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Ming Sound Tsao



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    ES17 - The New WHO Classification of Lung Tumors (ID 239)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
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      ES17.01 - Chair (ID 4079)

      15:30 - 16:30  |  Presenting Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Abstract

      No abstract for role as session chair

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    P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P14.09 - Early Expansion of M-MDSCs and High Plasma TSLP levels as Predictors of Primary Resistance to PD1 Inhibitors in Metastatic NSCLC (ID 1866)

      00:00 - 00:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Introduction

      Elevation of peripheral myeloid cell populations has been associated with poor response to PD-1 inhibitors in metastatic non-small cell lung cancer (mNSCLC). The mechanisms underlying this relationship remain poorly understood. Thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation, has been implicated in a complex feedback loop leading to expansion of myeloid populations and tumor growth. We hypothesized that TSLP levels directly correlate with the expansion of myeloid derived suppressor cell (MDSC) populations and sought to explore their association with response to PD-1 inhibitors in mNSCLC.

      Methods

      mNSCLC patients treated with PD-1 inhibitors underwent baseline and serial blood collection. Patients who received combination therapy with CTLA-4 inhibitors or chemotherapy were excluded from this analysis. Peripheral blood mononuclear cells (PBMCs) were analyzed by high-dimensional flow cytometry using validated panels to evaluate T/B/NK-cell, Treg and myeloid populations. Plasma cytokines including TSLP were analyzed using ELISA and Luminex assays. Cox and logistic regressions were utilized to correlate biomarkers with progression-free survival (PFS), overall survival (OS) and radiographic response.

      Results

      30 mNSCLC patients treated with single-agent PD-1 inhibitors were included in the analysis. Higher pre-treatment TSLP levels were significantly associated with a 2-fold increase of monocytic(M)-MDSCs (CD33+/HLA-DR-/CD14+) in response to ICI treatment (p=0.02). M-MDSC frequency after a median of 20 days (IQR 17-24 days) of ICI treatment was significantly associated with progressive disease (PD), shorter PFS and OS (all p<0.05) in the entire cohort including the subset of patients with PD-L1 expression ≥50% (n=24). No correlation was seen with baseline M-MDSC frequency. However, patients with a doubling of M-MDSCs (n=11) after treatment had a primary PD rate of 64% vs 24% (OR 7.0, p=0.04), significantly worse median PFS (2.5 vs 7.8 months; HR 2.6; p=0.04) (Figure 1) and a trend to worse median OS (7.7months vs NR; HR 3.7; p=0.08). Even after adjusting for PD-L1 expression, a doubling of M-MDSCs remained an independent predictor of poor PFS (multivariate HR 2.5; 95%CI 1.01-6.44; p=0.05). RNAseq of FACS-sorted myeloid populations is in progress.

      wclc myeloid graph.png

      Conclusion

      Early expansion of circulating M-MDSCs after treatment with PD-1 inhibitors is associated with elevated baseline TSLP levels and primary disease progression in mNSCLC. These findings suggest that elevated TSLP and early expansion of myeloid populations may represent an important mechanism of primary resistance to PD-1 inhibitors in mNSCLC.

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      P14.24 - Evolution of TCR Clonality during Chemoradiation and Durvalumab as Predictors of Survival in Stage 3 NSCLC (ID 1955)

      00:00 - 00:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Introduction

      Novel blood-based biomarkers evaluating T-cell receptor (TCR) clonality and the frequency/activation of immune populations hold significant potential for predicting the immune response in stage 3 NSCLC treated with durvalumab. TCR repertoire analysis includes characterization using diversity indices and quantification of individual clones. We hypothesized that low TCR clonality on treatment signals the lack of expansion of functional tumor-specific clones and predicts for worse outcomes. In this study, we characterized the evolution of TCR clonality on CRT and durvalumab and its correlation with response and survival.

      Methods

      Stage 3 NSCLC patients undergoing chemoradiation (CRT) and maintenance durvalumab were recruited prospectively to undergo serial blood collections at baseline and pre- and post- durvalumab. TCR repertoire analysis (capTCRseq) was performed on cfDNA using hybrid-capture TCR sequencing and TCR diversity/clonality was estimated using the Shannon’s and Simpson’s entropy index. Correlations between TCR clonality, response and PFS were examined using logistic and cox regressions.

