Background: Detection rates of early-stage lung cancer are traditionally low, which contributes to inconsistent treatment responses and high rates of annual cancer deaths. Currently, low-dose computed tomography (LDCT) screening produces a high false discovery rate. This limitation has prompted research to identify biomarkers to more clearly define eligible patients for LDCT screening, differentiate indeterminate pulmonary nodules, and select individualized cancer therapy. Biomarkers within the Insulin-like Growth Factor (IGF) family have come to the forefront of this research. Main Body: Multiple biomarkers within the IGF family have been investigated, most notably IGF-I and IGF binding protein 3. However, newer studies seek to expand this search to other molecules within the IGF axis. Certain studies have demonstrated these biomarkers are useful when used in combination with lung cancer screening, but other findings were not as conclusive, possibly owing to measurement bias and non-standardized assay techniques. Research also has suggested IGF biomarkers may be beneficial in the prognostication and subsequent treatment via systemic therapy. Despite these advances, additional knowledge of complex regulatory mechanisms inherent to this system are necessary to more fully harness the potential clinical utility for diagnostic and therapeutic purposes. Conclusions: The IGF system likely plays a role in multiple phases of lung cancer; however, there is a surplus of conflicting data, especially prior to development of the disease and during early stages of detection. IGF biomarkers may be valuable in the screening, prognosis, and treatment of lung cancer, though their exact application requires further study.
Multiplex technologies for interrogating multiple biomarkers in concert have existed for several decades; however, methods to evaluate multiple epitopes on the same analyte remain limited. This report describes the development and optimization of a multiplexed immunobead assay for serological testing of common immunoglobulin isotypes (e.g., IgA, IgM, and IgG) associated with an immune response to SARS-CoV-2 infection or vaccination. Assays were accomplished using a flow-based, multiplex fluorescent reader with dual-channel capability. Optimizations focused on analyte capture time, detection antibody concentration, and detection antibody incubation time. Analytical assay performance characteristics (e.g., assay range (including lower and upper limits of quantitation); and intra-and inter-assay precision) were established for either IgG/IgM or IgA/IgM serotype combination in tandem using the 'dual channel' mode. Analyte capture times of 30 min for IgG, 60 min for IgM, and 120 min for IgA were suitable for most applications, providing a balance of assay performance and throughput. Optimal detection antibody incubations at 4 µg/mL for 30 min was observed and are recommended for general applications, given the overall excellent precision (percent coefficient of variance (%CV) ≤ 20%) and sensitivity values observed. The dynamic range for the IgG isotype spanned several orders of magnitude for each assay (Spike S1, Nucleocapsid, and Membrane glycoproteins), which supports robust titer evaluations at a 1:500 dilution factor for clinical applications.Finally, the optimized protocol was applied to monitoring Spike S1 seroconversion for subjects (n = 4) that completed a SARS-CoV-2 vaccine regimen. Within this cohort, Spike S1 IgG levels were observed to reach maximum titers at 14 days following second dose administration, at a much higher (~40-fold) signal intensity than either IgM or IgA isotypes. Interestingly, we observed highly variable Spike S1 IgG titer decay
e21189 Background: Several parameters that have been associated with outcomes in patients with metastatic NSCLC treated with anti-PD1/PDL1 mAbs include tumor PD-L1 expression, tumor mutational burden, and baseline NLR. Further investigation into clinical correlates of benefit with immune checkpoint inhibitors remains an unmet need. Methods: The objective of this retrospective study was to examine the potential influence of pretreatment cachexia and chronic inflammation in patients with NSCLC that received second- or third- line single agent anti-PD1/PDL1 mAbs. Weight, BMI, and NLR, as well as longitudinal changes in these variables from at least six-weeks prior to initiation of treatment were correlated with progression-free and overall survival (PFS/OS). These associations were assessed using statistical methods for time-to-event analysis. Results: 192 patients were included: 59% female, 72% Caucasian, 18% African American, 79% current or former smokers. 185 patients had pretreatment NLR values and 63% and 42% had NLR ratios > 3.5 and > 5, respectively. 187 patients had pretreatment weight and BMI available. Of these, 63% had a loss in BMI prior to initiation of anti-PD1/PDL1 mAbs, 29% with > 5% loss. Any BMI loss as well as BMI loss > 5% over the time period prior to treatment initiation were associated with shorter PFS (p < 0.01, 2.1 vs 4.37 mos for loss > 5% vs ≤ 5%) and change in BMI assessed in continuous scale was also associated with PFS (HR = 0.94, p < 0.05). Similarly, any BMI loss and BMI loss > 5% were associated with shorter OS (p < 0.01. 7.33 vs 12.23 mos for loss > 5% vs ≤ 5%) and change in BMI and baseline BMI assessed in continuous scale were additionally associated with OS (HR = 0.97 and 0.94, p < 0.05). Baseline NLR > 5 was associated with shorter PFS (p < 0.01) and baseline NLR assessed in continuous scale was negatively associated (HR = 1.01, p < 0.05). Moreover, pre-treatment NLR > 5 and baseline NLR > 3.5 were associated with shorter OS (p < 0.05). Pre-treatment NLR, baseline NLR, and %change in NLR, assessed in continuous scale, were negatively associated with OS (HR = 1.04, 1.02, 1.12, p < 0.01). Conclusions: This retrospective study identified clinical features of NLR and BMI at treatment initiation and in the immediate pre-treatment period that were associated with PFS and OS on anti-PD1/PDL1 mAbs therapy. These parameters can easily be investigated in the front-line population. They may also have utility in identifying patients that would benefit from therapeutic strategies to reverse weight loss and inhibit immunosuppressive effects associated with elevated NLR in order to increase the effectiveness of immunotherapy.
