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D.T. Merrick



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    MINI 11 - Tobacco Control and Prevention (ID 108)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Prevention and Tobacco Control
    • Presentations: 2
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      MINI11.02 - Frizzled9 as a Predictor of Response to Iloprost Chemoprevention of Lung Cancer (ID 2397)

      16:45 - 18:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer remains the leading cause of cancer death in the United States and chemoprevention offers an appealing area of investigation in the face of limited therapeutic success. Improvement in endobronchial histology was recently demonstrated in former smokers after oral iloprost treatment. Of the 48 patients who received iloprost in the chemoprevention trial, 23 had regressive histology and 25 had stable or progressive histology. Identifying markers that predict which patients will respond to treatment will help refine target populations for future trials and clinical applications. In vitro studies of NSCLC indicate that iloprost, a prostacyclin analogue, acts through the G-protein coupled receptor Frizzled 9 (Fzd9) instead of the prostacyclin receptor. We hypothesize that Fzd9 expression status predicts response to iloprost chemoprevention and that current smokers may not respond to iloprost treatment due to carcinogen-induced decreases in Fzd9 expression. Prostacyclin may also induce expression of Fzd9, leading to increased anti-tumor signaling.

      Methods:
      Fzd9 expression was measured by quantitative real-time PCR in RNA extracted from mouse and human tissues, cultured dysplastic cell lines, and cultured human bronchial epithelial cells (HBEC). In the urethane model, FVB wild type and transgenic mice were exposed to a single dose of urethane and sacrificed after 20 weeks. In the smoking model, FVB wild type and transgenic mice were sacrificed after one week of cigarette smoke exposure. Human matched tumor and normal tissue and dysplastic cell lines were acquired from the University of Colorado SPORE in Lung Cancer Tissue Bank. HBEC were exposed to 5ug/ml cigarette smoke condensate and 10uM iloprost in culture media.

      Results:
      Human lung tumors demonstrated reduced Fzd9 mRNA expression compared to matched normal lung tissue. Fzd9 expression is also decreased in human primary dysplastic cell lines, suggesting that loss of Fzd9 expression occurs early in early lung lesions. In a urethane mouse model of lung cancer, Fzd9 mRNA expression is reduced in lung tumors compared to matched, uninvolved lung tissue. Tumors from urethane exposed prostacyclin synthase overexpressing (PGIStg) mice have higher Fzd9 expression compared to tumors from wild type mice. In a one-week smoking model, Fzd9 expression is decreased in lung from wild type smoked mice but higher in PGIStg smoked mice. In HBEC exposed to cigarette smoke, Fzd9 expression decreases and remains low with continued exposure from 1 to 28 weeks. After two weeks of exposure to iloprost alone, HBEC cells demonstrated increased Fzd9 expression.

      Conclusion:
      These initial studies suggest that Fzd9 expression is lost lung epithelial cells with early smoking-induced damage. Fzd9 expression will be measured in baseline and follow up biopsy tissues from the iloprost clinical trial. This study has the potential to improve iloprost lung cancer chemoprevention by allowing future trials to more effectively target high-risk patients and by providing a clinical biomarker for identification of chemoprevention candidates.

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      MINI11.04 - A New Preclinical Model of Airway Progenitor Cells to Identify Responders to Iloprost-Mediated Chemoprevention (ID 1698)

      16:45 - 18:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer related deaths worldwide. The 5-year survival rate for this cancer is only 16%. Chemoprevention can improve prognosis in these patients. However, previous attempts at lung cancer chemoprevention that were soley based on epidemiological data were ineffective. Squamous cell lung cancer develops through a series of bronchial lesions or dysplasia. Persistent dysplasia harbors similar genetic changes as the tumor and has significantly higher chance of progression. Thus, bronchial dysplasia is a risk biomarker for SCC and improvement in dysplasia grade can be used as an outcome for chemoprevention trials. The long-acting prostacyclin analogue, iloprost is the only drug that has improved dysplasia in former smokers (p = 0.006). Despite this positive outcome we have little insight into the mechanisms of iloprost function. Understanding these mechanisms would be essential to identify people who have the highest chance to benefit from iloprost treatment. We propose that this endeavor will require a preclinical model that recapitulates the human disease and is amenable to mechanistic studies.

