Author of

• 25958

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  P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 2
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27522

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    P3.04-13 - PD-L1-Gene Expression by nCounter Correlates with PD-L1 Protein Expression in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13944)

    12:00 - 13:30  |  Author(s): Carlos Cabrera
    • Abstract
    • Slides

    Background
    

    PD-L1 immunohistochemistry (IHC) staining is a Food and Drug Administration­-approved marker to identify patients for immunotherapy treatment in advanced non-small cell lung cancer (NSCLC). However, several antibodies and cut-off criteria have been used and pathological evaluation involves a certain degree of subjectivity. Multiplexed technologies can be of help in this setting and provide an objective measurement of PD-L1 levels.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    A 7-gene ‘immune signature’ comprising CD4, CD8, PD-1, PD-L1, IFNG, GZMM and FOXP3 was incorporated into our routine clinical practice as part of a customized nCounter panel (NanoString Technologies), which simultaneously screens for gene fusions (ALK, ROS1, RET and NTRK1), MET overexpression and MET exon 14-skipping mutations. Formalin-fixed paraffin embedded (FFPE) samples from advanced NSCLC patients were analyzed with the panel and compared with PD-L1 IHC evaluation on tumor cells, using 22C3 clone antibody.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Since 2017, a total of 296 FFPE samples have been analyzed with the nCounter panel. PDL-1 IHC has been performed in 113 FFPE samples, as requested by the oncologist. All samples were evaluable for nCounter and IHC (100%). By IHC, 48/113samples (42.5%) were scored as negative for PD-L1 protein expression, whereas 65/113 (57.5%) were evaluated as positive. Of those, 39 presented moderate (≥1-49%) and 26 (23%) high PD-L1 staining (≥50%). Using an appropriate cut-off value, the levels of PD-L1 mRNA, as determined by the nCounter panel, closely correlated the PD-L1 IHC evaluation, with a 78% of concordance and a 0.554 Cohen’s kappa (confidence interval 95% 0.400- 0.709).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    PD-L1 mRNA expression closely correlates with PD-L1 protein expression. Clinical validation is warranted to determine if nCounter can be an alternative to IHC for PD-L1 evaluation.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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  • 27525

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    P3.04-16 - A Seven-Gene Expression Signature Reveals Unique Immune-Phenotypes Related to Major Oncogenic-Drivers in NSCLC (ID 13991)

    12:00 - 13:30  |  Author(s): Carlos Cabrera
    • Abstract
    • Slides

    Background
    

    In oncogenic-driven non-small cell lung cancer (NSCLC), programmed death ligand 1 (PD-L1) expression is the result of a constitutive oncogenic activation leading to an immunosuppressive microenvironment. However, the relationship between the major driver mutations (KRAS, EGFR and ALK) and PD-L1 and other immune markers remains unclear. Gene expression signatures incorporating not only PD-L1 but also other components of the stroma might better capture the immune-context of these oncogenic subgroups.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    A 7-gene ‘immune signature’ comprising CD4, CD8, PD-1, PD-L1, IFNG, GZMM and FOXP3 was included in a customized nCounter panel (NanoString Technologies), used in our clinical institution on a routine basis and designed to simultaneously screen for gene fusion drivers (ALK, ROS1, RET and NTRK1), MET overexpression and MET exon 14-skipping mutations in formalin-fixed paraffin embedded (FFPE) samples. A total of 296 advanced NSCLC patients from two different institutions were analyzed by the panel. Among them, 115 patients (38.9%) were also submitted to next-generation sequencing (NGS, Ion Torrent PGM® or GeneReader) . Analyses of variance (ANOVA) were used to describe statistical significance between immune response genes in the two major oncogenic groups: KRAS mutant (n=33) andALK rearranged (n=44), compared to wild-type (WT) tumor samples (n=38).

    4c3880bb027f159e801041b1021e88e8 Result
    

    Oncogenic genes (ALK, KRAS) were mutually exclusive. The analysis of the 7-gene signature revealed distinct expression patterns in the oncogenic biomarker groups. A significantly higher mRNA expression of CD4 and PD-L1 was found in ALK rearranged tumors compared to the KRAS mutant, and WT groups (p=0.0014 and p=0.0467, respectively). In addition, a trend was observed between GZMM mRNA levels and the oncogenic groups (p= 0.0665) whereas no association was found with the other immune genes (CD8, PD-1, IFNG, FOXP3). There was a significant linear correlation between CD4 and PD-L1 in ALK positive patients (p= 0.0214), but not in KRAS mutant samples (p= 0. 112). Unsupervised clustering across mRNA expression data from 296 samples using 7-immune-related genes showed two clusters, high expression for ALK-rearranged patients and low expression for KRAS mutant patients. The correlation between each of the immune genes was performed and a high correlation was found between PD-1 and FOXP3 (r=0.9) and PD-1 with GZMM (r=0.8).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    NSCLC tumors with ALK alterations show a distinct CD4 and PD-L1 immune profile when compared to KRAS and WT samples.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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