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S. Ghosh



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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-042 - Acid suppression therapy impairs Erlotinib efficacy in Non-Small Cell Lung Cancer (ID 2930)

      09:30 - 09:30  |  Author(s): S. Ghosh

      • Abstract

      Background
      Erlotinib is a key treatment option in all advanced or metastatic non-small cell lung cancer (mNSCLC) subtypes regardless of epidermal growth factor receptor (EGFR) status. Despite side effect advantages over cytotoxic chemotherapy, a shortcoming of erlotinib is pH-dependent absorption. Recent evidence highlights this inconsistency further by showing reduced plasma levels of various oral tyrosine kinase inhibitors (TKIs) in the presence of acid suppression therapy. Given the prevalence of gastroesophageal reflux disease (GERD) and diseases that use acid suppression, goals of this study are to determine if coadministration of acid suppressants and erlotinib affected clinical outcomes in advanced NSCLC patients.

      Methods
      A cohort of patients with mNSCLC from 2007-2012 who received erlotinib through our institution was retrospectively reviewed. In addition to stage, age, gender, performance status, and NSCLC subtype, patients were then identified as receiving acid suppression (AS) if their pharmacy records included either proton pump inhibitors (PPIs) or histamine blockers (anti-H2). Patients were considered taking these medications concomitantly if dates for acid suppressants overlapped their erlotinib prescription by ≥ 20% of the treatment duration. Patients who received erlotinib for ≥ 1 week were analyzed for progression free survival (PFS) and overall survival (OS).

      Results
      544 stage IIIB/IV NSCLC patients were identified. Of those, 507 were eligible for review. Median age was 64 years, gender 235 male, and 272 female. By subtype, 318 were adenocarcinoma, 106 squamous, 43 poorly differentiated, 11 large cell, and 29 not otherwise specified (NOS). 124 patients received concomitant AS therapy with the most common type being PPIs. Analysis unselected for EGFR mutational status yielded median PFS and OS in the AS versus no-AS group as 1.4 v 2.3 months (p<0.001) and 12.9 v 16.8 months (p=0.003), respectively. In multivariate analysis with gender, NSCLC subtype, and performance status, Cox proportional hazards ratios for PFS and OS for AS and non-AS groups were 1.83 (95% CI 1.48-2.25) and 1.37 (95% CI 1.11-1.69) respectively. Subgroup analysis by subtype in the AS and non-AS groups was significant in the following types (p<0.05): adenocarcinoma, PFS 1.8 v 2.7 months, OS 13.2 v 17.5 months; squamous PFS 1.5 v 2.3 months, OS 13.4 v 15.9 months; poorly differentiated PFS 0.8 v 2.0 months, OS 7.6 v 15.5 months, and NOS PFS 1.2 v 1.7 months, OS 10.8 v 14.5 months. Effects of AS in EGFR mutated patients are being studied.

      Conclusion
      Despite limitations of retrospective analyses, this large population based study demonstrates erlotinib efficacy is dependent on gastric acidity and OS can be adversely affected. This is the first study the authors are aware of that demonstrates an impact on clinical outcomes by co-administration of acid suppression and TKI therapy. Caution should be taken with co-administration of other TKIs and acid suppressive therapy.

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    P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.20-011 - A prospective clinical study evaluating stage dependent sputum micro-RNA expression profiles for the detection of non-small cell lung cancer (ID 3440)

      09:30 - 09:30  |  Author(s): S. Ghosh

      • Abstract

      Background
      Lung Cancer accounts for the greatest cancer related mortality worldwide. To date, no effective screening tool for Non-Small Cell Lung Cancer (NSCLC) exists. For patients with operable stage IA NSCLC, the 5-year survival can be as high as 80%. Early detection is crucial in improving long-term survival. MicroRNAs (miRNAs), a class of short noncoding RNA molecules. miRNA expression in biological fluid samples such as sputum has shown promise as a potential means of detecting NSCLC. Our objective was to utilize an efficient, cost-effective panel consisting of 3 miRNAs (miR-21, miR-210 and miR-372) for prospective validation as a potential means of accurately detecting NSCLC. This panel was selected based on retrospective analysis of 11 miRNAs our group had previously undertaken using separate NSCLC and control cohorts.

      Methods
      21 early NSCLC (≤ Stage II) patients, 22 advanced NSCLC (≥ Stage III) patients and 10 control subjects were prospectively accrued. A single sputum sample was obtained through spontaneous expectoration from each study participant. Detailed study participant and tumor characteristics were obtained. miR-21, miR-210 and miR-372 expression was conducted on each sputum sample and normalized to an endongenous control (U6) relative to a MRC-5 reference sample, using RNA reverse transcription and Quantitative real-time Polymerase Chain Reaction (RT-qPCR). Statistical evaluation consisted of unsupervised hierarchical cluster analysis of the experimental-normalized miRNA expression profiles using within-group linkage.

