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Robert L. Keith

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    MS18 - Role of Biomarkers in Lung Cancer Screening (ID 81)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
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      MS18.05 - Sputum Biomarkers, Dysplasia and Chemoprevention (Now Available) (ID 3548)

      14:30 - 16:00  |  Presenting Author(s): Robert L. Keith

      • Abstract
      • Presentation
      • Slides


      The most dramatic improvements in lung cancer survival will emerge from both early detection and the prevention of disease development. Low dose CT screening trials (NLST and NELSON) have shown significant improvements in survival and advances in lung cancer screening will rely on our ability to better define at risk populations and to more personalize the management of indeterminate pulmonary nodules. This includes identifying and validating biomarkers of risk. The NIH defines biomarkers as ‘characteristics that are objectively measured and evaluated as indicators of normal biologic processes, pathologic processes, or pharmacologic responses to therapeutic interventions’1. The ideal biomarker has excellent sensitivity and specificity and applications to lung cancer screening will mostly focus on two specific areas. The first is improving the selection of at-risk subjects to be screened, and the second is to guide the management of screening detected pulmonary nodules.

      Biomarkers of lung cancer risk can include a variety of potential biospecimens, ranging from sputum and exhaled breath condensates to endobronchial and peripheral lung biopsies. Expectorated sputum has long been viewed as a ‘window to the central airways’ and cytologic changes have been observed in sputum samples to predict the presence of lung cancer2. While sputum cytology can also predict the presence of pre-malignant central airway lesions, sputum collection has largely fallen out of favor due to perceived difficulties in collecting and interpreting specimens, and advances in analyzing other specimens like blood, urine and exhaled breath. Sputum is a readily available resource, and recent methodological advances, most notably automated 3-dimensional morphologic analysis of sputum3, are currently being studied to determine the presence of cancer or pre-malignant lesions. It may also help risk stratify subjects with suspicious LDCT findings. Additional studies have also focused on sputum samples. For example, selected gene promoter methylation in exfoliated cells from sputum has been shown to predict cancer up to 18 months prior to diagnosis4. Other groups have examined sputum miRNA, and their stability make them potentially attractive biomarkers. One study conducted qRT-PCR studies of sputum from subjects with indeterminate pulmonary nodules and found a panel of 3 miRNAs (miRs 21, 31, and 210) with good sensitivity and specificity for identifying malignant nodules5. More recently, a pilot study using metagenetic sequencing of the sputum microbiome suggests there may be bacterial biomarkers indicating the presence of lung cancer6. Exhaled breath condensate is an additional biospecimen that has been studied as an adjunct to screening protocols, and the subject is extensively reviewed in a recent publication7.

      For NSCLC, specific pre-malignant histologic lesions have been used as biomarkers of risk and modifiable endpoints in chemoprevention trials. For adenocarcinoma, atypical adenomatous hyperplasia (AAH, a lesion more commonly found now that more ground glass opacities are noted during LDCT screening) can progress to adenocarcinoma in situ and eventually adenocarcinoma. Multiple studies are currently profiling AAH lesions with a goal of better understanding those that progress to invasive cancer. Lung squamous cell carcinoma (SCC) develops in the central airways where pre-malignant lesions progress through advancing levels of dysplasia (mild, moderate, and severe), followed by carcinoma in situ and ultimately invasive SCC. Change in endobronchial histology has been the primary endpoint in multiple SCC chemoprevention trials8, and longitudinal research has revealed an increased cancer risk in subjects with multiple lesions that persist or progress over time9. Endobronchial dysplasia that regresses (i.e. fails to become invasive cancer) is associated with specific immune responses and ongoing studies are characterizing the lesional immune microenvironment of bronchial dysplasia. This will allow for a better understanding of progressive lesions and advance the field of precision chemoprevention.

      1. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical pharmacology and therapeutics 2001;69:89-95.

      2. Saccomanno G, Archer VE, Auerbach O, Saunders RP, Brennan LM. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974;33:256-70.

      3. Wilbur DC, Meyer MG, Presley C, et al. Automated 3-dimensional morphologic analysis of sputum specimens for lung cancer detection: Performance characteristics support use in lung cancer screening. Cancer cytopathology 2015;123:548-56.

      4. Leng S, Do K, Yingling CM, et al. Defining a gene promoter methylation signature in sputum for lung cancer risk assessment. Clin Cancer Res 2012.

      5. Xing L, Su J, Guarnera MA, et al. Sputum microRNA biomarkers for identifying lung cancer in indeterminate solitary pulmonary nodules. Clinical cancer research : an official journal of the American Association for Cancer Research 2015;21:484-9.

      6. Cameron SJS, Lewis KE, Huws SA, et al. A pilot study using metagenomic sequencing of the sputum microbiome suggests potential bacterial biomarkers for lung cancer. PloS one 2017;12:e0177062.

      7. Marzorati D, Mainardi L, Sedda G, Gasparri R, Spaggiari L, Cerveri P. A review of exhaled breath: a key role in lung cancer diagnosis. Journal of breath research 2019;13:034001.

      8. Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013;10:334-43.

      9. Merrick DT, Gao D, Miller YE, et al. Persistence of Bronchial Dysplasia Is Associated with Development of Invasive Squamous Cell Carcinoma. Cancer Prev Res (Phila) 2016;9:96-104.

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