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Gabriela C Lobato
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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
- Moderators:Maurice Perol, Kaoru Kubota
- Coordinates: 9/09/2019, 14:00 - 15:30, Vancouver (2003)
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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): Gabriela C Lobato
- Abstract
- Presentation
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): Gabriela C Lobato
- Abstract
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.
