Author of

• 15382

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  P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

  • Event: WCLC 2015
  • Type: Poster
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)

  • 15502

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    P3.04-120 - Quantitative Immunofluorescence Based Expression Analysis in NSCLC Reveals Nuclear EZH2 as Poor Prognostic Biomarker (ID 2396)

    09:30 - 09:30  |  Author(s): K. Schalper
    • Abstract

    Background:
    EZH2 is a histone-lysine N-methyltransferase enzyme and the key functional enzymatic component of the polycomb repressive complex 2 (PRC2), which is a crucial epigenetic regulator in cancer cell survival. EZH2 methylates histone 3 at lysine 27 (H3K27me/me2/me3) and has been associated with the heterochromatin state, transcriptional repression and activation, hematopoiesis, development, and cell differentiation. Activating EZH2 mutations has been identified in lymphoma, and EZH2 overexpression has recently been reported in solid tumors including melanoma, breast, prostate, and lung cancer. Inhibition of EZH2 is a promising therapeutic strategy and a number of EZH2 targeting drugs are currently in clinical development.
    
    Methods:
    Multiplexed QIF assay was used to evaluate EZH2 expression using monoclonal antibody (clone D2C9, cell signaling technology) against human EZH2, and cytokeratin (AE1/AE3, Dako) in a retrospective cohort of 298 stages I-IV NSCLC represented in tissue microarray (TMA) format. H3122 NSCLC xenografts and control patient samples were used to determine staining specificity and optimal titer. The association between EZH2 level, clinico-pathological characteristics and survival were studied. The classification and regression tree (CART) analysis was used to determine the optimal cutoff of EZH2 expression to predict survival. Kaplan-Meier and log-rank test were used in statistical analysis of overall survival. Chi-square test was used for clinic-pathologic correlation statistical analysis.
    
    Results:
    EZH2 protein was detected predominantly in the tumor compartment with nuclear staining pattern. A high EZH2 level was detected in 82% of cases and was correlated with active smoking (92% vs. 64%, P=0.005) and squamous cell histology (94% vs 76%, P=0.013) (Table 1). Elevated tumor nuclear EZH2 expression was significantly associated with worse survival (median survival 53 vs. 104 months; log-rank P=0.002) (Figure 1).

    Table 1: Clinical Correlations of EZH2 expression in NSCLC
    		EZH2.in.Nuclear.AQUA.Norm> 570	Chi-square test
    	All (%)	No (%)	Yes (%)	p-value
    Age
    <70	120 (56.1)	22(18)	98(82)	0.864
    ≥70	94 (43.9)	19(20)	75(80)
    Gender
    Female	130 (60.7)	25(19)	105(81)	0.885
    Male	84 (39.3)	16(19)	68(81)
    Tobacco.history
    Current Smoker	49 (22.9)	4(8)	45(92)	0.005
    Former	113 (52.8)	21(19)	92(81)
    Never	39 (18.2)	14(36)	25(64)
    unknown	13 (6.1)
    Histology
    Adenocarcinoma	134 (62.6)	32(24)	102(76)	0.013
    Others	26 (12.1)	6(23)	20(77)
    Squamous Cell	54 (25.3)	3(6)	51(94)
    Tumor Size
    <3cm	115 (53.7)	23(20)	92(80)	0.778
    ≥3cm	97(45.3)	17(18)	80(82)
    unknown	2 (1)

    Figure 1
    
    
    
    Conclusion:
    Our study shows that high nuclear EZH2 protein expression is a poor prognostic biomarker in NSCLC, and is correlated with smoking status and squamous cell histology.