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R.L. Keith
Moderator of
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ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 8
- Moderators:B.C. Cho, R.L. Keith
- Coordinates: 9/09/2015, 16:45 - 18:15, 201+203
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ORAL34.01 - Compliance with Follow-Up Programs After Surgery for Non-Small Cell Lung Cancer in the Phase III IFCT-0302 Trial (ID 2148)
16:45 - 16:56 | Author(s): V. Westeel, F. Barlesi, P. Foucher, J. Lafitte, J. Domas, P. Girard, J. Trédaniel, M. Wislez, P. Dumont, E. Quoix, O. Raffy, D. Braun, M. Derollez, F. Goupil, J. Hermann, E. Devin, M.P. Lebitasy, F. Morin, G. Zalcman
- Abstract
- Presentation
Background:
In patients operated on for non-small cell lung cancer, several guidelines recommend a follow-up based on regular clinic visits and chest CT-scans. However, evidence to support these recommendations is poor, in the absence of randomized data. The IFCT-0302 trial is a randomized multicenter trial which compared 2 follow-up programs after complete resection for a clinical stage I, II, IIIA and T4 (pulmonary nodules in the same lobe) N0-2 NSCLC (TNM 6[th] edition). We present the results of compliance with the follow-up programs for the first 2 years after randomization.
Methods:
In the CXR arm, follow-up consisted of clinic visit and chest X-rays. In the CCT arm, patients underwent clinic visit, chest X-rays, thoraco-abdominal CT scan plus fiberoptic bronchoscopy (only mandatory for squamous cell and large cell carcinomas). In both arms, procedures were repeated every 6 months after randomization during the first 2 years, and yearly until 5 years, in the absence of recurrence or second primary cancer. Supplementary procedures were allowed in case of symptoms. Primary endpoint was overall survival.
Results:
Between January 2005 and November 2012, 1775 patients were randomized (CXR: 888; CCT: 887). Patient characteristics were well balanced between the two arms : males 76.3%, median age 62 years (range: 33-87), adenocarcinomas 56.7%, stage I-II 82.1%, lobectomy or bilobectomy 86,8%, pre- and/or post-operative radiotherapy 8.7%, and pre- and/or post-operative chemotherapy 45%. Surveillance was performed in 97% of patients at 6 months, in 94% at 12 months, in 90% at 18 months and in 84% at 24 months, and did not differ between the 2 arms. Intervals between randomization and visits were respected with no difference between arms (mean +/-SD in months from randomization: 5.93 +/- 0.84; 11.95 +/- 0.98; 18.05 +/- 0.99; 24.18 +/-1.30, respectively). In the 757 patients of the CXR arm, who had a follow-up visit at 6 months and no recurrence, 754 (99.6%) had a clinic visit and 730 (96.4%) a chest X-ray. In the 706 patients of the CCT arm who had a follow-up visit at 6 months and no recurrence, 702 (99.4%) had a clinic visit, 478 (67.7%) a chest X-ray, 678 (96%) a chest CT-scan, and 342 (48.4%) a bronchoscopy. Comparable compliance results were observed at 12, 18 and 24 months. In the CXR arm, supplementary thoracic CT-scans were done in 119 patients (15.7 %) at 6 months, in 96 (14.4 %) at 12 months, in 78 (13.2%) at 18 months and in 58 (11.4%) at 24 months. Other supplementary procedures were more frequent in the CCT arm than in the CXR arm, consisting mostly of brain imaging (at 6 months, in 93 (13.2%) and 39 (5.2%) patients, respectively, p<.001).
Conclusion:
Compliance with the follow-up programs was excellent in terms of timing. Chest X-ray was often omitted in the CCT arm. In the CXR arm, supplementary CT-scans that did not lead to a diagnosis of recurrence or second primary cancer were performed in 10 to 15% of patients. In the CCT arm, the most frequently performed supplementary procedure was brain imaging.
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ORAL34.02 - Impact of Attainment of National Comprehensive Cancer Network (NCCN) Quality Parameters on Patient Survival after Resection of Lung Cancer (ID 2190)
16:56 - 17:07 | Author(s): N. Faris, X. Yu, R. Eke, M.P. Smeltzer, G. Relyea, F.E. Rugless, C. Fehnel, N. Chakraborty, C. Houston-Harris, F. Lu, E.T. Robbins, R.S. Signore, L. McHugh, B. Wolf, C. Mutrie, L. Deese, P. Levy, E. Crocker, L. Wiggins, R.U. Osarogiagbon
- Abstract
- Presentation
Background:
The NCCN surgical resection guidelines for non-small cell lung cancer (NSCLC) recommend lobectomy or greater extent of resection, negative margins, and examination of lymph nodes from the hilum, and 3 or more mediastinal stations. We sought to determine the impact of these guidelines on patients’ long-term survival.
