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P. Maxwell



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.02 - Association between Gene Expression Profiles and Clinical Outcome of Pemetrexed-Based Treatment in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: Exploratory Results from a Phase II Study (ID 185)

      10:30 - 12:00  |  Author(s): P. Maxwell

      • Abstract
      • Presentation
      • Slides

      Background
      We report exploratory gene expression profiling data from a prospective single-arm Phase-II-study in patients with non-squamous non-small cell lung cancer (nsNSCLC) treated with pemetrexed. Main results indicated a significant association of low thymidylate-synthase (TS) expression with longer PFS and OS [1].

      Methods
      Treatment-naive nsNSCLC patients (Stage IIIB/IV) received 4 cycles of first-line pemetrexed/cisplatin; non-progressing patients continued on pemetrexed maintenance [1]. Diagnostic tissue samples were used to assess TS expression (nucleus/cytoplasm) by immunohistochemistry (IHC, H scores), and to extract total mRNA for expression-array profiling (expression of 1,030 genes summarized from 60,000 transcripts). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS, mRNA gene expression was used both as continuous and binary (cutpoint: median) variable. Unadjusted p-values (significance level =0.01) and false discovery rates (FDR) were calculated. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman rank test). Finally, unsupervised clustering was applied to all samples with mRNA expression (n=51) for all 1,030 selected array genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n=47) previously described [2].

      Results
      51/70 (72.9%) biopsies were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01). 8/9 genes were negatively correlated with nuclear TS expression; the test was statistically significant for 5/8 genes (unadjusted p<0.01, Table 1). None of these genes has a known relationship to folate metabolism. Cluster analysis of all 51 samples based on 1,030 genes revealed no clear trend regarding PFS/OS. Cluster-analysis of 47 ADC samples identified 3 groups (n=21, 11 and 15 patients, respectively) with median (95%CI) PFS and OS of 8.1 (6.9, not estimable [NE]) and 20.3 (17.5, N.E) months; 2.4 (1.2, NE) and 4.3 (1.4, NE) months; and 4.4 (1.2, NE) and 8.3 (3.9, NE) months, respectively. Figure 1

      Conclusion
      This exploratory analysis provides insights on key genes potentially linked to low TS expression. Nine genes were significantly associated with PFS/OS; however such association cannot be differentiated as prognostic or predictive since this study is single arm. Further research would be needed to understand the relationship of these markers with clinical outcomes. [1] Nicolson et al, J Thorac Oncol 2013, May 29 [Epub]. [2] Wilkerson et al, PLoS One 2012;7(5):e36530.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-005 - A Prospective Protocol for Simultaneous Genomic Testing in Patients with Non-Small Cell Lung Cancer (ID 993)

      09:30 - 16:30  |  Author(s): P. Maxwell

      • Abstract

      Background
      Molecular testing in lung cancer has dramatically evolved over the past few years with a large number of targeted therapies and associated biomarkers. This has created a demand for tissue preservation. A careful consensus for prioritization of the different assays is needed to identify the right therapy for the patient. It is necessary to have protocols available that give access to results rapidly and accurately without depleting the sample throughout the process. We have designed a prospective study to demonstrate an efficient biomarker testing workflow (EGFR, ALK and KRAS) in a real clinical setting that preserves limited, valuable clinical samples

      Methods
      This prospective study was conducted at two independent pathology laboratories (Laboratorio de Dianas Terapeuticas of Madrid, Queen’s University of Belfast). Each site performed tissue sectioning for diagnosis and molecular testing according to laboratory protocols or to the assay specific package insert. Digital pathology was used to annotate specimens. NSCLC specimens were obtained by each lab (surgical resections and small biopsies of primary and metastatic lesions), excluding cytology specimens, with the exception of cells blocks. EGFR and KRAS mutation testing was performed using the cobas[®] EGFR Mutation Test and the cobas[®] KRAS Mutation Test (both CE-IVD), using a single 5µm section per test. FISH analysis was performed using the Vysis LSI ALK probe. Figure 1

      Results
      A total of 103 cases were included. 100% of the specimens were successfully tested for EGFR mutation status. Failure rates were 1.9% for ALK and KRAS analysis. Failed DNA extraction/PCR amplification was 3.9%/2.9% for EGFR and 5.8%/12.6% for KRAS. The prevalence of molecular alterations identified in EGFR (4% and 13.2%), ALK (4% and 7.8%) and KRAS (26% and 29.4%) was somewhat similar to that described in earlier studies. ALK rearrangements were mutually exclusive with EGFR and KRAS mutations. The median turnaround time was almost identical between sites: 6-7 days for all biomarkers (EGFR range 1-12 days, ALK range 2-14 days and KRAS range 1-17 days).

      Conclusion
      We have demonstrated that it is feasible to incorporate this protocol into the routine analysis of thoracic samples. The pattern of retesting to achieve full analysis in all samples suggests that, while EGFR testing is easily achievable with a one-section approach, the analysis of KRAS and ALK may require another round of testing in a small percentage of cases. Our results thus provide a pre-analytical and analytical rationale for comprehensive genotyping in patients with NSCLC.