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M. Joshi



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    MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Early Stage NSCLC
    • Presentations: 1
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      MA 13.02 - Comprehensive Genetic Analysis Related to  PD-L1 Expression in Early-stage Lung Squamous Cell Carcinoma (ID 9077)

      15:45 - 17:30  |  Author(s): M. Joshi

      • Abstract
      • Presentation
      • Slides

      Background:
      Recently, anti PD-1/PD-L1 immunotherapies have yielded promising outcomes in advanced squamous NSCLC. Several studies have suggested that tumor PD-L1 protein expression status might correlate with outcome and response to treatment. The aim of this study is to identify mRNA gene signatures and microRNAs associated with tumor PD-L1 expression in early-stage lung squamous cell carcinoma (SCC).

      Method:
      Early stage (I-II) SCC resected patient tumors were collected from 6 cancer centers as part of the SPECS II program. Gene expression profiling was performed on the specimens. PD-L1 protein expression was evaluated by immunohistochemistry on SCC FFPE tissue using the Dako 22C3 PD-L1 antibody. The tumor proportion score (TPS) for PD-L1 protein expression was compared with comprehensive clinicopathological, mRNA and miRNA data.

      Result:
      The prevalence of PD-L1 expression in this cohort of 255 Stage I-II SCC patients was 46.7% with a TPS cutoff of ≥ 1%, and 9.8% with a cutoff of ≥ 50%. Among 202 cases with available clinical and expression data, no significant association was observed between PD-L1 expression and clinical outcome. We identified a 12-gene signature from mRNA microarray using the Minimax Concave Penalty (MCP) regression method with an AUC of 0.92 at ≥ 5% TPS cutoff. A subset of 138 miRNAs was shown to be significantly differentially expressed between PD-L1 positive and PD-L1 negative groups at false discovery rate (FDR) of 0.05 with TPS cutoffs of ≥ 1%, ≥ 5% and ≥ 10%. No miRNAs were found to be significantly differentially expressed between the groups using a TPS cutoff of ≥ 50%. Gene Set Enrichment Analysis (GSEA) identified two pathways with gene sets that were significantly enriched (FDR < 0.05) in the PD-L1 negative group. No significant association was found between tumor mutation burden and PD-L1 expression level.

      Conclusion:
      PD-L1 expression prevalence is lower in early-stage lung SCC than in advanced NSCLC. No significant association was found between PD-L1 expression and prognosis in this cohort. Both mRNA gene signatures and miRNAs were identified to be predictive of PD-L1 expression. Through GSEA, two distinct gene sets were identified with expression correlated to PD-L1, one comprising genes related to ovary and another related to collagens and extracellular matrix (ECM). No significant association was found between tumor mutation burden and PD-L1 expression level. Following validation, these predictive signatures could be used to select patients with positive PD-L1 expression who may benefit from immunotherapy.

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    MA 19 - Mesothelioma: Bench to Bedside (ID 680)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Mesothelioma
    • Presentations: 1
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      MA 19.09 - The Role of Neoadjuvant Chemotherapy in Patients with Malignant Pleural Mesothelioma (ID 10187)

      11:00 - 12:30  |  Author(s): M. Joshi

      • Abstract
      • Presentation
      • Slides

      Background:
      The treatment of localized malignant pleural mesothelioma (MPM) involves multimodality therapy, however, there is no standard of care with respect to operative procedure and timing of chemotherapy. We analyzed data from a single institution to identify whether the use of pemetrexed-platinum neoadjuvant chemotherapy impacts survival.

      Method:
      Patients with histologically-proven MPM who had surgery from 1996 to 2016 were identified. Follow-up was complete for a median of 24 months. Survival was calculated from time of diagnosis to last follow up or death. Univariate and multivariate Cox proportional hazards were used.

      Result:
      From 1996 to 2016 we identified 376 patients. Mean age was 66+/-8 years and 54 (14%) were female. There was no difference in survival for pleurectomy/decortication or extrapleural pneumonectomy. Neoadjuvant chemotherapy significantly improved survival compared to surgery followed by chemotherapy (table 1). Multivariate analysis was significantly associated for increased survival for epithelioid histology, T-status, node positivity, and neoadjuvant chemotherapy (table 2).

      Table 1. Univariate Analysis
      Variable (n) Median survival (mo.) P value
      Gender Male (322) Female (54) 13.6 17.2 P=0.043
      Histology Epithelial (252) Mixed (91) Sarcomatoid (26) 18.3 12.1 6.5 P<0.0001
      T stage T 1-2 (33) T 3-4 (343) 42.6 14.3 P=0.0002
      N status N 0 (129) N 1-2 (113) 23.1 11.3 P<0.0001
      Neoadjuvant chemotherapy Yes (153) No (223) 19.8 11.3 P<0.0001
      Table 2. Cox Proportional Hazards Model
      Covariate Hazard Ratio 95% CI p-value
      Histology (ref: Epithelioid) Biphasic Sarcomatoid ref 1.66 4.24 [ref] [1.17-2.36] [1.77-10.1] ref 0.005 0.001
      T-status 3-4 vs 1-2 3.07 [1.32-7.15] 0.009
      Node-positivity 1.93 [1.40-2.66] <0.001
      Neoadjuvant chemotherapy 0.65 [0.47-0.91] 0.011
      Cox proportional hazards model including histology, t-status, n-status, and neoadjuvant chemotherapy C-index: 0.69

      Conclusion:
      Our results suggest that neoadjuvant chemotherapy increases survival and likely enhances the complete resection rate. These data are being evaluated in a multi-institutional cohort of five major mesothelioma programs in North America to improve guidelines for mesothelioma therapy.

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