Methods:
We conducted a retrospective review of patient-level data from all curative-intent NSCLC resections at 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, North Mississippi, and Western Tennessee from 2004 to 2013. Following a descriptive analysis of the cohort, we used a Cox proportional hazard model to assess the overall survival impact of attaining the NCCN guidelines. All models were adjusted for patient age and pathologic stage.
Results:
Of the 2,410 eligible resections, 314 (13.1%) were sub-lobar, 86.9% were lobectomy or greater; 90.2% had negative margins, 5.8% had positive margins, 4% unknown margin status; 73.2% had hilar nodes sampled; but only 25.9% of surgeries had three or more mediastinal nodal stations sampled. Overall, although only 18% of surgeries met all four criteria, there was a significant increasing trend from 4% in 2004 and 12% in 2009, to 39% in 2013 (p<0.001). Patients whose surgery met all four criteria had a 23% survival benefit compared with those who did not (Hazard Ratio [HR]: 0.77, 95%CI: 0.64-0.94, p=0.009). Patients with negative margins had 15% survival benefit compared to those with positive margins (HR: 0.85, 95%CI: 0.66-1.08, p=0.18); those with lobectomy or greater resection had a 14% survival benefit over those with sub-lobar resection (HR: 0.86, 95%CI: 0.70-1.04, p=0.12); those with hilar node sampling had a 3% survival benefit (HR: 0.97, 95%CI: 0.83-1.13, p=0.68); and those with three or more mediastinal stations examined had a 17% survival benefit over those without (HR: 0.84, 95%CI: 0.71-0.98, p=0.03). Figure 1
Conclusion:
Although only 18% of NSCLC resections in this cohort from a high lung cancer mortality region of the US met all four NCCN good-quality surgical resection criteria, the rate of quality attainment has significantly increased during the past decade. Patients whose resections met NCCN quality criteria had a substantially survival benefit, which is particularly driven by the recommendation for sampling of ≥3 mediastinal nodal stations. Intraoperative mediastinal lymph node retrieval should be a focus of quality improvement for NSCLC resections.
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ORAL34.03 - Prognostic Factors in Early Stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study (ID 24)
17:07 - 17:18 | Author(s): B.C. Cho, T. De Pas, H. Kalofonos, Q. Wang, M. Holzer, R. Ramlau, S. Thongprasert, Y. Cheng, H. Asamura, F. Vitiello, Q. Zhou, W. Mao, A. Prokop-Staszecka, T. Laisaar, A. Nusch, C. Hu, S.I. Park, E. Vallieres, B. Kubisa, S. Orlov, K. Park, T. Ohira, M. Debois, C. Debruyne, K. Langfeld, P. Therasse, J. Vansteenkiste
- Abstract
- Presentation
Background:
The MAGRIT study was a worldwide, multicenter, phase-3 double-blind, randomized trial evaluating efficacy of the MAGE-A3 Cancer Immunotherapeutic in resected non-small cell lung cancer (NSCLC) (www.clinicaltrials.gov NCT00480025). We examined baseline patient and disease characteristics associated with overall survival (OS) and disease-free survival (DFS) among patients assigned to placebo.
Methods:
Study participants were ≥18 years, with histologically proven, MAGE-A3-positive stage IB, II or IIIA NSCLC (AJCC 6.0). Participants had undergone complete anatomical resection of the tumor (lobectomy or pneumectomy) with mediastinal lymph node (LN) dissection or sampling according to standard of care. Up to four cycles of platinum-based adjuvant chemotherapy were allowed. Cox regression models were used to explore characteristics that could predict DFS and OS. Factors statistically significant in univariate analysis (p<0.05) were included in multivariate models using a stepwise approach (p<0.05 to enter/remain in the model).