      Results

      Among 73 stage 3 NSCLC patients prospectively recruited to study, a pilot group of 22 patients who had completed induction CRT was analyzed for clonal TCR changes on treatment. In total, 17 received consolidation durvalumab, with best response of CR/PR in 7(41%) SD in 8(47%) and PD in 2 (12%). The median PFS from the start of durvalumab is 12.0 months (3.3-NR) and 53% of patients had progressed at the time of analysis. Baseline TCR clonality was not associated with response to CRT or durvalumab. However, lower TCR clonality measured pre-durvalumab trended with lower response (OR 0.82, p=0.09). Lower TCR clonality pre-durvalumab also trended with worse PFS (HR 1.16 P=0.10). Importantly, a decrease in TCR clonality compared to baseline, signaling the lack of clonal expansion on treatment, is significantly associated with a worse PFS (p=0.05). In patients whose TCR clonality decreased by 50% after CRT, the median PFS was 1.7 vs 12.0 months (HR 3.5, p=0.14) (Figure A). Clonal tracking, flow cytometry and measurement of minimal residual disease (CAPPseq) is in progress.

      wclc oracle graph.png

      Conclusion

      A decrease in TCR clonality on CRT is associated with poor PFS on consolidation durvalumab. TCR clonality may be a potential biomarker that can select for patients likely to benefit from durvalumab. Further characterization of TCR clonality, clonal tracking with treatment, percentage of shared tumor TCR clones is ongoing in the larger cohort.

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    P35 - Pathology - Genomics (ID 105)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P35.03 - Methylation Signatures Associated with T790M Status in Progressive NSCLC (ID 2337)

      00:00 - 00:00  |  Author(s): Ming Sound Tsao

      • Abstract
      • Slides

      Introduction

      Emergence of the EGFR T790M mutation accounts for acquired first generation EGFR tyrosine kinase inhibitor (TKI) resistance in over half of patients with EGFR mutant NSCLC. In patients without emergent T790M, resistance mechanisms are less well understood. We explored the impact of DNA methylation status and TKI treatment failure in these patients.

      Methods

      Using a prospective cohort of patients with acquired TKI resistance, tumour tissue samples pre/post TKI exposure were identified. DNA was extracted from FFPE tissue using the Qiagen AllPrep DNA/RNA FFPE Extraction Protocol, and subsequently analyzed using the Illumina Infinium EPIC array. Raw microarray data files were processed using the software package minfi for data normalization (Illumina method) and extraction of methylation levels (M-values). Samples were split into two groups according to the T790M status of each sample (T790M + or T790M-). The set of most informative probes, those whose M-value profiles align most closely with the T790M status of the study samples, was generated by selecting the 1,000 probes with lowest ANOVA’s p-value. The stability of the resulting sample clustering was assessed by hierarchical clustering (Euclidean distance), classification with internal cross-validation (SVM leave-one-out), and non-parametric dimensional reduction (t-SNE).

      Results

      40 samples from 36 EGFR mutant NSCLC patients were successfully profiled. Pre TKI samples were available in 10 patients with an EGFR mutation of which 4 had matched post TKI tissue (3 T790M+, 1 T790M-). The remaining 26 samples in post TKI patients included 17 T790M + and 9 T790M- cases. A DNA methylation-based signature was developed by selecting the array probes that best discriminated T790M+ from T790M- cases. Group membership was stable, as shown by cross-validation by three different methods (hierarchical clustering, SVM leave-one-out and t-SNE). The 1,000 probe cut-off was arbitrarily selected; however, identical sample clusters were obtained using 500 or 2,000 methylation array probes. When analyzing the genomic location of the set of probes that form the signature, we found broad distribution across all chromosomes, thus, ruling out the possibility of selection bias due to focal or chromosome-level aberrations. Several genes contained a higher number of the selected probes, including EGFR, whose expression levels are known to be regulated at the methylation level in certain cancer types. Cluster analysis using the 1,000-probe signature revealed a high degree of concordance between EGFR T790M and DNA methylation status. All post-TKI (n=20) T790M+ samples concentrated within epi-group 2, whereas 8/10 T790M- samples were found within epi-group 1. Of the 4 patients with matched samples, 2 had baseline samples within epi-group 2 and went on to develop EGFR T790M post TKI. Of the 2 with baseline samples within epi-group 1, one went on to develop T790M (post-TKI epigroup 2) and one did not (post-TKI epigroup 1).

      Conclusion

      We observed a concordance between T790M status and epi-group suggesting that the development of resistance to EGFR-TKIs may be associated with distinct DNA methylation signatures. This signature may be present at baseline and predict for subsequent emergence of T790M.