      Results
      The median ages of the early NSCLC cases, advanced NSCLC cases and controls were 68, 68 and 58.5 respectively. The majority of the early and advanced NSCLC patients had smoking histories (>90%). 60% of the controls had smoking histories. Mean tumor size (± standard deviation) for early and advanced NSCLC cases were 3.4 cm (± 2.1 cm) and 4.8 cm (± 1.7 cm) respectively. Adenocarcinoma and squamous cell carcinoma comprised 62% and 23.8% of early NSCLC cases. Adenocarcinoma and squamous cell carcinoma comprised 45.5% and 22.7% of advanced NSCLC cases. Comparing early NSCLC to controls, the use of miR-21, miR-210 and miR372 expression yielded a diagnostic sensitivity of 66.7% and a specificity of 90.0%. Advanced NSCLC patients had an improved sensitivity of 81.8% with the same specificity of 90.0%.

      Conclusion
      The utilization of miR-21, miR-210 and miR372 sputum expression might provide a sensitive and specific means of detecting NSCLC. The potential linkage between their expression and NSCLC stage may account for the higher sensitivity observed in the advanced NSCLC group. Future use of this promising panel on a larger population will be required to establish its potential application as a screening tool.

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    P3.17 - Poster Session 3 - Bronchoscopy, Endoscopy (ID 185)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track:
    • Presentations: 1
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      P3.17-009 - A Prospective Clinical Study of MicroRNA Expression Profiling of Bronchoalveolar Lavage Fluids and Sputum as a Means to Distinguish Early Stage Non-Small Cell Lung Cancer Cases From Cancer-Free Controls (ID 3403)

      09:30 - 09:30  |  Author(s): S. Ghosh

      • Abstract

      Background
      MicroRNAs (miRNAs) post-transcriptionally regulate hundreds of gene targets involved in tumorigenesis and miRNA expression profiling is an emerging tool for the early detection of malignancy. We assessed the ability of microRNA (miRNA) expression profiling of bronchoalveolar lavage (BAL) fluids and sputum samples to distinguish early stage non-small cell lung cancer (NSCLC) cases from cancer-free controls.

      Methods
      The expression levels of 3 miRNAs (miR-21, miR-210, miR-372) were quantified in BAL fluids and sputum, normalized to an endongenous control (U6) relative to a MRC-5 reference sample, using RNA reverse transcription and Quantitative real-time Polymerase Chain Reaction (RT-qPCR). All sputum samples were collected by a single spontaneous expectoration while BAL fluids were obtained just prior to surgical resection. Unsupervised hierarchical cluster analysis was performed on the experimental-normalized miRNA expression profiles using within-group linkage and cosine correlation similarity.

      Results
      From April 2011 to January 2012, twenty-one eligible cases and 10 controls were entered into this study. The median age of cases was 70 years of which 17 were male and 4 were females. Thirteen cases had adenocarcinoma, five had squamous cell carcinoma, and 3 had large cell carcinoma. Twelve cases had stage I and 9 had stage II NSCLC. The median short axis diameter of the primary tumour amongst cases was 1.6 cm. With exception of one case, endobronchial lesions were not detected on inspection by flexible bronchoscopic examination prior to BAL fluid collection. The vast majority of cases were smokers (20/21). The median age of the control group was 58.5 and five were healthy without active medical conditions while five had COPD. Six controls had prior or current histories of smoking while 4 were never smokers. Cluster analysis of the miRNA expression profiles of BAL samples from 21 NSCLC cases and sputum samples from 10 cancer-free controls yielded a diagnostic sensitivity of 85.7% and specificity of 100%. Cluster analysis of sputum samples from the same 21 NSCLC cases and 10 cancer-free controls yielded a diagnostic sensitivity of 67.8% and specificity of 90%. A cosine similarity analysis of matched pairs of concordant and discordant BAL and Sputum samples was conducted and indicated that sampling error accounted for 6 of the 7 false negative results. This suggests that triplicate sputum sample collection could improve the overall sensitivity of this method for use as a safe, non-invasive screening test for NSCLC or as a pre-screening test to select patients for low-dose CT screening.

      Conclusion
      Hierarchical cluster analysis of 3 expressed miRNAs obtained from sputum and brochoalveolar lavage samples are highly specific and relatively sensitive methods for the timely diagnosis of early stage NSCLC. Larger, population-based studies are necessary for further validation of this promising approach in both the diagnostic and screening setting.