Results:
There were 757 placebo patients in the total treated population; median age 63 years, 76% male, 53% with squamous cell carcinoma (SCC), 34% with adenocarcinoma, 98% with performance status 0-1, 52% had received adjuvant chemotherapy.In univariate analyses, SCC, lower N-category and earlier disease stage were associated with improved DFS. Lower N-category, earlier stage and smaller tumor size were associated with improved OS. In multivariate analysis, N-category (HR 1.34, 95%CI [1.16-1.55]) and histological type (HR for SCC vs non-SCC 0.64, 95%CI [0.51-0.81]) remained significant for DFS. N-category (HR 1.47, 95%CI [1.21-1.79]) and tumor size (HR by unit increase 1.08, 95%CI [1.01-1.15]) did so for OS. No association was found between DFS or OS and age, gender, race, region, baseline performance status, quantitative MAGE-A3 expression, chemotherapy administration or type of chemotherapy, smoking status or type of LN sampling (minimal/systematic). Among patients with SCC, univariate analysis identified increased number of chemotherapy cycles and operative technique (pneumectomy) as associated with improved DFS (p<0.05). Only operative technique remained in the multivariate model. When including N-category (p<0.10 in univariate analysis) in the multivariate model, N-category and number of chemotherapy cycles were also selected. Lower N-category and smaller tumor size were significantly associated with improved OS, in univariate and multivariate analyses. Among patients with non-SCC, univariate analysis identified younger age, being female, lower N-category and earlier disease stage with improved DFS, and lower N-category, earlier disease stage and region (East Asia) with improved OS. N-category and gender, and N-category and region remained significant in the multivariate analysis for DFS and OS, respectively.
Conclusion:
This is the first prognostic factor analysis in resected NSCLC performed on data from a large, prospective randomized study. It highlighted that in terms of DFS, SCC patients have a better prognosis than non-SCC patients. N-category plays a major role in determining prognosis. Operative technique (pneumectomy), number of chemotherapy cycles (SCC) and gender (non-SCC) are also associated with outcome. Variables predictive for OS are N-category and tumor size (all) and region (non-SCC). These results confirm retrospective studies done within the context of TNM classification, but add that histopathology subtype is a strong determinant for DFS in resected NSCLC.
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ORAL34.04 - Discussant for ORAL34.01, ORAL34.02, ORAL34.03 (ID 3373)
17:18 - 17:28 | Author(s): R.U. Osarogiagbon
- Abstract
- Presentation
Abstract not provided
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ORAL34.05 - Survival Implications of Variation in the Lymph Node (LN) Count in ACOSOG Z0030 (Alliance) (ID 654)
17:28 - 17:39 | Author(s): R.U. Osarogiagbon, P.A. Decker, K. Ballman, D. Wigle, M. Allen, G. Darling
- Abstract
- Presentation
Background:
Variation in the thoroughness and accuracy of pathologic lymph node (LN) staging may contribute to within-stage variation in survival after curative-intent resection of non-small-cell lung cancer. Accurate staging mandates effective collaboration between surgeons and pathologists. ACOSOG Z0030 tightly controlled surgeon practice, but not pathology practice. We tested the impact of the thoroughness of pathologic examination (using the number of examined LNs as a surrogate) on detection of LN metastasis and survival.
Methods:
We reanalyzed the mediastinal LN dissection arm of ACOSOG Z0030, using linear regression to examine the clinical and demographic factors associated with LN count, Cox proportional hazards models to determine the association between the number of LNs examined and survival of patients with pN0 and pN1 disease, and logistic regression to determine association of number of LN examined and the discovery of unexpected N2 LN metastasis. Overall (OS) and recurrence-free survival (RFS), were analyzed without and with adjustment for T-category.
Results:
The 524 patients, had a mean age of 66.8 years, and were 52% male. Forty-four percent had adenocarcinoma, 27% squamous, 4% large cell, and 25% ‘other’ histology; 96% had T1/2 disease. Four hundred and thirty-nine (84%) were pN0, 63 (12%) pN1, and 21 (4%) pN2. In patients with pN0, pN1, and pN2 respectively, the mean number of mediastinal LNs examined was 13.5, 12.9, and 17.4; station 10 LNs were 2.4, 2.7, and 2.5; station 11-14 LNs were 4.6, 6.2, and 6.2; total LNs (from all stations) were 19.7, 21.3, 25. Tumor histology and pN-category were the only factors associated with the number of LNs examined: patients with squamous histology tended to have the most number of non-hilar N1 LNs examined (p<0.001); patients with pN1/N2 had more non-hilar N1 nodes than those with pN0 (p=0.005); those with pN2 had more N2 nodes examined than those with pN0 or pN1 (p=0.085). There was a consistent association between the number of LNs examined and survival. Patients with pN0 had better OS (HR 0.96; p=0.12) and RFS (HR 0.97; p=0.2) with examination of more non-hilar nodes; patients with pN1, had better OS and RFS with increased examination of LNs from N2 (OS HR=0.96, p=0.059; RFS HR=0.95, p=0.03) and all stations (OS HR=0.97, p=0.048; RFS HR=0.96, p==0.012). Adjustment for T-category strengthened these relationships between the number of LNs, pN-stage and survival. The likelihood of discovering N2 disease was associated with increased examination of LNs from mediastinal (odds ratio=1.04; p=0.035) and all stations (OR=1.03; p=0.035).
