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Ricard Ramos



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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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      MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)

      14:00 - 15:30  |  Author(s): Ricard Ramos

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.

      Method

      Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.

      Result

      T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).

      kaplanmeier_immunegroups.png

      IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.

      Conclusion

      Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.

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    P2.13 - Staging (ID 315)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Staging
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.13-04 - Molecular Nodal Restaging Based on Embryonic Markers Expression Adds No Relevant Clinical Information in Resected Lung Cancer (ID 1149)

      10:15 - 18:15  |  Author(s): Ricard Ramos

      • Abstract
      • Slides

      Background

      The relapse rate in non-small cell lung cancer (NSCLC) is high, even in localised disease, suggesting that the current approach to pathological staging is insufficiently sensitive to detect occult micrometastases present in resected lymph nodes. Therefore, we aimed to determine the prognostic value of the expression of embryonic molecular markers in histologically-negative lymph nodes of completely-resected NSCLC.

      Method

      76 NSCLC patients undergoing radical resection were included. Primary tumours and 347 lymph nodes were studied. The molecular markers finally were selected based on testing of 27 normal lung and 129 lung tumour samples as well as 25 lymph nodes obtained from non-neoplastic diseases. CEACAM5, FGFR2b, and PTPN11 expression levels were evaluated through mRNA analysis using real-time RT-qPCR assay. Statistical analyses included the Kruskal-Wallis test, Kaplan Meier curves, and log-rank tests.

      Result

      CEACAM5 expression levels were scored as high in 90 lymph nodes (26%). The molecular-positive lymph nodes lead to the restaging of 37 (62%) pN0 patients as molecular N1 or N2 and 5 (31%) pN1 cases were reclassified as molecular-positive N2. Surprisingly, molecular-positive patients (42, 55%) associated with a better OS (overall survival, p=0,04) than molecular-negative patients (34, 45%). FGFR2b overexpression was observed in 41 (12%) lymph nodes leading to the restaging of 17 patients (22%). Again a trend was observed towards a better DFS (disease-free survival) in the restaged patients (p=0,09). PTPN11 expression levels were high in 109 (31%) lymph nodes and led to the restaging of 41 (54%) patients who did not correlate with clinical outcome (p=0,61). The combination of CEACAM5-FGFR2b restaged the same number of patients than CEACAM5 only. Accordingly, high expression levels of CEACAM5 or FGFR2b in the primary tumour were related to better DFS (p<0,06; p<0,02, respectively); PTPN11 did not correlate with prognosis (p=0,37).

      figura 3.jpg

      Conclusion

      Molecular nodal restaging based on expression levels of CEACAM5 and/or FGFR2b, does not add relevant clinical information to pathological staging of NSCLC likely related to the better prognosis of their overexpression in primary tumors.

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