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K.M. Kerr



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    E04 - Lung Cancer Pathology Classification (ID 4)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 1
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      E04.3 - Large Cell and Sarcomatoid Carcinoma (ID 389)

      14:00 - 15:30  |  Author(s): K.M. Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract
      Large cell and sarcomatoid carcinomas account for approximately 10% of all lung cancers. For all practical purposes, each of these diagnoses can only be made with accuracy in surgically resected cases since tumour definitions mandate a feature be excluded from or present in at least 10% of the whole lesion. Although features suggesting a large cell variant or sarcomatoid tumour may be recognised in a small biopsy or cytology sample, these diagnoses are inappropriate in such samples. Large cell carcinoma (LCC) is morphologically defined as comprising large undifferentiated tumour cells lacking any evidence of squamous, glandular or small cell carcinoma (SCLC). Epidemiologically these cases are no different from most other non-small cell carcinomas (NSCLC). They favour a more peripheral location in the lung and necrosis is common. Cells are generally large, with open nuclei, prominent nucleoli and abundant cytoplasm, but some cases show hyperchromatic, granular nuclei, inconspicuous nucleoli and less cytoplasm. In the classical case, the cells show no organisation, just sheets of cells with little intervening vascular stroma, but some cases show cellular stratification with more abundant fibrous stroma. Several variants of large cell carcinoma are described. Large cell neuroendocrine carcinoma (LCNEC) additionally requires demonstration of neuroendocrine differentiation, usually by immunohistochemistry. These are often large, necrotic tumours and share many epidemiological and molecular features with small cell lung carcinoma. Organoid morphology with trabeculae and rosettes are common. A significant proportion of LCNEC are combined with other tumour types in the same lesion, most often adenocarcinoma. These cases would more logically reside in a separate category with other NE tumours. The basaloid variant of LCC largely meets the above definition, but tends to have rather smaller cells, peripheral nuclear palisading around discrete nests/sheets of cells, frequent intercellular basement membrane material, like basaloid carcinomas at other sites. An infrequent and unusual form of small keratin pearl may be seen but basaloid carcinomas lack the larger cells with eosinophilic cytoplasm and intercellular bridges of squamous cell carcinomas (SCC). They share immunohistochemical features (p63, p40, CK5/6, desmocollin3) with SCC and could represent de-differentiated SCC. Defining basaloid carcinoma apart from SCC remains a controversial issue. Lymphoepithelioma-like lung carcinoma (LELC) comprises a syncytium of large undifferentiated cells with indistinct cell borders and a heavy lymphoplasmacytic infiltrate. Commoner in East Asian countries, this tumour is still rare and is closely associated with EBV genome. Distinction from other poorly differentiated carcinomas with a heavy immune cell infiltrate may be impossible in the absence of evidence of EBV infection and the latter should, perhaps, be incorporated into the tumour definition. Clear cell carcinoma of the lung features large cells with clear cytoplasm. This histological feature is, however, seen in a range of other NSCLC and as such, serves little useful purpose, apart from awareness of potential confusion with metastatic renal cell carcinoma. This would be better used as a descriptor rather than defining a separate tumour category. Large cell carcinoma with rhabdoid phenotype is rather ill-defined and extremely rare. A few cases reports or small series reflect the heterogeneity of so-called cases with no clear definition. One common impression is that of an aggressive tumour but again, this terminology is better used as a descriptor rather than defining a separate subtype. Emerging immunohistochemical and molecular data have questioned the nature of large cell carcinoma and our current classification. Many cases share a molecular and/or immunohistochemical phenotype with either squamous cell or adenocarcinoma, suggesting that they should be classified by their molecular profile, effectively deleting the LCC category. This approach has several problems including the following: (a) Not all cases can be so re-classified as squamous cell or adenocarcinoma, (b) these immune/molecular profiles are not specific for either diagnosis, and (c) the definition of these differentiated tumours is based on H&E morphology, not immune/molecular findings. Further confusion stems from the inappropriate use of the term ‘large cell carcinoma’ in the small biopsy/cytology setting. Any sample containing large undifferentiated cells lacking features of small cell carcinoma should be referred to as NSCLC, not otherwise specified (NOS) and not ‘large cell carcinoma’. Most of these cases, if resected, derived from differentiated adeno- or squamous cell carcinomas. The legitimate, recommended use of IHC to predict tumour subtype in small samples is neither validated nor justified in resected tumours under the current classification. However, it may be useful to characterise resected LCC cases by immunophenotype since this may correlate with some targetable mutations but it should not lead to a major change in diagnosis. Mutations of EGFR or KRAS are rarer than in adenocarcinoma but correlate with TTF1 positivity. Sarcomatoid carcinomas show pleomorphic, spindle or giant cells comprising at least 10% of the tumour. Usually all three cell types are seen. They account for 3-4% of resected tumours and are usually large, invasive, necrotic tumours. They are clinically aggressive and frequently chemorefractory, justifying their separation in our classification. Most lesions also show differentiated squamous cell or adenocarcinoma components. As for LCC, this diagnosis should not be made in the small biopsy/cytology setting but if these cell types are present in the sample they should be described in the report. Immunohistochemical and/or molecular studies are few. Most cases show an immunoprofile in the sarcomatoid component consistent with the differentiated tumour also present. Pure sarcomatoid cases may also show a ‘differentiation-associated’ immunoprofile but often it is inconclusive or IHC is negative. KRAS mutations have been consistently reported in a few case series. Carcinosarcoma is an exceptionally rare tumour, defined in the lung as a lesion showing carcinoma plus differentiated, heterologous sarcomatous elements, such as rhabdomyo, osteo or chondrosarcoma. Pulmonary Blastoma is a biphasic lesion combining primitive mesenchymal tumour and well-differentiated adenocarcinoma, the latter described as endometrioid or ‘fetal’ in pattern. Regarding the more typical cases of LCC, sarcomatoid and basaloid carcinoma, the molecular evidence supports the concept that these tumours may represent dedifferentiated carcinomas of the lung. How this emerging concept is reflected in our classification is a matter of ongoing debate.

