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W.J. Feser
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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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MINI12.02 - Clinical Utility of Chromosomal Aneusomy in High Risk Individuals (ID 1299)
16:45 - 18:15 | Author(s): W.J. Feser
- Abstract
- Presentation
Background:
In the context of CT screening in current and former smokers at high risk for lung cancer, the false positive rate is high (26% at first NLST screening; 13% with Lung-RADS criteria applied to NLST) and indeterminate nodules are frequently discovered. Noninvasive biomarkers are urgently needed to reduce false positives with screening CT and to improve risk stratification in those with indeterminate nodules. The Colorado (CO) Lung SPORE program performed a retrospective longitudinal evaluation (Pepe Phase 3 validation) to assess the potential of chromosomal aneusomy detected in sputum via fluorescence in situ hybridization (CA-FISH) as a biomarker for early detection in four nested case-control studies. Two of the cohorts (ACRIN/NLST and PLuSS) enrolled current and former smokers to investigate use of low dose CT to diagnose lung cancer. The other two were Colorado cohorts in which pulmonary clinic patients (mostly current and former smokers) were enrolled to investigate biomarkers to predict lung cancer. One of these cohorts (CO High Risk) was a COPD population and the other, still in the accrual phase, comprises patients referred for care of indeterminate lung nodules (CO Nodule).
Methods:
The cohorts were grouped into a Screening cohort (ACRIN/NLST (49 cases, 96 controls) and PLuSS (48 cases, 89 controls)) and a High Risk cohort (CO High Risk (55 cases, 59 controls) and CO Nodule (13 cases, 10 controls)). The CA-FISH assay was a 4-target panel including genomic sequences encompassing the EGFR and MYC genes, and the 5p15 and centromere 6 regions or the FGFR1 and PIK3CA genes. At the subject level, the assay was scored on a 4-category scale representing normal, probably normal, probably abnormal and abnormal. Operating characteristics (with 95% CI) of the assay were estimated for each group of cohorts overall and separately for COPD patients: sensitivity, specificity, likelihood ratio+ (LR+) and likelihood ratio- (LR-).
Results:
Using the cutoff of abnormal vs. not abnormal for CA-FISH, sensitivity and specificity for Screening subjects are 0.20 (0.13, 0.30) and 0.84 (0.78, 0.89), respectively; and for High Risk subjects are 0.67 (0.55, 0.78) and 0.94 (0.85, 0.98), respectively. Likelihood ratios for Screening subjects are LR+: 1.36 (0.81, 2.28) and LR-: 0.93 (0.83, 1.05), and for High Risk subjects are LR+: 11.66 (4.44, 30.63), and LR-: 0.34 (0.24, 0.48). Similar results were observed when only COPD subjects were analyzed.
Conclusion:
The high LR+ of sputum CA-FISH indicates that this noninvasive biomarker could be a clinically useful adjunct to CT among patients in high risk settings. Whether this same high level of LR+ will be reproducible in patients at high risk because of their indeterminate nodules remains to be seen. If so, a hypothetical patient with indeterminate nodules and a pre-test (CA-FISH) lung cancer risk of 20% would have a post-test probability of lung cancer of 78% if the CA-FISH test were positive. In the screening setting, however, the low LR+ of CA-FISH limits its clinical utility. Prospective assessment of sputum CA-FISH is ongoing in the Nodule Cohort of the CO Lung SPORE.
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P2.06 - Poster Session/ Screening and Early Detection (ID 219)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.06-007 - A miRNA Signature Derived From Independently Replicated Biomarkers of Non-Small Cell Lung Cancer (ID 1728)
09:30 - 17:00 | Author(s): W.J. Feser
- Abstract
Background:
miRNAs have shown exceptional promise as biomarkers of lung cancer; however, no miRNA signatures have yet reached the clinic. Towards developing a signature with a high likelihood of being validated externally for clinical use, we screened a panel of 50 miRNAs shown to be effective biomarkers in at least two previous studies for distinguishing human lung cancer samples from non-cancer samples.
Methods:
Sixty tumor-normal pairs (33 adenocarcinoma, 27 squamous cell carcinoma) were used to identify the best-performing combination of 4 miRNAs for distinguishing tumor samples from normal. The miRNA levels were measured by RT-qPCR using Taqman custom-made microfluidics cards and primer pools purchased from Life Technologies. All possible combinations of 4 miRNAs were tested, and best performance was defined as the highest median area-under the receiver operating curve (AUC) obtained from 1000 bootstrap replicates. A second, independent set of 68 tumor-normal samples (half adenocarcinoma, half squamous) was used as a test set, and bootstrapping was used to determine the 95% confidence interval for the AUC.
Results:
The median AUC for the top-performing panel of 4 miRNAs in our training set was 0.96. Several other miRNA combinations exhibited AUCs > 0.95 as well. In our test set, the top-performing panel (and only panel tested) exhibited an AUC of 0.97 (0.93, 0.99). This panel consisted of miRs 26a, 145, 183 and 486. miRs 145 and183 have previously been shown, when used individually, to be significant lung tumor biomarkers in at least 4 previous studies; miR-486 has been replicated 8 times.Figure 1
Conclusion:
Consistent with previous studies, we’ve identified a panel of 4 miRNAs that shows excellent potential for diagnosing lung tumors. Each of these miRNAs has been replicated as a biomarker of lung cancer in at least two previous studies, suggesting a high likelihood of achieving clinical validation. Several previous studies have also shown that these four miRNAs are potentially useful as biomarkers for diagnosing lung cancer using blood samples, and we are currently pursuing such validation studies.