      Methods:
      Airway progenitor cells are critical for the maintenance of normal airways, because of their ability to self-renew (i.e. replicate) and differentiate into all cell-types of the airway (i.e. multipotentiality). Together these properties allow progenitors to return injured tissue to normal structure and function. In dysplasia, normal bronchial epithelium is changed into one that contains increased numbers of basal cells and lacks ciliated cells. These findings led to our hypothesis that ‘airway progenitors are malfunctioning in dysplasia’. Previously we showed that Keratin (K) 5/p63-expressing basal cells are the multipotential progenitors of the airway epithelium. During in vitro culture these cells form a unique 3-deimensional structure called the rim clone, which allows them to be distinguished from non-progenitors. To investigate a role of epithelial progenitors in dysplasia, we have collected bronchial biopsies from high-risk smokers and purified rim clone forming basal progenitor cells.

      Results:
      We demonstrate that both self-renewal and multipotentiality of progenitors is significantly (p < 0.001 for both) decreased in dysplasia. During differentiation in vitro at the air-liquid interface, progenitors from normal biopsies generated a normal epithelium. In contrast, progenitors from dysplasia made a squamous epithelium containing only basal cells and lacking ciliated cells. Mutational analyses of paired samples from epithelial brushings and biopsy-derived progenitors identified the same somatic mutations in p53, Notch 1, Notch 3, Survivin and FGFR1. Thus, epithelial progenitor culture reflects the histologic and genetic changes of dysplasia and therefore can be used as a personalized, preclinical model. A proof of concept study where dysplastic progenitor cells were treated with iloprost resulted in decreased dysplasia in 2 out of 3 cases.

      Conclusion:
      Thus our data indicate that progenitor cell cultures from a patient’s dysplasia may be used to identify responders versus non-responders to iloprost, as well as other chemopreventives. Future studies could focus on identifying downstream mechanisms via which iloprost exerts its beneficial effect.

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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
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      MINI12.02 - Clinical Utility of Chromosomal Aneusomy in High Risk Individuals (ID 1299)

      16:45 - 18:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      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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    MINI 13 - Genetic Alterations and Testing (ID 120)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI13.01 - Clinicopathological Profiles of ROS1 Positive Patients Screened by FISH (ID 1450)

      10:45 - 12:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Background:
      ROS1 fusion variants represent an important subset of oncogenic driver mutations in approximately 0.7 – 3.4% of non-small cell lung cancers. Since the frequency of ROS1 positive lung cancer patients is relatively low, it is unclear whether there are significant clinicopathologic associations for positive cases. Thus far, ROS1 positive patients tend to be younger and never-smokers with tumors displaying adenocarcinoma histology. This study describes a further cohort of ROS1 positive lung cancer patients in an effort to identify clinicopathologic associations.

      Methods:
      The data represent a retrospective analysis of the clinicopathological profiles of primary and metastatic lung cancer patients tested for ROS1 gene rearrangements by break-apart (BA) FISH at the University of Colorado School of Medicine.

      Results:
      The cohort consisted of 452 patients enriched for triple-negative (EGFR-, KRAS- and ALK-) non-squamous cell carcinomas screened for ROS1 rearrangements using the BA FISH assay. Nineteen cases (4.2%) were identified as positive for rearrangement, the majority (68%) of which were female, with a mean cohort age of 54.9 years (range 30-79); as compared to negative cases which included 56% female patients (P= 0.1083), and had a mean cohort age of 62.9 (range 21-90) (P= 0.0058). Seventeen out of the 19 ROS1 positive tumors were classified as adenocarcinomas, one was diagnosed as adenosquamous carcinoma, and the histology on one specimen was not otherwise specified (NOS). Among 12 individuals with information on pathologic stage at diagnosis, the majority (75%) were stage IV. The prevalent FISH pattern for rearrangement was a split 5’ and 3’ signal (68%) with the remaining specimens showing primarily single 3’ signals (21%) or a mix of split and single 3’ signals (11%).