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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 2
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      MO10.05 - DISCUSSANT (ID 3984)

      16:15 - 17:45  |  Author(s): K.M. Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO10.07 - ALK immunohistochemistry and fluorescence in-situ hybridization in Lung adenocarcinomas from the ETOP Lungscape tumour cohort (ID 2267)

      16:15 - 17:45  |  Author(s): K.M. Kerr

      • Abstract
      • Presentation
      • Slides

      Background
      The European Thoracic Oncology Platform LungScape database contains 2614 cases of primary resected lung carcinoma from 16 centres with patient demographics, pathological tumour data and detailed clinical follow-up. A total of 1281 cases of adenocarcinoma with >2 years clinical follow-up were selected for analysis of ALK status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Test positive cases were matched, in order of importance at ratio 1:2, by stage, gender, smoking status, study centre, year of surgery and age with test negative cases -both for IHC and for FISH testing.

      Methods
      Testing was performed in all centres using the same protocol (IHC: Novocastra 5A4 clone antibody at 1:10 dilution, Novolink detection system. FISH: Abbott Vysis ALK break-apart probe). Each centre passed an external QA test using unknown cases in a tissue microarray before conducting the LungScape tumour testing. IHC was scored according to three intensity scores (1+, 2+, 3+) using ‘objective’ methodology previously described [1]. Maximum staining intensity was recorded. Any IHC staining was defined as IHC positive result. FISH preparations were assessed according to the Vysis protocol on all 82 IHCpositive cases plus their 164 IHCnegative matches.

