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S. Lantuejoul
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-021 - Reproducibility of Comprehensive Histologic Assessment and Refining Histologic Criteria in P Staging of Multiple Tumour Nodules (ID 5365)
14:30 - 15:45 | Author(s): S. Lantuejoul
- Abstract
Background:
Multiple tumor nodules (MTNs) are being encountered, with increasing frequency with the 8[th] TNM staging system recommending classification as separate primary lung cancers (SPLC) or intrapulmonary metastases (IM). Pathological staging requires assessment of morphological features, with criteria of Martini and Melamed supplanted by comprehensive histologic assessment of tumour type, predominant pattern, other histologic patterns and cytologic features. With publication of the 2015 WHO classification of lung tumours, we assessed the reproducibility of comprehensive histologic assessment and also sought to identify the most useful histological features.
Methods:
We conducted an online survey in which pathologists reviewed a sequential cohort of resected multifocal tumours to determine whether they were SPLC, IM, or a combination. Specific histological features for each nodule were entered into the database by the observing pathologist (tumour type, predominant adenocarcinoma pattern, and histological features including presence of lepidic growth, intra-alveolar cell clusters, cell size, mitotic rate, nuclear pleomorphism, nucleolar size and pleomorphism, nuclear inclusions, necrosis pattern, vascular invasion, mucin content, keratinization, clear cell change, cytoplasmic granules¸ lymphocytosis, macrophage response, acute inflammation and emperipolesis). Results were statistically analyzed for concordance with submitting diagnosis (gold standard) and among pathologists. Consistency of each feature was correlated with final determination of SPLC vs. IM status (p staging) by chi square analysis and Fisher exact test.
Results:
Seventeen pathologists evaluated 126 tumors from 48 patients. Kappa score on overall assessment of primary v. metastatic status was 0.60. There was good agreement as measured by Cohen’s Kappa (0.64, p<0.0001) between WHO histological patterns in individual cases with SPLC or IM status but proportions for histology and SPT or IM status were not identical (McNemar's test, p<0.0001) and additional histological features were assessed. There was marked variation in p values among the specific histological features. The strongest correlations (<0.05) between p staging status and histological features were with nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intra-alveolar clusters and necrosis pattern. Correlation between lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization and emperipolesis did not reach a p value of 0.05.
Conclusion:
Comprehensive histologic assessment shows good reproducibility between practicing lung pathologists. In addition to main tumour type and predominant patterns, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate appear to be useful in distinguishing between SPLC and IM.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-059 - CD70 Immune Checkpoint Ligand is Associated with Epithelial-To-Mesenchymal Transition in Non-Small Cell Lung Cancer (ID 4317)
14:30 - 15:45 | Author(s): S. Lantuejoul
- Abstract
Background:
Recent advances in the modulation of immune checkpoints (ICPs) or their ligands (ICPLs) indicate their role in anti-tumor immunity and in mediating durable cancer regressions in NSCLC and other cancers. Epithelial-to-mesenchymal transition (EMT) enables the reprogramming of polarized epithelial cells towards a mesenchymal phenotype with migratory and invasive properties. EMT promotes cancer cell plasticity and favors tumor adaptability to encountered selective pressures. We hypothesize that EMT represents an escape mechanism to immune-surveillance.
Methods:
ICPLs gene expression patterns were analyzed in silico in 129 NSCLC cell lines (CCLE) in relation to their EMT status (Mak. CCR, 2015). These observations were validated using the TCGA RNAseq data available for lung adenocarcinomas (n=488) and squamous-cell carcinomas (n=501) and the GSE41271 dataset (n=275 NSCLC tumors). In vitro, CD70 expression was evaluated by FACS in (1) epithelial Vs mesenchymal lung cancer cell lines, (2) HCC44 cells (mesenchymal) that underwent CRISPR/Cas9-mediated knock out of ZEB1 and in (3) H3255 (epithelial) that overexpress SNAIL. The expression of CD70 and markers of immune infiltrate was assessed by immunohistochemistry in a cohort of 132 NSCLC.
