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W.N. Rom
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MINI 12 - Biomarkers and Lung Nodule Management (ID 109)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:J.M. Siegfried, H.I. Pass
- Coordinates: 9/07/2015, 16:45 - 18:15, 401-404
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MINI12.12 - Validation of Blood-Based Biomarker for Classification of Patients with Indeterminate Pulmonary Nodules (ID 559)
16:45 - 18:15 | Author(s): W.N. Rom
- Abstract
- Presentation
Background:
The United States Preventive Services Task Force recommends annual CT-screening for lung cancer in high risk adults but also acknowledges that one disadvantage of CT-screening is the large number of false positive results. Circulating biomarkers may provide a noninvasive, cost-effective means of addressing this disadvantage by assisting with classification of patients with indeterminate pulmonary nodules. Here, we describe the development and testing of a blood-based 5-analyte panel to classify these patients.
Methods:
A 5-analyte panel was developed in a training study comprising stage I NSCLC patients (n=95) and healthy smoker controls (n=186). The ability of the biomarker to resolve patients with benign nodules from those with malignant lesions was investigated in two validation studies: (1) Prostate, Lung, Colorectal, Ovarian (PLCO), a CXR-based screening trial, cases n=56, controls n=56; (2) Conversant Bio (CB), cases n=22, controls n=22.
Results:
In the training study, the 5-marker classifier (TFPI, OPN, CEA, CYFRA, SCC) resolved malignant cases with 72% sensitivity and 90% specificity (AUC=0.90). In the PLCO validation study, the biomarker distinguished pre-diagnostic cases with an AUC=0.65. In the CB study, a clinical model developed integrating nodule size, nodule location and gender, classified subjects with an AUC=0.79. When added to the clinical model, the biomarker significantly improved overall accuracy (P=0.016; AUC=0.86).
Conclusion:
A blood-based biomarker has been developed that accurately classifies patients with indeterminate nodules. Adding this biomarker to currently employed clinical and imaging-based evaluations of pulmonary nodules, may prove valuable in assessing malignant risk.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-078 - Induction of Achaete-Scute Homologue 1 (ASCL1) by Cigarette Smoke Condensate in A549 Cells (ID 326)
09:30 - 17:00 | Author(s): W.N. Rom
- Abstract
Background:
About 10% of lung adenocarcinomas express neuroendocrine features, which are thought to denote a subset of adenocarcinomas with poor prognosis. Achaete-scute homologue 1 (ASCL1) is a transcription factor implicated in the neuroendocrine differentiation of lung tissue. Recently, ASCL1 was identified as a neuroendocrine marker in lung adenocarcinomas, and its expression was upregulated in lung adenocarcinomas of smokers when compared to adenocarcinomas of non-smokers and other types of lung cancers. ASCL1 expression in the peripheral airways of cancer-free smokers has not been studied. Moreover, the effect of cigarette smoke exposure on the neuroendocrine differentiation of lung cancer cells has not been examined in vitro.
Methods:
Distal airway brushings for epithelial cells were obtained in 8 subjects who participated in CT scan lung cancer screening at the NYU Lung Cancer Biomarker Center (part of the NCI Early Detection Research Network); never (n=1), former (n=4) and current (n=3) smokers. ASCL1 mRNA expression was measured using real time reverse transcription polymerase chain reaction (RT-PCR). A549 cell line was incubated with cigarette smoke condensate (CSC; extracted to DMSO) at 10 or 40 mcg/mL for 4, 24 or 48 hours. Following the incubation periods, ASCL1 expression levels were measured via western blot with lamin B1 as the nuclear protein loading control. Three individual experiments were performed. Statistical analyses were performed with Kruskal-Wallis test (RT-PCR) and Student's t-test (western blot). Figure 1
Results:
Real time RT-PCR data for ASCL1 in the distal airway brushing samples of the 8 subjects suggested a trend toward higher ASCL1 mRNA titers (p = 0.26) in current smokers (mean = 33 pack-years) compared to former smokers (mean = 51 pack-years), whose ASCL1 mRNA expression levels were higher than that of a never-smoker [Figure 1A]. A549 cells exposed to 10 mcg/mL of CSC for 4 hours had 4.1 fold (p = 0.023) and 2.0 fold (p = 0.017) increases in ASCL1 expression compared to those exposed to 1% DMSO and serum-free media (SF) only, respectively [Figure 1B]. No statistically significant change in ASCL1 expression was noted in the other CSC exposure groups.