      Conclusion:
      The ROS1 positive tumors in this cohort were primarily classified as adenocarcinomas, diagnosed at an advanced stage, in patients significantly younger and more likely to be women, although the sample set was biased for non-squamous lesions thereby limiting the application of this information to squamous cell lung carcinoma. The higher prevalence of ROS1 positive cases in this cohort compared to unselected cohorts is best explained by the inclusion of specimens with known negative status for EGFR and KRAS mutations and ALK fusions. As such, these data are in agreement with previous descriptions of ROS1 positive cohorts. Screening for ROS1 rearrangements in lung cancer patients displaying adenocarcinoma histology and negative for EGFR, KRAS and ALK activating events should identify a higher frequency of ROS1 rearranged tumors compared to unselected approaches and facilitate this subset of patients to be treated with targeted ROS1 inhibitors.

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    MINI 22 - New Technology (ID 134)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI22.10 - A New Approach to Large Scale Proteomic Profiling to Uncover Tumor Phenotypes (ID 2166)

      16:45 - 18:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Background:
      Genomic profiling is a powerful method for identifying mutations that drive tumors and matching patients to targeted therapies. However, this may only be a transient solution and resistance commonly emerges as the mechanism of targeted inhibition is overcome. Proteomic profiling of the tumor provides a dynamic tool to survey altered protein expression and deregulated pathways, which in turn may implicate specific treatments or identify novel therapeutic targets. Mass spectrometry offers highly multiplexed proteomic measurements, but extensive sample pre-processing and low sample throughput can lead to extended analysis times of weeks or months. Thus a need exists for a high throughput, sensitive and quantitative platform for proteomic analysis.

      Methods:
      We used the SOMAscan proteomic platform, which measures 1129 proteins with a median limit of detection of 40 fM and 5% CV, to analyze protein lysates from 63 lung tumor samples. The assay does not require sample pre-fractionation, and this study (which generated over 142,000 protein measurements) represents less than one day of SOMAscan throughput. The study consisted of matched tumor/non-tumor protein lysates prepared from 18 squamous cell carcinoma and 45 adenocarcinoma fresh-frozen resected specimens, 86% of which were Stage I/II. The paired log~2~ tumor/non-tumor ratio was calculated and hierarchical clustering heat maps and dendrograms were constructed to identify related protein regions and tumor phenotypes.

      Results:
      Common proteomic changes and unique tumor phenotypic groups were identified by unbiased clustering algorithms. Large, consistent tumor/non-tumor differences of at least 4-fold were observed for 35 proteins in at least 20 (32%) of the tumors. Some of these proteins were more than 100-fold higher in individual tumors. The two most commonly elevated proteins were thrombospondin 2 and MMP12, which were increased in 81% and 61% of the tumors, respectively. We have previously reported higher levels of MMP12 in the serum of lung cancer patients, and the current data supports a tumor-associated origin for circulated MMP12. A second analysis identified sub-phenotypes of tumors clustered by common protein alterations independent of histological classification or mutation status. Many of these tumor subsets had increased expression of known oncology drug targets.

      Conclusion:
      Broad, unbiased high-throughput proteomic profiling of tumor tissue may reveal individual phenotypes that hold the potential to respond to targeted therapies and to monitor therapeutic efficacy throughout treatment. Measuring proteins complements mutation analysis by enabling therapeutic selection beyond driver mutation targets, including immune modulator therapies, repurposing existing drugs and enriching clinical trials with likely responders. While genomics is a fixed snapshot, blood- and tissue-based serial proteomic measurements respond to change and can lead to the personalized adaptation of treatment and identification of novel therapeutic targets.

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    MS 14 - Chemo Prevention Clinical Trials (ID 32)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Prevention and Tobacco Control
    • Presentations: 1
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      MS14.03 - Pathologic Biomarkers of Risk and Benefit of Treatment (ID 1910)

