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Conner Wakefield



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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA13.01 - Associations Between Baseline Serum Biomarker Levels and Cachexia/Pre-Cachexia in Pretreated Non-Small Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 2991)

      14:00 - 15:30  |  Author(s): Conner Wakefield

      • Abstract
      • Presentation
      • Slides

      Background

      We previously reported associations of pretreatment serum biomarkers with clinical outcomes in a cohort of advanced NSCLC patients that progressed on front-line therapy. This study aims to elucidate mechanisms underlying cancer cachexia/ pre-cachexia by evaluating relationships between baseline serum biomarker values and sequential changes in body weight, body mass index (BMI), and neutrophil/lymphocyte ratio (NLR) in NSCLC patients.

      Method

      We used Luminex immunobead assays to survey 101 protein biomarkers in sera from advanced NSCLC (n=138) collected prior to their salvage regimen. Serial parameters associated with cancer cachexia included body weight, BMI, and NLR. Outcome variables (progression-free survival (PFS) and overall survival (OS)) were extracted with full IRB-approval. Biomarkers were evaluated as continuous variables with the cachexia surrogates using Pearson correlations, whereas associations of PFS and OS were accomplished with the Cox PH test.

      Result

      High baseline values of BMI and low baseline NLR were associated with both OS and PFS (each p<0.05), though weight failed to reach significance. PFS and OS were similarly associated with percent changes (relative to baseline) in weight (p<0.01), BMI (p<0.01), and NLR (p<0.001). Thirteen biomarkers were found to be associated (p<0.05) with baseline BMI values, including positive correlations with leptin, sol.VEGFR2, and c-peptide and inverse correlations with adiponectin, ferritin, ghrelin, IGFBP-1 and IL-8; fifteen biomarkers were associated with baseline NLR (all p<0.05), including positive correlations with visfatin, insulin, and serum amyloid A and inverse correlations with IGF-II. Fifteen biomarkers were found to be associated (p<0.05) in common with percent weight and BMI changes, including positive correlations with IGFBP-3 and inverse correlations with insulin, FGF-2, TNF-alpha, and resistin. Only prolactin and placental growth factor were found to be associated (p<0.05) with percent change in NLR.

      Conclusion

      A series of circulating protein biomarkers primarily connected with metabolic regulation and systemic inflammation/ acute phase response were found to be associated with cachexia/ pre-cachexia in NSCLC patients. Additional cohorts are currently being tested to verify these findings.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-15 - Validation of Tumor Organoids from Lung Adenocarcinoma as a Model of Primary Tumor Genotype (Now Available) (ID 2791)

      10:15 - 18:15  |  Author(s): Conner Wakefield

      • Abstract
      • Slides

      Background

      Tumor organoids have shown promise as a model to predict clinical treatment response in patients with certain malignancies. However, there is a paucity of data supporting the utility of tumor organoids derived from patients with non-small cell lung cancer (NSCLC). Here, we demonstrate the feasibility of establishing tumor organoids from patients with NSCLC and examine molecular fidelity of tumor organoids derived from early-stage lung adenocarcinomas relative to their primary tumors.

      Method

      140 patients who underwent lung resection for NSCLC were consented for organoid culture. Primary tumor specimens were processed to single cell suspensions and tumor cells were grown in extracellular matrix and chemically defined media. Tumor organoids and their corresponding primary tumors were evaluated by next generation sequencing for copy number and somatic alterations.

      Overall concordance between primary tumor and organoid was determined by dividing the percentage of overlapping somatic single-nucleotide variant (SNV) alterations by the total somatic SNV alterations present in both tumor and organoid model.

      Result

      A subset (n=11) of tumor organoids developed from patients with early-stage lung adenocarcinoma were assessed for molecular concordance as compared to the primary tumor within 12 weeks of establishment (approximately 2-4 passages). The tumor organoids enriched for protein coding SNV somatic mutations with an average of 6.8% overlap of all somatic SNV variants (n=2382) vs 34.8% overlap in coding SNV mutations (n=72); p<0.001. Additionally, the overlapping coding SNV mutations are further enriched in the tumor organoid as measured by allelic fraction where on average they are present at 35.3% allelic fraction as compared to 20.9% in the original tumor specimen samples tested.

      Conclusion

      Early-stage primary lung adenocarcinoma tumor organoids can be reliably generated and robustly profiled in a clinically compatible time frame. Further investigation into individual driver mutations and tumor mutational burden are underway to support this novel tumor model’s stability with sequential passaging and ability to prospectively predict therapeutic response, including strategies targeting immune checkpoint inhibition.

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