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    PL01 - Opening Plenary Session (Japanese, Mandarin, Spanish Translation Available) (ID 140)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 1
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      PL01.05 - The New WHO Classification of Lung Tumors (ID 3898)

      18:00 - 20:00  |  Presenting Author(s): Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract

      The 5th Edition of WHO Classification for the Thoracic Tumours is expected to be published in 2021. As the 4th Edition was published in 2015, significant changes in the tumour classification system was not expected. However, majority of chapters, thus new text and perspectives, mostly written by new authors/co-authors. Several changes were brought in to introduce greater clarity to the classification system. Structural changes involve closer groupings of benign, precursor/pre-invasive, and invasive lesions or tumours of the same histogenesis. For each chapter, many old terminologies that were previously considered “synonyms” have been omitted or specifically mentioned as “Not recommended”. Tumours with distinctive histological patterns and clinical correlates within each tumour type are designated as “subtypes”. Newly added to each tumour entity are sections on “Diagnostic molecular pathology” and on “Essential/desirable diagnostic criteria”; these are meant to improve pathologists’ diagnostic accuracy.

      While the tumor entities included in the 5th Edition are mostly unchanged from the previous edition, there was some changes in how they are presented. Major chapters include tumours of the lung, the pleura and pericardium, the heart, and the thymus. While some mesenchymal tumours specific to the lung or heart are included in their respective chapters, mesenchymal tumours that may involve multiple sites in the thorax are grouped into one chapter. Germ cell tumors and Hematolymphoid tumors of the mediastinum also constitute separate chapters. Additional chapters are devoted to metastases to the thorax, ectopic tumors of thyroid and parathyroid origin, and genetic tumour syndromes involving thorax.

      Only few new tumor entities in the lung and pleura/pericardium have been reported since 2015, thus new in the 5th Edition. These include bronchiolar adenoma/ciliated muconodular papillary tumour (1), thoracic SMARCA4-deficient undifferentiated tumour (2), and mesothelioma in situ (3). Although these are rare incident lesions, they demonstrate distinct clinical, histopathological and/or molecular features that merit establishment as new pathological entities. The inclusion of these new entities in the 5th Edition of the Blue Book on Thoracic Tumours may stimulate their greater recognition, research and further understanding.

      In invasive non-mucinous lung adenocarcinoma, the five major pattern-based subtypes have been maintained. However, based on studies conducted by the IASLC Pathology Committee, a new IASLC grading system has been proposed (4). Well differentiated adenocarcinoma includes lepidic predominant adenocarcinoma with <20% high grade (micropapillary, solid and complex gland) patterns, while moderately adenocarcinoma is acinar/papillary predominant tumor with <20% high grade patterns. High grade adenocarcinoma is a tumour with any primary pattern and 20% or more high grade patterns. The prognostic significance of this grading system has been validated in 2 independent patient cohorts and demonstrated superior performance when compared to the grading system based on predominant pattern.

      In diffuse mesothelioma, two major additions include: (1) role of BAP-1/MTAP immunohistochemistry (IHC) and CDKN2/P16 fluorescent in situ hybridization (FISH) as diagnostic markers for in situ and diffuse malignant mesothelioma, and (2) grading system for epithelioid type diffuse mesothelioma for prognostication (5). The grading system is based on the degree of nuclear atypia of tumour cells, mitotic count, and presence or absence of necrosis (6). The new Edition will also include recommendation on the clinical reporting of mesothelioma cases.

      Lastly, while there are no significant changes in the classification of other types of lung cancers, recent new data suggest the existence of multiple molecularly defined subtypes of lung neuroendocrine tumours including small cell carcinoma and large cell neuroendocrine carcinoma (7-10). The clinical and therapeutic implication of these molecular subtypes require further studies.

      Overall, the 5th Edition will significantly improve the WHO classification system for thoracic tumours.

      References:

      1. Chang JC, et al. Am J Surg Pathol 2018 Aug;42(8):1010-1026.

      2. Perret R, et al. Am J Surg Pathol 2019 Apr;43(4):455-465.

      3. Churg A, et al. J Thorac Oncol 2020 Jun;15(6):899-901.

      4. Moreira AL et al, J Thorac Oncol 2020 Oct;15(10):1599-1610.

      5. Nicholson AG, et al. J Thorac Oncol 2020 Jan;15(1):29-49.

      6. Rosen LE, et al. Mod Pathol 2018 Apr;31(4):598-606.

      7. Fernandez-Cuesta L and Foll M. Trans Lung Cancer Res 2019;8 (Suppl 4): S430-434.

      8. Baine MK, et al. J Thorac Oncol 2020 Dec;15(12):1823-1835.

      9. Baine MK and Rekthman N. Transl Lung Cancer Res 2020 Jun;9(3):860-878.

      10. Lantuejoul S, et al Transl Lung Cancer Res 2020 Oct;9(5):2233-2244).

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