      14:15 - 15:45  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Prevention of lung cancer could lead to a significant reduction in the mortality associated with this disease. Identification of individuals at high risk for the development of invasive lung cancer is critical to establishing efficient and effective screening and prevention programs. The presence of premalignant lesions including atypical adenomatous hyperplasia/adenocarcinoma-in-situ (AAH/AIS) and bronchial dysplasia (BD), which represent precursors of adenocarcinoma and squamous cell carcinoma (SCC) respectively, provide targets that can be studied by histologic, radiographic and molecular techniques to define biologic characteristics that are indicative of risk and potential cellular activities that can be targeted for prevention. The histologic features of premalignant lesions have been well described in published WHO defined classification systems (1). Accurate histologic assessment of precursor lesions of lung adenocarcinoma prior to development of invasive cancer is limited by sampling considerations. To establish a diagnosis of premalignant AAH or AIS, the whole lesion must be examined and size criteria and histologic confirmation of lack of invasion must be documented. Because resection is generally restricted to cases of invasive cancer, tissue from AAH or AIS prior to development of invasive adenocarcinoma are rare, and most analyses of these lesions are performed on lesions that are associated with or occur as synchronous independent lesions of invasive cancer in resection specimens. However, a number of recent publications have begun to describe non-lesion associated biomarkers that can be correlated with radiographic features that appear to faithfully distinguish premalignant from invasive peripheral lung lesions. While AAH and AIS are considered to be precursors of adenocarcinomas derived from the terminal respiratory unit (TRU), a recently described premalignant lesion, mucous columnar cell change (MCCC), appears to be the precursor of a less common subset of adenocarcinomas derived from a region of the distal airways that is proximal to the TRU. This lesion has been reported to be present in up to 70% of the mucinous variant adenocarcinomas that are derived from these more central sites (2). This suggests that MCCC may be amenable to sampling at a pre-invasive stage by bronchoscopic means. In contrast, BD is detectable prior to development of invasive cancer by bronchoscopy but cannot be identified by radiographic examination. Higher rates of progression to invasive SCC and/or carcinoma-in-situ for lesions with higher grades of atypia have been suggested in a number of studies and meta-analyses (3). We have assessed the relationship between persistence of BD and risk for development of invasive lung cancer employing a numeric scoring system (1=normal; 2-7=increasing levels of precursor atypia; 8=invasive cancer). These analyses have shown that higher histologic scores on follow-up biopsies at specific sites within the airway of individuals sampled over time are associated with higher baseline histologic score, the presence of papillary angiogenic change, and current smoking status (4). Multivariable analyses including these parameters show that sites in subjects that develop SCC have mean histologic scores on follow-up biopsy that are 1.55 higher than those in patient’s without development of invasive lung cancer. On a per subject basis, the frequency of SCC was significantly increased in subjects that showed multiple sites of BD at baseline that persisted as or progressed to high grade dysplasia (moderate dysplasia or worse, histology score > 5). A 33% increase in risk for development of SCC is associated with every 10% increase in percent of sites that persist/progress to HGD corresponding to an overall hazard ratio of 17.14 (CI 2.4, 123.3) for multifocal persistent BD. These findings lend support to the importance of a field effect in lung carcinogenesis and suggest a potential role for histologic demonstration of persistent field change as an indicator of risk for the development of lung SCC. A number of biomarkers have been studied to determine their relationship with outcomes in premalignant lung lesions. Direct analyses of AAH and AIS have shown that a significant number of these lesions harbor the activating EGFR driver mutations seen in invasive adenocarcinoma of the lung. The potential of these mutational events to act as predictors of progression is under investigation, and a case report has demonstrated response to EGFR inhibitors of radiographically established multifocal premalignant disease in which an EGFR mutation was demonstrated in biopsy tissue of one of the lesions (5). Interestingly, the tumors associated with MCCC show a higher proportion of KRAS mutations. Non-lesional biomarkers of risk such as a recently reported assay measuring germline DNA repair activity that correlates decreased repair capability with increased risk for malignancy show promise for risk prediction (6). BDs, like SCC, demonstrate frequent genetic alterations in tumor suppressor genes and show characteristic associated alterations in gene methylation, loss of heterozygosity and gene copy number gains that have been associated with increased risk (7-10). In an analysis of a small series of cases in which sites with BD were observed to directly progress to invasive SCC, we have demonstrated frequent TP53 and some other mutations in precursor lesions. Furthermore, via pathway analysis of genes that we have found to be differentially expressed between persistent and regressive bronchial dysplasia, we have identified altered control of cell cycle, adhesion and immune activity (see abstract #3026) to be associated with persistence of BD. Overexpression of polo-like kinase 1 (PLK1) is the most prominent cell cycle control alteration associated with persistence and its role as a mediator of progression through the G2-M DNA damage checkpoint suggests a potential mechanism by which genomic instability can be promoted in high risk premalignant BD. PLK1 inhibitor treatment of primary cultures derived from sites of persistent BD causes an arrest of growth in S/G2 phase and induces apoptosis, neither of which occurs when PLK1 inhibitor is applied to primary cultures of normal bronchial epithelium. Histologic features and molecular biomarkers of premalignant lung lesions provide means by which risk can be assessed, appropriate targets for prevention can be identified and efficacy of preventive therapies can be measured. References 1. Travis WD, Brambilla E, Muller-Hermelink HK and Harris CC. Pathology and genetics: tumors of the lung, pleura, thymus and heart. World Health Organization Classification of tumours. Lyon: IARC; 2004. p. 9-124. 2. Weichart W and Warth A. Early lung cancer with lepidic pattern: adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Curr Opin Pulm Med 2014, 20:309–316 3. Ishizumi T, McWilliams A, Macaulay C, Gazdar A and Lam S. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev 2010;29:5-14. 4. Merrick DT, Haney J, Petrunich S, Sugita M, Miller YE, Keith RLet. al. Overexpression of vascular endothelial growth factor and its receptors in bronchial dysplasia demonstrated by quantitative RT-PCR analysis. Lung Cancer 2005;48(1):31-45. 5. Pastorino U, Calabro E, TamboriniE, MarchianoA, Orsenigo M, Fabbri A, Sozzi G, Novello S, and De Marinis F. Prolonged Remission of Disseminated Atypical Adenomatous Hyperplasia Under Gefitinib. J Thorac Oncol 2009;4: 266–267. 6. Sevilya Z, Leitner-Dagan Y, Pinchev M, Kremer R, Elinger D, Rennert HS, Schechtman E, Freedman LS, Rennert G, Paz-Elizur T, and Livneh Z. Low Integrated DNA Repair Score and Lung Cancer Risk. Cancer Prev Res; 7(4); 398–406. 7. Nakachi I, Rice JL, Coldren CD, Edwards MG, Stearman RS, Glidewell SC, Varella-Garcia M, Franklin WA, Keith RL, Lewis MT, Gao B, Merrick DT, Miller YE, and Geraci MW. Application ofSNPMicroarrays to theGenome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions. Cancer Prev Res; 7(2); 255–65. 8. Massion, P., Zou, Y., Uner, H., Kiatsimkul, P.,Wolf, H. J., Baron, A. E., et al. Recurrent genomic gains in preinvasive lesions as a biomarker of risk for lung cancer. PLoS ONE 2009;4(6):e5611. 9. Wistuba, I. I., Behrens, C., Virmani, Ak, Mele, G., Milchgrub, S., Girard, L., et al. High resolution chromosome 3p allelotyping of human lung cancer and bronchial epithelium reveals multiple, discontinuous sites of 3pallele loss and three regions of frequent breakpoints. Cancer Res 2000;60:1949–1960. 10. Belinsky SA[1], Liechty KC, Gentry FD, Wolf HJ, Rogers J, Vu K, Haney J, Kennedy TC, Hirsch FR, Miller Y, Franklin WA, Herman JG, Baylin SB, Bunn PA, Byers T. Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort. Cancer Res 2006; 66(6):3338-44.