      Results

      IHC cases, n=1281 FISH positive(264 tested)
      IHC negative 1199 (93.6%) 0 (0.0% of 164 controls) FISH specificity: 100%
      IHC 1+ 43 (3.35%) 2 (4.6% of IHC 1+)
      IHC 2+ 16 (1.25%) 6 (37.5% of IHC 2+)
      IHC 3+ 23 (1.8%) 20 (87% of IHC 3+)
      IHC any positive 82 (6.4%) 28 (34.1% of IHC+) FISH sensitivity: 34.1%
      FISH sensitivity was 87% for IHC 3+. IHCpositive/FISHnegative cases (n=54) were mostly IHC 1+ (75.9%), sometimes IHC 2+ (18.5%) and rarely IHC 3+ (5.5%). The frequency of never smokers was higher in the ALK IHCpositive group (29.3%) versus IHCnegative group (18.3%) {p=0.011}. Age, gender and tumour stage did not differ between IHC groups. The hazard of an event for IHCpositive cases decreases by 32% in relapse-free survival {RFS; p=0.03} and by 38% in either time-to-relapse {TTR; p=0.02} or overall survival {OS; p=0.016}. Multivariate models -adjusted for patient and tumour characteristics- indicated that IHC-ALK was a significant predictor for all three time-to-event outcomes (RFS, TTR, OS). In stratified Cox analysis, significantly higher OS was retained in the IHCpositive (HR=0.59, p=0.04) and FISHpositive (HR=0.34, p=0.03) cases in the matched cohorts, while conditional logistic regression yielded non-significant associations with 3-year survival status.

      Conclusion
      In this large cohort of surgically resected primary lung adenocarcinoma: ALK IHC positivity was 6.4%. IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity ALK IHC positivity was higher in never smokers and related to better clinical outcome ALK testing can be reliably implemented across multiple laboratories {1} Ruschoff et al. Virchows Arch. 2010;457(299-307).

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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.02 - Association between Gene Expression Profiles and Clinical Outcome of Pemetrexed-Based Treatment in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: Exploratory Results from a Phase II Study (ID 185)

      10:30 - 12:00  |  Author(s): K.M. Kerr

      • Abstract
      • Presentation
      • Slides

      Background
      We report exploratory gene expression profiling data from a prospective single-arm Phase-II-study in patients with non-squamous non-small cell lung cancer (nsNSCLC) treated with pemetrexed. Main results indicated a significant association of low thymidylate-synthase (TS) expression with longer PFS and OS [1].

      Methods
      Treatment-naive nsNSCLC patients (Stage IIIB/IV) received 4 cycles of first-line pemetrexed/cisplatin; non-progressing patients continued on pemetrexed maintenance [1]. Diagnostic tissue samples were used to assess TS expression (nucleus/cytoplasm) by immunohistochemistry (IHC, H scores), and to extract total mRNA for expression-array profiling (expression of 1,030 genes summarized from 60,000 transcripts). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS, mRNA gene expression was used both as continuous and binary (cutpoint: median) variable. Unadjusted p-values (significance level =0.01) and false discovery rates (FDR) were calculated. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman rank test). Finally, unsupervised clustering was applied to all samples with mRNA expression (n=51) for all 1,030 selected array genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n=47) previously described [2].

      Results
      51/70 (72.9%) biopsies were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01). 8/9 genes were negatively correlated with nuclear TS expression; the test was statistically significant for 5/8 genes (unadjusted p<0.01, Table 1). None of these genes has a known relationship to folate metabolism. Cluster analysis of all 51 samples based on 1,030 genes revealed no clear trend regarding PFS/OS. Cluster-analysis of 47 ADC samples identified 3 groups (n=21, 11 and 15 patients, respectively) with median (95%CI) PFS and OS of 8.1 (6.9, not estimable [NE]) and 20.3 (17.5, N.E) months; 2.4 (1.2, NE) and 4.3 (1.4, NE) months; and 4.4 (1.2, NE) and 8.3 (3.9, NE) months, respectively. Figure 1

      Conclusion
      This exploratory analysis provides insights on key genes potentially linked to low TS expression. Nine genes were significantly associated with PFS/OS; however such association cannot be differentiated as prognostic or predictive since this study is single arm. Further research would be needed to understand the relationship of these markers with clinical outcomes. [1] Nicolson et al, J Thorac Oncol 2013, May 29 [Epub]. [2] Wilkerson et al, PLoS One 2012;7(5):e36530.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-023 - Anaplastic Lymphoma Kinase (ALK)-detection in Non-small Cell Lung Cancer: results of the first European IHC-based (D5F3-Optiview) panel test within 16 institutes (ID 1825)

