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B.H. Nelson

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    ORAL 13 - Immunotherapy Biomarkers (ID 104)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL13.05 - Predictive Biomarker Testing for Programmed Cell Death 1 Inhibition in Non-Small Cell Lung Cancer (ID 1081)

      16:45 - 18:15  |  Author(s): B.H. Nelson

      • Abstract
      • Presentation
      • Slides

      Lung cancer is the largest cause of cancer-related mortality in the developed world. Advances in molecular targeted therapies have led to improved survival in a subset of non-small cell lung cancer (NSCLC) patients. Recently, inhibitors of the programmed cell death receptor 1 (PD1) have proven clinical efficacy in NSCLC. Only a subset of patients respond to PD1 inhibitors, likely reflecting variation in tumor-expression of the PD1 ligand (PD-L1). Many clinical trials have evaluated PD-L1 as a possible predictive biomarker for immune therapy; however several parallel and uncoordinated efforts have led to a high amount of heterogeneity, uncertainty, and ambiguity in the literature around PD-L1 and its use as a biomarker. We aim to investigate the feasibility of PD-L1 biomarker testing in NSCLC using immunohistochemistry (IHC).

      Cases of stage II, surgically resected NSCLC, adenocarcinoma were identified retrospectively from the archives of the British Columbia Cancer Agency. A tissue microarray (TMA) was constructed with matched primary and metastatic lung tumors. IHC directed towards PD-L1 was performed with 3 different primary antibody clones: E1L3N (Cell Signaling Technology), SP142 (Spring Bioscience), and 28-8 (Dako), each stain was prepared using a unique protocol. Additional cases of NSCLC with available whole-genome sequence were also stained. Staining results were reviewed and scored by intensity of staining and the percentage of positive tumor cells. Cases with positive staining of any intensity in greater than 1% of tumor cells were considered positive (H score > 1). Clinical, pathological, and genomic features of PD-L1 positive cases were reviewed.

      Eighty cases of NSCLC were identified and used in TMA construction. 78 cases had matched lymph node metastases included in the TMA. 29 cases (36%) were positive by the SP142 clone, 19 (24%) by E1L3N, and 27 (34%) by the 28-8 clone. The 3 clones showed concordant results in 61 (76%) of cases, 15 (19%) discordant cases showed low level staining with SP142/28-8 and no staining with E1L3N, 2 (2.5%) cases showed no staining by 28-8 with moderate staining by SP142/E1L3N. Lymph node metastases showed a concordant PD-L1 score in 65 (83%) cases, with no detectable trend in the discordance. Comparison of primary antibodies showed a high rate of concordance (κ=0.68). Exploratory analysis of 6 additional cases with whole-genome and transcriptome data showed no statistical correlation between PD-L1 IHC and tobacco-induced hypermutation signature (p=0.22), or PD-L1 mRNA expression (R[2] = 0.35) by linear regression.

      PD-L1 IHC is reproducible in the setting of an academic reference laboratory. There are small, but potentially clinically relevant, differences between commercially available PD-L1 diagnostic antibodies. Primary tumor PD-L1 status is generally reflective of metastatic tumor PD-L1 status. Molecular correlates of PD-L1 positive cases remain to be elucidated and warrant further investigation.

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