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    ORAL 23 - Prevention and Cancer Risk (ID 121)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Prevention and Tobacco Control
    • Presentations: 1
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      ORAL23.02 - Pioglitazone for the Chemoprevention of Lung Cancer (ID 2419)

      10:45 - 12:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Background:
      Prior clinical studies have shown that the oral prostacyclin agonist iloprost improves bronchial dysplasia in former smokers. Prostacyclin is a PPAR gamma agonist, and epidemiologic and pre-clinical studies suggest PPAR gamma agonists like pioglitazone may chemoprevent lung cancer. Based on these promising results, a double-blind, placebo controlled, phase II trial of pioglitazone in subjects at increased risk for lung cancer was sponsored by the Department of Veterans Affairs.

      Methods:
      Subjects were selected for the trial if they met one the following criteria: current or former smoker (> 10 pack years); biopsy proven endobronchial dysplasia; airflow obstruction (FEV1/FVC < 0.70); or at least mild sputum cytologic atypia. Fluorescent bronchoscopy was performed with biopsy of 6 standard endobronchial sites and all other abnormally appearing areas. Subjects also had pulmonary function testings and quantitative high resolution CT scans at the start and completion of the trial. Subjects were then randomized to oral pioglitazone or placebo for 6 months and then a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled on the first bronchoscopy. The endobronchial biopsies were scored on a 1-8 scale based on WHO criteria. The primary endpoint for the study is change in maximum (worst) endobronchial histology.

