type and macroscopic complete resection were predictive of extended survival in our analysis.

      Conclusion

      Total Pleurectomy /Decortication is a safe and well-tolerated procedure associated with no mortality and acceptable morbidity. Most patients can receive prophylactic radiotherapy and systemic chemotherapy in due time. Many can receive second-line or further therapy on progression, resulting in prolonged survival.

      figure survival based on histological type.jpg

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)

      10:15 - 18:15  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.

      Method

      The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).

      Result

      344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.

      Conclusion

      There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.

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    P2.11 - Screening and Early Detection (ID 178)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.11-13 - What Is the Impact of Localised Data When Training Deep Neural Networks for Lung Cancer Prediction?  (Now Available) (ID 2485)

      10:15 - 18:15  |  Author(s): Andrew G Nicholson

      • Abstract
      • Slides

      Background

      Deep neural networks (DNN) have been shown to offer a viable alternative for risk cancer prediction of indeterminate pulmonary nodules (IPNs). While the type of data used for training is known to impact performance, this issue has not been extensively studied. We present, for the first time, a study of the effect of including training data that matches the clinical pathway of the independent validation dataset, a nodule clinic of incidental findings.

      Method

      Two identical DNNs were trained on the task of diagnosis prediction of pulmonary nodules from CT images. The first one (DNNnlst) used purely screening data from the US National Lung Screening Trial (922 cancer and 14733 benign nodules), while the second one (DNNnlst+incidental) included data of incidentally detected nodules from European hospitals (1064 cancer and 7207 benign nodules). Both models were evaluated in an independent validation set of nodules coming from a referral center in the UK (Royal Brompton and Harefield Hospital, London) consisting of baseline scans of 406 cancer and 325 benign nodules. The models were compared in terms of AUC, as well as their ability to reclassify cancer patients with intermediate risk nodules. The Intermediate risk sub-population was defined by selecting patients with nodules in the size range of 8 to 15mm, and who were followed-up within a year with CT, referred to PET-CT, or referred to biopsy. Within this sub-population, a cancer prevalence of 30% was assumed. The operating points of the cancer prediction models were chosen by setting a cancer risk of 70%, corresponding to high-risk nodules in the guidelines of the British Thoracic Society.

      Result

      The DNNnlst and DNNnlst+incidental models achieved an AUC of 84.33 (95%CI: 81.49, 87.15) and 87.43 (95%CI: 84.79, 89.82) respectively on the entire validation set, showing an improvement in the discrimination capabilities (p < 0.01). For reference, using the nodule’s maximum axial diameter as a predictor led to an AUC of 79.07 (95%CI: 75.73, 82.73). Additionally, considering only the intermediate risk population of the data, all of which would require workup according to guidelines, the DNNnlst+incidental model correctly classified as high risk 34.34% more cases than the DNNnlst model (sensitivity 59.39% (95%CI: 47.68, 75.17) vs. 44.21% (95%CI: 20.98, 64.42)), an improvement significant at p < 0.05.

      Conclusion

      Although a DNN trained only on the US lung cancer screening data could have clinical utility in an incidental setting, exposing it to further incidental data can not only increase its discriminability, as expected, but also make it a potentially more effective tool for speeding up the diagnosis of cancer patients with intermediate risk nodules and reducing unnecessary workups.

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    WS02 - Mesothelioma Workshop (Ticketed Session) (ID 102)

    • Event: WCLC 2019
    • Type: Workshop
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      WS02.02 - Pathology Section I: Synopsis EURACAN/IASLC (Now Available) (ID 3831)

      08:00 - 11:30  |  Presenting Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Whilst molecular and immunologic breakthroughs have transformed the management of lung cancers, changes have not been as marked for malignant pleural mesothelioma. Therefore, in 2018, a multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists and oncologists), sponsored by EURACAN/IASLC, met in order to critically review the current classification, in which pathologic diagnosis has hitherto been essentially limited to three histologic subtypes.1

      Subsequent recommendations in relation to pathology classification were firstly to include architectural patterns, and stromal and cytologic features that refine prognostication. Second, subject to data accrual, malignant mesothelioma in situ could be an additional category. Third, grading of epithelioid MPMs should be routinely undertaken,2 Fourth, other prognostically relevant histologic characteristics should be routinely reported.

      Clinically relevant molecular data such as PD-L1, BAP1, CDKN2A) should be incorporated into reports, if undertaken and other molecular data accrued as part of future trials.

      Resection specimens (i.e. extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged. When surgical biopsies are taken, at least 3 separate areas should be sampled from the pleural cavity, if feasible.

      Image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging.

      Multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered and all histologic subtypes should be considered potential candidates for chemotherapy and first line clinical trials unless there is a compelling reason.

      REFERENCES

      1. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyons, France.: International Agency for Research on Cancer (IARC); 2015.

      2. Rosen LE, Karrison T, Ananthanarayanan V, et al. Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study. Mod Pathol 2018.

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