Conclusion:
Despite uniformly thorough surgical hilar/mediastinal LN harvesting, the number of LNs examined was associated with the likelihood of detecting nodal metastasis, and survival. Patients with more LNs examined were more likely to have LN metastasis, examination of more LNs was associated with better survival in patients within the same pN-category. This may indicate an effect of variable thoroughness in pathologic examination processes on the accuracy and prognostic value of the pathology nodal staging system. Heterogeneity in the cancer immune response may be an alternative hypothesis to explain these findings.
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ORAL34.06 - Impact of Surgeons' Attainment of Quality Resection Parameters on Non-Small-Cell Lung Cancer (NSCLC) Patients' Survival (ID 2189)
17:39 - 17:50 | Author(s): R.U. Osarogiagbon, G. Relyea, N. Faris, X. Yu, R. Eke, M.P. Smeltzer, F.E. Rugless, C. Fehnel, N. Chakraborty, C. Houston-Harris, F. Lu, R.S. Signore, L. McHugh, L. Deese, P. Levy, E. Crocker, L. Wiggins, C. Mutrie, B. Wolf, E.T. Robbins
- Abstract
- Presentation
Background:
The 60,000 patients who annually undergo curative-intent resection for lung cancer in the US constitute the vast majority of long-term NSCLC survivors. However, >50% of patients die within 5 years after curative-intent resection. We sought to directly measure the effect of variability in surgeon practice on patients’ survival.
Methods:
We collected patient-level data from all NSCLC resections performed in 8 mid-south hospitals from 2009 to 2013. Recipients of preoperative adjuvant therapy were ineligible. We grouped surgeons by their resection proportions for pneumonectomy and wedge resection, resections with positive margins, and resections without mediastinal lymph nodes. We assigned scores of 1 = <5%, 2 = 5-15%, and 3 = ≥ 15% for pneumonectomy and wedge resection rates; 1 = <5%, 2 = 5-10%, and 3 = ≥ 10% for resections with positive margins; 1 = < 10%, 2 = 10-50%, and 3 = ≥ 50% for resections without mediastinal lymph node examination. The individual scores were then combined for an aggregate surgeon score. Surgeons were then grouped into three tiers: 1 =≤6, 2 = 7-8, and 3 = ≥9. A survival analysis was conducted for patients aggregated by surgeon score tier, adjusted for patient race, gender, and age at surgery, pathologic stage, and surgeon’s case-volume.
Results:
1,339 resections were performed by 39 surgeons: 17 surgeons (43.6%) in tier 1(aggregate score ≤ 6) operated on 623 patients (44.5%); 14 surgeons (35.9%) in tier 2 operated on 669 patients (47.8%); and 8 surgeons (25.5%) in tier 3 operated on 107 patients (7.65%). Figure 1 plots the Kaplan – Meier survival curve for patients in each surgeon tier. Tiers 2 and 3 patients had significantly higher hazard rates than tier 1 patients, with Hazard Ratio (HR)=1.76, 95%CI: 1.17, 2.64, p=.007 and HR=1.39, 95%CI: 1.11, 1.75, p=.004, respectively. Hazard rates between patients in surgeon tiers 3 and 2 were not significantly different, HR=1.26, 95%CI: 0.87, 1.82, p=.221. Figure 1
Conclusion:
We have developed a simple method of measuring the effect of variability in surgeon practice on patient outcomes. Patients who had resection by surgeons with lower rates of pneumonectomy and wedge resections, positive margins, and non-examination of mediastinal lymph nodes show improved survival over patients operated by surgeons with higher rates. Deficiency in attaining these quality parameters can be corrected at the individual surgeon level. Surgeon-level corrective interventions are warranted.
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ORAL34.07 - Prevalence, Prognostic Implications and Survival Modulators of Incompletely Resected Non-Small Cell Lung Cancer (NSCLC) in the US (ID 650)
17:50 - 18:01 | Author(s): R.U. Osarogiagbon, C.C. Lin, M.P. Smeltzer, A. Jemal
- Abstract
- Presentation
Background:
The survival impact of incomplete resection of NSCLC has never been systematically quantified, nor has the value of postoperative adjuvant therapy in this situation. Current clinical practice guidelines are based on single-institutional retrospective studies with few patients. The studies have contradictory findings about the survival impact of non-R0 resection and the benefit of adjuvant therapy.