      09:30 - 16:30  |  Author(s): K.M. Kerr

      • Abstract

      Background
      The study was supported by Ventana Medical Systems, Inc., a Member of the Roche Group Background: The reliable identification of NSCLC patients with anaplastic lymphoma kinase (ALK) gene rearrangement is crucial for the prescription of ALK tyrosine kinase inhibitors (e.g. crizotinib). Whereas the US FDA-approval (2011) is based upon FISH-testing, the European EMA-approval (2012) refers to the definition of “ALK-positive” NSCLCs without mandating a particular test. Therefore a reliable ALK-immunohistochemistry (IHC) could be a promising option in daily routine practice.

      Methods
      Material and methods: To test the reliability of ALK-IHC-diagnosis in a multi-centre environment (17 European institutes from Belgium, Denmark, France, Germany, Scotland, Spain, Sweden and Switzerland) two tissue microarrays (TMA) consisting of 15 NSCLC cases (all adenocarcinomas; 3 cores for each case) were independently tested for ALK-expression by each laboratory using Ventana Medical System’s ALK (D5F3) primary antibody combined with OptiView DAB IHC detection and OptiView Amplification kits. Cases included in the study were unequivocal ALK-break positive or negative (by FISH), as well as so called “ALK-borderline” cases (low percentage of ALK-break positive cells by FISH, around the cut-off of 15%, therefore challenging in diagnosis, but PCR-confirmed as harbouring EML-4-ALK-fusion variants and thus eligible for therapy). Prior to the TMA-based case testing, each participating instrument was qualified using the VENTANA ALK 2 in 1 Control Slides. To provide a uniform baseline interpretation, a webinar-based training was given to all observers. This training included an overview of the ALK Interpretation Guide, a guided review of 50 patient cases using digital whole slide images, and a proficiency exam certifying each observer.

      Results
      Results: Detailed data analysis was only partly accomplished at the time of abstract submission and will be presented in detail at the “World Conference on LUNG Cancer” in Sydney. Besides the binary evaluation of the cases (ALK-negative vs. ALK-positive) observers were asked to estimate the staining intensity (0-3) within positive cases in correlation to the number of tumor cells and to generate the H-score.

      Conclusion
      Conclusion: Referring to the EMA-approval text our multi-centre study may contribute to validation and accuracy of IHC-based ALK-testing. Such a validated and reliable IHC-assay could be used: (a) as a good pre-screening method reducing time consuming and costly FISH analysis (shorten turn-around time for test results) and (b) as a final predictive approach in cases with reduced interpretability of FISH results (e.g. minimal tumor cell content in small biopsies, decalcified or artificial altered tissue, FISH in doubt/”borderline”).

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-011 - MesobanK: A UK based bioresource for malignant pleural mesothelioma (ID 1314)

      09:30 - 16:30  |  Author(s): K.M. Kerr

      • Abstract

      Background
      Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures will facilitate better understanding of mesothelioma biology. Currently, few bioresources of mesothelioma tissue exist, the largest being the National Mesothelioma Virtual Bank hosted by the University of Pittsburgh (http://www.mesotissue.org/). A few other clinical/research groups hold fresh tissue from small numbers of mesothelioma patients but these collections are not formally linked and often do not involve collection of tissue and data to Standard Operating Procedures. The British Lung Foundation/Mick Knighton Mesothelioma Research Fund has recently funded MesobanK, a UK based bioresource of malignant mesothelioma tissue samples.