      Results:
      A total of 90 subjects (46 pioglitazone, 44 placebo) have been enrolled in the trial, with 76 completing both bronchoscopies. Subjects are well matched in terms of age, gender, tobacco exposure, and sputum cytology. No significant differences in lung function were observed between the treatment groups. While the investigators remain blinded in regards to treatment group, aggregate data is available. Overall, mild dysplasia or worse was seen in 26% of the initial biopsies. Similar to prior studies, current smokers exhibited more dysplasia at baseline compared to former smokers (32.4% vs. 16.6%) and also had more angiogenic squamous dysplasia (11.7% vs. 3.2%). Our primary endpoint is change in maximum histology, and histologic scores from matched biopsies in all participants showed a change of at least 1 grade in 50.2% (25.9% improved, 24.3% progressed). More histologic changes were observed in current smokers (59.2%) than former smokers (41.7%). Summary data for the non-normal biopsy pairs (ie those with a histologic score of at least 2 on baseline biopsy) showed that the majority of pairs (73.7%) changed by at least one grade. Current smokers exhibited more progression (29.3%) compared to former smokers (14.6%).

      Conclusion:
      The pioglitazone lung cancer chemoprevention trial is currently in progress. The treatment has been well tolerated and histologic changes were observed in many of the subjects.

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    ORAL 24 - CT Detected Nodules - Predicting Biological Outcome (ID 122)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Screening and Early Detection
    • Presentations: 1
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      ORAL24.05 - Reclassification of Lung Cancers Detected by CT Imaging in the American College of Radiology Imaging Network National Lung Screening Trial (ID 1454)

      10:45 - 12:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Background:
      The National Lung Screening Trial (NLST) found a 20% reduction in lung cancer-specific mortality using low dose CT vs chest radiography for screening. The magnitude of mortality benefit has been questioned given that a higher proportion of tumors in the CT arm were diagnosed as “bronchioloalveolar cell carcinoma”. Subsequent to the initiation of the NLST, the pathological classification of lung cancer was revised to take into account the reported favorable outcome for solitary in situ nodules <3 cm. The term “bronchioloalveolar carcinoma” (BAC) was eliminated in favor of the more explicit terms adenocarcinoma in situ (AIS), microinvasive adenocarcinoma (MIA), and invasive carcinoma with various predominant histological patterns. To better assess the impact of these recent changes in the Pathological classification of lung cancer on possible over-diagnosis in the NLST, we have reviewed the histology of lung tumors detected through the ACRIN-NLST trial and reclassified them according to the most recent WHO pathology classification.

      Methods:
      Histology was initially classified by the pathologists at sites where NLST participants were managed. Representative slides of 192 surgical resection specimens and 15 non-surgical biopsies from 207 patients were collected from 19 participating institutions. Digital images were prepared from 533 glass H&E stained slides using an Aperio digital slide imager. Digital images were examined by three pulmonary pathologists (WAF, DTM and JDH) and reclassified according to criteria and nomenclature of the recently published 2015 edition of the WHO classification.

      Results:
      There was 92% concordance between submitting and reference pathologists when cases were grouped into the broad categories of adenocarcinoma, squamous carcinoma, neuroendocrine and large cell lung carcinoma (LCLC). The WHO classification permitted a more detailed analysis of the tumors. Invasive adenocarcinoma was the largest tumor category comprising 61% (127) of all tumors and included 70 acinar tumors, 23 solid, 13 papillary, 8 micropapillary, 5 mixed mucinous/non-mucinous, 4 invasive mucinous, 3 lepidic and 1 adenocarcinoma that could not be further classified. There were 48 (23%) squamous tumors, 10 (5%) LCLC, 15 (7%) neuroendocrine tumors including 6 (3%) small cell lung carcinomas. Finally, one tumor had sarcomatoid histology and an additional tumor was classified at sclerosing pneumocytoma. On reclassification, only 5 of the 26 tumors originally referred to as BAC or as having BAC features by submitting pathologists met criteria for adenocarcinoma in situ or minimally invasive carcinoma. Twenty-one of these 26 tumors were reclassified as invasive adenocarcinoma, most frequently acinar pattern predominant (8 cases).