Conclusion:
CSC induced ASCL1 expression in A549 cells, and the stimulatory effect of CSC was no longer observed at the higher concentration and the longer exposure times. This in vitro finding is in agreement with the RT-PCR data, which also suggest a trend toward increased ASCL1 expression with more recent smoking history in the distal airways of cancer-free human subjects.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-085 - Anti-Glycan Antibody Profiling in De-Novo Stage IV Non-Small Cell Lung Cancer: A Pilot Study (ID 1447)
09:30 - 17:00 | Author(s): W.N. Rom
- Abstract
Background:
NSCLC is a heterogeneous disease with marked molecular and genomic variability that usually presents in advanced stage. Aberrant glycosylation occurs early during malignant transformation producing tumor-associated carbohydrate antigens (TACAs). Immune response to TACAs can be evaluated by immunoprofiling serum anti-glycan antibodies (AGAs) using printed glycan arrays (PGA), a new biomarker-discovery platform. Control and stage I NSCLC immunoprofiles were evaluated in a parallel study involving 70 subjects with high risk for developing lung cancer enrolled in low-dose CT lung cancer screening trial, 20 of who subsequently developed stage I NSCLC and a putative signature for early stage NSCLC has been obtained. The objective of this study was to obtain a putative signature of de-novo stage IV NSCLC patients using serum AGA immunoprofiles.
Methods:
18 patients were enrolled in this prospective study. Data collected included demographics, tumor histology, EGFR mutational status, and cancer treatment details. Blood sample was collected at each visit. Response was assessed after every two cycles of first-line chemotherapy regimen by a radiologist using RECIST 1.1 and the best overall response and time-to-progression (TTP) were recorded. Patients were dichotomized as “good” or “poor” responders by median TTP. AGAs were immunoprofiled in 30 microliters of serum using PGA with 382 glycans. The raw PGA data were screened to remove glycans with critically low signal intensities, low Intra-array Correlation Coefficient (ICC) and high coefficient of variation (CV) of on-slide replicates. The raw data were normalized with intra-slide linear normalization, and log-transformed. The putative glycan signature was obtained by our novel Compound ImmunoRuler (CIR) algorithm based on bootstrap aggregation of multiple signatures derived from correlation-adjusted Wilcoxon ranking using projections based on multivariate logistic regression. The training of CIR was performed on the baseline immunoprofiles of de novo stage IV samples with control immunoprofiles from the screening trial.
Results:
Study population included 11 males and 7 females. Mean age was 62 years (range 47-80). 15 patients (83%) had adenocarcinoma, two squamous, and one poorly differentiated. Two had EGFR mutation. Most common regimen was platinum/pemetrexed (n=14) followed by platinum/gemcitabine (n=2) and erlotinib (n=2). One patient had a complete response (CR); 6 PR and 4 had stable disease while 7 progressed. The median TTP was 140 days (41-387). For PGA data analyses, 278 glycans with ICC>80% were used for downstream analysis which delivered 3 glycans-based putative signature of Stage IV de novo NSCLC with AUC value 0.956; specificity 86%, and sensitivity 88.9%. Glycans in signatures of stage I and de-novo stage IV NSCLC were distinctly different. When immunoprofiles of stage IV NSCLC were projected on stage I ImmunoRuler, 13 out of 18 (72%) stage IV patients were accurately recognized as malignant. AGA binding to 4 glycans was significantly different between the sub-groups of “poor” vs. “good” responders.
Conclusion:
Uniquely different serum AGA-signatures of early stage and de novo stage IV lung cancer may provide basis for minimally-invasive test for early detection of risk for these malignancies and for better understanding their underlying pathologies. Further study in a larger population should help validate these findings.
