Author of

• 10583

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  P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10635

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    P1.06-052 - Biomarkers of phenotypic plasticity associated with clinical outcomes in patients with locally-advanced NSCLC treated with chemoradiation with and without surgery. (ID 3019)

    09:30 - 16:30  |  Author(s): K. Kaiser-Walters
    • Abstract

    Background
    Thoracic chemoradiotherapy (CRT) with or without surgery (S) is the standard-of-care in management of stage III NSCLC. However, it appears that plateau has been reached. New treatment strategies are needed. The objective of this retrospective study was to evaluate the relationships between patient outcomes and expression of biomarkers associated with either the epithelial-to-mesenchymal transition, or EMT ( E-cadherin and vimentin), or a lung cancer “stem-cell” phenotype (CD133), DNA repair enzyme (ERCC1), and cell survival/apoptosis (BCL-2, surviving and PTEN) in attempt to identify new therapeutic strategies.

    Methods
    Stage III NSCLC pts who were treated with chest radiation (40-65Gy) and concurrently with platinum doublet and who had sufficient pretreatment tissue were included in this study. Surgical pts received 40-45 Gy of radiation preoperatively and non-surgical patients received 60-65 Gy. Immunohistochemistry was used to detect nuclear and cytoplasmic expression of ERCC1, bcl-2, survivin, PTEN, vimentin, E-cadherin, and CD133. Scores were calculated using the Allred scoring system. The log-rank tests used to evaluate progression free survival (PFS) and overall survival (OS) with Kaplan-Meier plots used to plot group characteristics.

    Results
    A total of 119 patients receiving chemoradiotherapy with adequate tumor specimens for analysis were enrolled in this study; 61 had definitive chemoradiation whereas 58 had pulmonary resection after chemoradiation. Patients (n=79) with low nuclear survivin immunostaining (score ≤6) had significantly improved PFS as compared to those patients (n=34) with higher expression levels (14.1 vs. 10.5 months, p=0.042). Patients (n=72) with a cytoplasmic vimentin score ≤ 5 had superior PFS than the with higher expression levels (n=33) (13.17 vs. 9.99 months, p=0.045). High nuclear ERCC1 values (n=72) were associated with a worse OS than those patients (n=44) with low immunostaining (22.7 vs. 59.1 months; p=0.023). Patients with low cytoplasmic E-cadherin (n=25) had a significantly better OS than those patients (n=85) with immunostaining scores (62.6 vs. 24.6 months, p=0.036). The cytoplasmic vimentin/ E-cadherin ratio provided the most impressive separation of cohort performance with high V/E ratios being associated with a poor PFS (12.6 vs. 3.1 months; score ratio 10 cutoff; p=0.00073). No significant associations with cytoplasmic CD133 were observed in this cohort for either PFS or OS.

    Conclusion
    The association of inferior overall survival in locally-advanced NSCLC patients whose tumors express high ERCC1, high cytoplasmic E-cadherin (which is associated with mesenchymal phenotype and lower adherence of cells which are able to metastasize easier), and lower progression free survival with high survivin and high vimentin/ E-cadherin ratio suggests that combining inhibitors of survivin, DNA repair, EMT pathways might improve outcomes in molecularly defined subset of stage III NSCLC patients.

• 12441

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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
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12491

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    P3.06-051 - Circulating biomarkers may help guide selection of erlotinib versus chemotherapy in pretreated advanced NSCLC patients. (ID 3364)

    09:30 - 16:30  |  Author(s): K. Kaiser-Walters
    • Abstract

    Background
    Recent data suggests a trend for prolonged progression-free survival (PFS) in patients with wild-type EGFR (wtEGFR) non-small cell lung cancer (NSCLC) treated with second-line docetaxel over erlotinib. In this same study, however, overall survival (OS) appeared unaffected. In the maintenance setting, erlotinib was also shown to improve both PFS and OS in wtEGFR advanced NSCLC patients. More recently, evaluating serum protein patterns by mass spectroscopy revealed inferior PFS with erlotinib compared to docetaxel in patients with a particular protein pattern. The individual proteins in the mass spectroscopy peaks were not identified. The objective of this study was to develop a multi-analyte serum panel of specific proteins with predictive value for erlotinib versus palliative chemotherapy in pretreated advanced NSCLC patients that were unselected for EGFR mutation status.

    Methods
    74 biomarkers were evaluated using Luminex immunobead assays against a total of 120 patients with stage IV NSCLC that were previously treated with chemotherapy and were unselected for EGFR mutation status. Patients were treated either with single agent erlotinib or platinum-based chemotherapy at the discretion of the treating physician. Patients were evaluated for disease progression using RECIST criteria and association of biomarker with survival outcomes was assessed using Cox proportional hazards regression model. The differential association of the biomarkers in the two treatment groups (erlotinib or chemotherapy) with survival outcomes was assessed using a proportional hazards (PH) interaction model.

    Results
    In univariate PH regression analysis, we identified 7 serum biomarkers (osteopontin, CA-125, sTNF-RII, PlGF, leptin, IGFBP5, and amphiregulin) which were strongly associated (p<0.01) and nine additional biomarkers (IGFBP4, sTNF-RI, CA 15-3, IGFBP1, sIL-2Rα, sFAS, VEGF-A, sIL-1RI, and sIL-4R) which had significant association (p<0.05) with PFS in the erlotinib subgroup (n=92). Similarly, 9 biomarkers (osteopontin, sTNF-RI, sTNF-RII, CA 15-3, sIL-2Rα, epiregulin, PILG, IL6 and CA 125) were found to be strongly associated with OS. In our assessment of differential association with PFS, we found eight serum biomarkers (sIL-2Rα, IL-8, sIL-1RI, Tensascin C, FGF2, HGF, Leptin, and TGF-α) with significant to strongly significant positive interaction terms, thus indicating differentially increased hazard of progression in the chemotherapy subgroup with high biomarker levels. Four markers (IL-8, TGF-α, HGF, VEGF-A) were found to have significantly positive interaction, indicating a decreased hazard of death in the erlotinib group with high biomarker levels; whereas two (sTNF-RII, PSA) had significant negative interaction with OS, demonstrating a increased hazard of death in the erlotinib group.

    Conclusion
    We identified a series of circulating surrogate biomarkers associated with epithelial-to-mesenchymal transition (EMT) that have promise for algorithm development to help physicians determine whether erlotinib as a single agent of chemotherapy is capable of improving outcomes in patients that progressed after first-line platinum-based chemotherapy. Current efforts focus on evaluating biomarker relationships with EGFR mutation status and algorithm validation in an effort to enhance survival in advanced stage NSCLC.