      Conclusion:
      Reclassification of tumors identified through low dose CT screening in the National Lung Screening Trial permitted a detailed analysis of histological features and should permit a more nuanced assessment of biology and prognosis of this important cohort than has been available to date. Reclassification of BAC mainly as invasive adenocarcinoma conflicts with the suggestion that much of the benefit in the NLST CT screening trial was derived from surgical removal presumably non-invasive low grade tumor. *ACRIN received funding from the National Cancer Institute through the grants U01 CA079778 and U01 CA080098.

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    ORAL 37 - Novel Targets (ID 146)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL37.06 - Defining MET Copy Number Driven Lung Adenocarcinoma Molecularly and Clinically (ID 2379)

      16:45 - 18:15  |  Author(s): D.T. Merrick

      • Abstract
      • Presentation
      • Slides

      Background:
      Increases in MET copy number define an oncogenic driver state sensitive to MET inhibition (Camidge et al, ASCO 2014). However, the level at which the genomic gain is relevant remains uncertain. When testing is performed by fluorescence in situ hybridization (FISH), variable cut-points in both mean MET/cell and MET/CEP7 ratio have been used. Partially overlapping datasets from the Lung Cancer Mutation Consortium (LCMC1) and Colorado Molecular Correlates (CMOCO) Laboratory were explored for a distinct MET-copy number driven lung adenocarcinoma subtype.

      Methods:
      MET was assessed by FISH. Data from non-adenocarcinomas and EGFR mutant patients with acquired resistance to an EGFR inhibitor were excluded. Positivity criteria were mean MET/cell ≥5 (low ≥5-<6, intermediate ≥6-<7, high ≥7) or MET/CEP7 ≥1.8 (low ≥1.8-≤2.2, intermediate >2.2-< 5, high ≥5). MET metrics were compared by race, sex, smoking status, stage at diagnosis, number of metastatic disease sites, site of metastases, presence of other known drivers (EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1 and RET), response to first line chemotherapy and overall survival using Fisher’s exact tests, chi-square tests, Spearman correlations and log-rank tests, as appropriate. Statistical significance was set at the 0.05 level without adjustment for multiple comparisons.

      Results:
      1164 unique adenocarcinomas were identified (60% female, 85% Caucasian, 66% ex/current smokers). MET/CEP 7 data was available on 1164 and mean MET/cell on 700. 52/1164 (4.5%) had MET/CEP7 ≥1.8 (48% female, 83% Caucasian, 69% smokers). 50/52 (98%) had ≥1 other oncogenic driver tested (25/50 (50%) positive). 113/700 (16%) had mean MET/cell ≥ 5 (57% female, 82% Caucasian, 58% smokers). 109/113 (96%) had ≥ 1 other oncogenic driver tested (73/109 (67%) positive). Among patients with ≥1 additional driver oncogene tested, alternate drivers in low, indeterminate and high categories of mean MET/cell were 44/60 (67%), 17/24 (70%) and 12/28 (43%) respectively and for MET/CEP7: 16/29 (55%), 9/18 (50%) and 0/4 (0%) respectively. MET positive with additional drivers were excluded from further analyses. Men exceeded women in MET/CEP7 (men 4% vs women 1.6%, p = 0.019) and mean MET/cell positive cases (men 9.6% vs women 5.4%, p = 0.058). 6.4% of adrenal metastasis cases were MET/CEP7 positive vs 2% all other sites, p=0.031. Mean MET/cell: 12% adrenal vs 5% other sites, p=0.082. MET/CEP7 or mean MET/cell positive and negative groups did not differ by other variables (p > 0.05).

      Conclusion:
      The proportion of ‘MET positive’ adenocarcinomas varies by definition and positivity cut-point. Mean MET/cell ≥5 defines nearly 4x more positives than MET/CEP7 ≥1.8 and no mean MET/cell positive category was free from overlap with other drivers. As only high MET/CEP7 had no overlap with other drivers, MET/CEP7 ≥ 5 is the clearest candidate for a pure MET-copy number driven state, however cases free from other drivers do exist at lower MET positivity levels. MET/CEP7 positive cases free from other known drivers are more likely to be male, but unlike other known oncogenic states, race and smoking status are not significant in determining positivity. MET positivity may have a specific biological phenotype, being more likely to present with adrenal metastases.

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