      Methods
      Tissue Microarray: MesobanK will construct a tissue microarray (circa 1000 cases) using historical formalin fixed paraffin embedded blocks of tissue taken at thoracoscopy/surgical resection. Inclusion criteria requires sufficient tissue to permit multiple 0.5 mm cores (to allow for tumour heterogeneity) and a clinical minimum data set. Fresh tissue: Fresh frozen mesothelioma tissue (300 cases over 3 years) will be collected prospectively from multiple centres across the UK together with parallel pleural fluid, whole blood, serum and plasma. Each case will have a detailed anonymised linked clinical data set with follow up data. Cell lines: MesobanK plans to create 20 new fully annotated mesothelioma primary cell lines. The bioresource will be supported by a web-based IT infrastructure for annotating and searching the collection. Clinical data will be collected on each case and supplemented by laboratory and pathology results, Hospital Episode Statistics data and UK Cancer Registry data in order to achieve as complete a data set as possible. MesobanK will follow the Guiding Principles laid out by the NCRI Confederation of Cancer Biobanks and the UK Medical Research Council Operational and Ethical Guidelines on Human Tissue and Biological Materials for Use in Research. It will also be managed within the scope of all relevant regulatory frameworks and quality management/quality assurance systems. In addition, we share the aim of the US National Cancer Institute (NCI) National Biospecimen Network Blueprint: to create a comprehensive framework for sharing and comparing research results through a robust, flexible, scalable and secure bioinformatics system that supports the collection, processing, storage, annotation and distribution of biospecimens and data using standard operating procedures based on best practices. A steering committee will have overall control of MesobanK. An independent scientific advisory board will review applications for samples and advise the steering committee. Prioritisation for access to samples will be based solely on scientific merit. All researchers, whether in the UK National Health Service, universities, charities, government agencies or commercial companies, and whether based in the UK or abroad will be subject to the same application process and approval criteria.

      Results
      Not applicable

      Conclusion
      It is anticipated that initial tissue (TMA and cell lines) will be available in 2014.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-004 - Oligometastatic non-small cell lung cancer: a simulation expert multidisciplinary tumor board. (ID 1122)

      09:30 - 16:30  |  Author(s): K.M. Kerr

      • Abstract

      Background
      Series on aggressive local treatment in selected patients with oligometastatic non-small cell lung cancer (NSCLC) are mostly retrospective, and prospective data are scarce (De Ruysscher et al, JTO 7:1547-1555, 2012). Although a precise definition is lacking, ‘oligometastatic NSCLC’ is considered an intermediate biologic state of restricted metastatic capacity with a limited number of metastases. The turning point between oligometastatic and polymetastatic is merely based on personal opinion and situated somewhere between 1 and 5 distant metastases. In the absence of clear definitions or clinical practice recommendations, a treatment decision is mainly driven by the opinion of each local multidisciplinary tumor board (MDTB).

      Methods
      As the consideration of and the treatment modality for oligometastatic NSCLC is a controversial area in respiratory oncology, in preparation of a recent dedicated workshop, we simulated a MDTB with international experts in the field. Multiple disciplines from 7 different centers participated in the MDTB, including pathology (1), nuclear medicine physician (1), thoracic surgery (3), radiation oncology (3), and respiratory oncology (3). Participants were asked to assess an electronic file describing 10 clinical ‘oligometastatic NSCLC’ cases, with 2 simple questions per case: 1. Do you consider this case ‘oligometastatic’ (Yes/No) and 2. What is your preferred treatment proposal.

      Results
      A full response was returned by all 11 specialists taking part in the simulated MDTB. Only 1 case was considered ‘oligometastatic NSCLC’ by all MDTB members. The presented cases were considered by a median of 78% (range 36-100%) of responders as true oligometastatic disease. Despite the fact that each responder gave only one treatment proposal, a median of 4 different treatment proposals (range 2-6) was made per case. Except for brain metastases, most team members would treat the locoregional thoracic disease before the distant metastases. No preference towards neo-adjuvant or adjuvant chemotherapy could be found. The option for surgery or radiation therapy as part of a combined modality treatment was mainly driven by the physicians’ preference.

      Conclusion
      Our simulated MDTB shows that oligometastatic NSCLC is an entity with many unanswered questions, and thus a major challenge for clinicians. Patients with oligometastatic NSCLC are in the need of 1. discussion at an experienced multidisciplinary tumor board to select patients for a radical combined modality approach; 2. multidisciplinary prospective research protocols to set better definitions of oligometastic NSCLC, evaluate the validity of a radical approach, and to optimize therapeutic modalities.