8543 Background: Patients with early stage, non-small cell lung cancer (NSCLC) with solitary pulmonary lesions ≤4 cm typically have favorable outcomes. However, disease recurrence impacts up to 30% of patients, leading to either additional surgical or systemic interventions. New methods to risk stratify patients based on clinical and molecular parameters may improve our ability to select cases that would benefit from more frequent surveillance or enrollment in clinical trials evaluating systemic therapy. Methods: We retrospectively analyzed data from 179 patients with early stage (T1a-2aN0M0) NSCLC from a single institution. All patients had anatomic resection, negative margins, and systematic nodal sampling. Clinical and demographic data were abstracted from patient charts and tumor samples were molecularly profiled using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage, whole exome-capture RNA-seq). Pathogenic alterations (single nucleotide variants and insertion/deletions) and RNA expression were examined. Bivariate Cox-proportional Hazards models were used to assess the association of individual clinical, demographic, and molecular variables with recurrence-free survival, defined as the time from surgery until recurrence or death. Results: Our dataset included 166 stage IA1-3 patients and 13 stage IB patients, of which 36 patients experienced a recurrence or death event after surgery. Clinical and DNA-seq data was available for all patients, and RNA expression data was available for 172 patients. Across all patients, the most common somatically mutated genes were TP53 (33% of tumors) and KRAS (16% of tumors), consistent with previous studies. Increasing log10-RNA expression for NTRK1 (HR: 5.95; 95% CI, 1.16-30.4; p = 0.027) and CD274 (PD-L1) (HR: 7.88; 95% CI, 1.61-38.6; p = 0.013) and decreasing log10-RNA expression for EGFR (HR: 0.24; 95% CI, 0.05-1.21; p = 0.071) and ERBB2 (Her2) (HR: 0.20; 95% CI, 0.04-0.97; p = 0.042) were associated with increased risk of recurrence or death. Conclusions: Increased expression of NTRK1 and CD274 (PD-L1) and decreased expression of EGFR and ERBB2 (Her2) were associated with a increased risk for recurrence following surgery. This may have mechanistic implications for heightened tumor aggressiveness and/or metastatic potential. Future work will expand our cohort and validate our findings in a broader set of early-stage NSCLC patients.
e21087 Background: While laboratory parameters including PDL1 expression and NLR are associated with outcomes in patients with metastatic NSCLC treated with ICIs, these measures have not identified patients with rapid progression (RP) defined as progressive disease within 30 days. Clinical factors including patient age and weight loss have been associated with cancer outcomes in general. Identifying clinical correlates for NSCLC patients who experience RP on ICI therapy would be useful. Methods: The objective of this retrospective study was to evaluate relationships between pre-treatment cachexia and inflammation and RP in NSCLC patients who received 2nd- or 3rd- line single agent ICIs. Associations of age, race, gender, smoking status, and longitudinal changes in weight and NLR (from at least 6 weeks prior to treatment initiation) with RP were analyzed by univariate and multivariate statistical (Kaplan-Meier and related) methods. Results: 195 patients were included: 59% female, 18% Black, and 78% current or former smokers. 14% of patients had RP. Black race was associated with RP (HR = 2.32, p = 0.03). 191 patients had pretreatment weight available. 63% had weight loss prior to ICI, 25% with > 5% loss. Any weight loss and weight loss > 5% over the time period ≥6 weeks prior to treatment initiation were associated with RP (HR = 3.19 and 6.40, p = 0.03 and < 0.01). 188 patients had pretreatment NLR values, 63% and 42% had NLRs > 3.5 and > 5, respectively. Pre-treatment NLR > 5 and higher baseline NLR were associated with increased risk of RP (p = 0.03 and p < 0.01). In multivariate analysis adjusted by age, smoking status and weight change, higher pre-treatment NLR is found to differentially increase RP risk for black patients (interaction HR = 1.27, p = 0.03). A model with these 5 variables provided 84.5% AUC of ROC curve (80% sensitivity, 75% sensitivity) for prognosticating RP. Conclusions: This retrospective study identified clinical variables including pre-treatment NLR > 5, weight loss > 0% & > 5%, black race, smoking status, and age that were associated with RP in previously treated advanced NSCLC patients receiving single agent ICIs. Though this requires validation with racially diverse data sets, these clinical parameters may be useful in identifying patients at high risk of RP on 2nd or 3rd line ICI therapy. Future directions include evaluating clinical characteristics and laboratory parameters in NSCLC patients treated with ICIs combined with chemotherapy and novel immunotherapy regimens, as well as single agent ICIs in the first line setting. If these clinical characteristics are associated with frequent RP in the setting of first line ICI treatment, it would be reasonable to consider novel immune strategies in this patient subset.
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