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Philip Bonomi



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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): Philip Bonomi

      • 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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      P2.03-29 - Circulating Levels of Ligands for Receptor Tyrosine Kinases May Contribute to an Immunosuppressive Tumor Microenvironment (Now Available) (ID 2972)

      10:15 - 18:15  |  Author(s): Philip Bonomi

      • Abstract
      • Slides

      Background

      Metabolic reprogramming of tumor cells is one of the key mechanisms leading to an immunosuppressive tumor microenvironment (TME) that dampens the therapeutic benefit of immune checkpoint inhibition in subsets of patients. An improved understanding for the role of circulating factors that regulate the tumor’s metabolic phenotype may provide insights that will help identify adjunct therapeutic strategies for PD-1/-L1 directed immunotherapy. Metabolic reprogramming in lung adenocarcinoma is predominately regulated at the level of receptor tyrosine kinase (RTK) activation and post-translational modifications (PTM) of intracellular proteins that ultimately regulates the metabolic phenotype of the tumor. In this study we evaluated the impact of circulating ligands for 17 common RTKs for their ability to induce RTK activation and intracellular signaling cascades capable to modulating central metabolism.

      Method

      Pretreatment peripheral blood were prepared from either from non-cancer control patients (n=30) from lung cancer screening studies or those with pathologically-confirmed lung adenocarcinoma, consisting of patients with stage I (T1a/bN0M0, n=25); locoregionally progressed (T1-4N1-3M0, n=31) or stage IV disease (n=48). All sera were individually used to screen cultures of A549 lung adenocarcinoma cells for the ability to induce RTK autophosphorylation in a high-throughput manner using Luminex immunobead assays. RTKs evaluated as part of this study included: c-Kit, c-Met/HGFR, EGFR, ErbB2, ErbB3, ErbB4, FLT3, IGF-1R, IR, M-CSFR, PDGFR-α, PDGFRß, Tie1, Tie2, VEGFR1, VEGFR2, VEGFR3, and FGFR1. In parallel, we characterized each patient serum specimen for relevant RTK ligands and decoy receptors also via Luminex. ANOVA with LSD post-hoc was used to assess differences in each group to induce intracellular signaling cascades.

      Result

      Patient sera were contrasted based on groupings consisting of the following: a control group from lung cancer screening studies, stage I disease, cases with locoregional progression, and cases with disseminated disease. IGF-1R autophosphorylation was significantly lower (p=0.002) in stage I adenocarcinoma cases relative to control cases lacking a malignancy, which corresponded well with reduced free IGF-1 levels (p=0.011) observed in the stage I group. Any additional stage-based changes in free IGF-1 levels were likely due to ligand sequestration by increased IGFBP-1, IGFBP-3, and IGFBP-5 levels (all p<0.05), but had no impact on IGF-1R activation. Circulating HGF (c-Met ligand) levels were significantly increased in both locoregional metastatic progression and systemic dissemination (both p<0.01), which was accompanied by level-dependent increase in c-Met autophosphorylation (p=0.004). Circulating levels of soluble c-Met are pending analysis. Similarly, metastasis-associated increases in the ligands for VEGFR3 were observed, particularly upon systemic dissemination (p<0.01 for both VEGF-C and VEGF-D), but were accompanied by an unanticipated decrease in RTK autophosphorylation (p=0.002). Other RTKs differentially modulated by sera from the patient groups include c-Kit (locoregionally advanced vs stage IV; p=0.01); Insulin Receptor and PDGFRα (locoregionally advanced vs stage IV; p=0.05) and EGFR (control vs stage IV, p<0.01).

      Conclusion

      Stage-dependent differences in circulating ligands for RTKs associated with the modulation of tumoral metabolic phenotype were observed and associated with stage-dependent RTK activation. This study is currently being expanded to provide direct metabolic flux information in conjunction to the RTK data using Seahorse metabolic phenotype assays.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-69 - Impact of Antibiotic Usage on Survival During Checkpoint Inhibitor Treatment of Non-Small Cell Lung Cancer (NSCLC) (ID 2741)

      10:15 - 18:15  |  Author(s): Philip Bonomi

      • Abstract

      Background

      Growing evidence suggests that the gut microbiome influences response to second line checkpoint inhibitor (ICI) therapy. Little has been reported about the influence of antibiotics (ABX) while on ICI.

      Method

      This is an IRB approved retrospective study. Patients with advanced (stage IV or relapsed disease) NSCLC that had progressed after platinum based chemotherapy and were subsequently treated with ICIs were identified from an institutional database. Demographics, ABX usage, and survival outcomes were recorded and analyzed. Cox proportional hazard models adjusted for age at diagnosis and sex were performed.

      Result

      161 NSCLC patients met inclusion criteria for this analysis and were treated with ICIs from 2015 to 2019. Median age was 66 years old (range 46-88) and 60% were female. Most patients had prior separate lines of systemic therapy (median 2 lines, range 1-4). Histological subtypes included adenocarcinoma (70%), squamous cell carcinoma (24%) and other histologies (6%). Median ICI treatment length was 2 months. ICIs included Nivolumab and Pembrolizumab. 58 patients (36%) had ABX usage in the 90 days prior to ICI initiation. 33 patients (20%) used ABX during ICI treatment. 71 patients (44%) had no ABX usage prior or during ICI treatment. There were no progression-free survival (PFS) differences for patients receiving antibiotics in the 90 days prior to treatment start (HR 1.024, p=0.92). The use of ABX during ICI therapy was associated with increased PFS (HR 0.597, p=0.02). There were no overall survival (OS) differences for patients receiving ABX in the 90 days prior to the start of ICI therapy (HR 1.122, p=0.64). The effect of ABX utilization on OS was not significant (HR 0.660, p=0.07).

      Conclusion

      Improved PFS and a trend toward improved OS was noted in patients receiving ABX during ICI therapy. This suggests that ABX during ICI therapy may not have a detrimental effect on outcomes. Further studies are needed to determine the regimen, length of ABX treatment and its relation to survival benefits or detriment prior to and during ICI therapy.