Results:
Unsupervised hierarchical cluster analysis revealed that expression of CD70 was significantly associated with the mesenchymal status in NSCLC cell lines (p < 0.001). These results were confirmed in silico in all three datasets of NSCLC samples. We identified the E-box sequence CANNTG in the CD70 gene promoter, suggesting the possible regulation of CD70 by ZEB1 and/or SNAIL. CD70 expression was increased in mesenchymal Vs epithelial NSCLC cell lines. Overexpression of SNAIL in H3255 cells did not result in the acquisition of mesenchymal properties or in changes in CD70 expression. CRISPR/Cas9-mediated knock out of ZEB1 was successful in HCC44 cells and resulted in increased expression of E-cadherin and EpCAM when compared to the control. The analysis of CD70 expression in this model will be presented. We found increased CD70 positivity in sarcomatoid tumors compared to non-sarcomatoid NSCLC. Of note, the expression of CD70 in sarcomatoid tumors was limited to the mesenchymal compartment and co-localized with ZEB1. It is known that CD70 by tumor cells can facilitate evasion of the immune system. The analyses of tumor immune infiltrate markers and T-cell exhaustion in a cohort of 18 lung sarcomatoid tumors will be presented.
Conclusion:
The association of EMT and CD70 in lung tumors may play an important role of this interaction in immune scape. CD70 might represent a relevant target in sarcomatoid lung tumors.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.04 - Multicentric French Harmonization Study for PD-L1 IHC Testing in NSCLC (Abstract under Embargo until December 7, 7:00 CET) (ID 4910)
08:45 - 09:40 | Author(s): S. Lantuejoul
- Abstract
- Presentation
Background:
PD-L1 immunohistochemistry (IHC) is considered as a predictive biomarker for most anti PD-1/PDL-1 therapies in non-small cell lung cancer, but different assays were used in clinical trials. Several studies have compared 4 assays (22C3, 28-8, SP142, SP263) performed in central laboratories on dedicated platforms. In order to harmonise and make PD-L1 testing widely available on most IHC platforms and centers, we compared PD-L1 Dako (22C3, 28-8) and Ventana (SP263) assays and laboratory-developed tests (LDT).
Methods:
IHC with five anti-PD-L1 clones (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers. The IHC platforms used were Ventana BenchMark Ultra (2 centers), Leica Bond (2 centers) or Dako Autostainer Link 48 (3 centers). For each matching platform, 22C3, 28.8 and SP263 assays were performed. For non-matching platforms and other antibodies, LDT were developed in each center and harmonised based on tonsil tissue staining. A total of 35 stainings were performed across different platforms and antibodies for each case. Seven thoracic pathologists trained to PD-L1 scoring in expert courses participated. Each pathologist analysed 6 cases and compared the stainings obtained with the 5 antibodies on all platforms. Tumor cell and immune cell D-L1 stainings were scored semi-quantitatively as recommended in PD-L1 Dako and Ventana assays. For statistical analysis, 1, 5, 25, 50% and 1, 5, 10% thresholds were used for tumor cells and immune cells, respectively.
Results:
28-8, 22C3 and SP263 assays were highly concordant for tumor cell and immune cell stainings across the 5 Dako or Ventana platforms (R2=0.886 to 0.953). LDT demonstrated various levels of concordance as compared to those 3 assays. Notably, LDT using SP263 clone were the most concordant across all platforms for both immune cell and tumor cell stainings, whereas some selected LDT with clones 28-8, 22C3 and E1L3N, but not SP142, showed a good correlation with the 3 assays regarding tumor cells only.
Conclusion:
28-8, 22C3 and SP263 assays gave comparable results across dedicated platforms for tumor cells staining, as well as some selected LDT protocols using 28-8, 22C3, SP263 and E1L3N clones. These results will be further validated at the national level in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.
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