Methods:
We analyzed pathologic stage I-IIIA NSCLC resections in the National Cancer Data Base from 2004 to 2011 to determine clinical, socio-demographic and institutional factors associated with margin involvement using multivariate logistic regression models. We compared the survival of patients with and without positive margins and evaluated the impact of postoperative adjuvant therapy, using proportional hazards models.
Results:
Of 112,998 resections over 8 years, 5335 (4.72%) had positive margins. This population represents >4-fold the sum of all previous English-language publications on margin-positive resections. The annual incomplete resection rate was stable over the 8-year time-span, ranging between 4.38% and 5.23% (trend-test p=0.07). Patient demographic and clinical factors associated with increased adjusted odds ratio (aOR) of incomplete resection included black race (p=0.006), age-based Medicare insurance (p=0.006), urban residence (p=0.01), squamous histology, high tumor grade, tumor overlapping more than 1 lobe, tumor location in the main bronchus, and advanced pathologic stage (p < .001 for all clinical factors). Surgery performed at Community Cancer Programs (p=0.002), institutions with high proportions of underinsured patients (p=0.01), and institutions with lower cancer resection volumes (p=0.006), also had increased aOR. The crude 5-year survival rate of patients with complete v incomplete resection was 58.5% v 33.8% (p < 0.001). The survival difference persisted when patients were stratified by tumor size, T-category and aggregate American Joint Committee on Cancer stage. The survival curve of patients with margin-positive stage I disease overlapped that of patients with completely resected stage II. Patients with incompletely resected stage II disease had worse survival than those with completely resected stage III disease. The survival detriment was consistent at 1, 3, and 5 years. After incomplete resection, adjuvant chemotherapy was associated with improved 5-year survival across all stages (p<0.01); radiotherapy was associated with worse survival in stage I patients (p<0.001), and had no significant impact in patients with stage II and III disease; chemo-radiation therapy had no significant impact in patients with stage I, but was associated with improved survival in patients with stage II and III disease (p<0.001).
Conclusion:
Margin involvement significantly impaired survival after NSCLC resection, irrespective of stage. Causative institutional and provider practices should be identified, to minimize this adverse outcome. Postoperative adjuvant chemotherapy mitigated the mortality risk independently of stage, whilst postoperative radiotherapy exacerbated the risk in patients with stage I disease, and chemoradiation therapy was associated with improved survival in patients with stage II and III disease. These findings need validation in prospective clinical trials.
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ORAL34.08 - Discussant for ORAL34.05, ORAL34.06, ORAL34.07 (ID 3408)
18:01 - 18:11 | Author(s): M. Krasnik
- Abstract
- Presentation
Abstract not provided
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Author of
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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
- Moderators:S.M. Janes, E. Stone, K.M. Cummings
- Coordinates: 9/07/2015, 16:45 - 18:15, 601+603
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MINI11.02 - Frizzled9 as a Predictor of Response to Iloprost Chemoprevention of Lung Cancer (ID 2397)
16:50 - 16:55 | Author(s): R.L. Keith
- Abstract
- Presentation
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)
16:55 - 17:00 | Author(s): R.L. Keith
- Abstract
- Presentation
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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MS 14 - Chemo Prevention Clinical Trials (ID 32)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:Y.E. Miller, P.E. Postmus
- Coordinates: 9/08/2015, 14:15 - 15:45, 401-404
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MS14.01 - Preclinical Models: How Good Are They? (ID 1908)
14:20 - 14:40 | Author(s): R.L. Keith
- Abstract
- Presentation
Abstract:
A commonly employed approach to understanding the pathogenesis of lung neoplasia is to use experimental animal models. The testing of potential chemopreventive (and chemotherapeutic) agents involves pre-clinical testing, and numerous animal models have been developed. In primary mouse lung tumor models, lung cancer develops through a predictable series of airway lesions that progress from normal epithelium to invasive cancer. Permanent genomic DNA alterations occur through either spontaneous, chemically, or environmentally-induced initiation events. The lung cancer chemoprevention field is increasingly reliant on animal studies as the results of negative, early, large scale human studies (for example, β-carotene) may have been predicted with extensive pre-clinical testing. Agents progressing to human trials now undergo extensive pre-clinical studies, and this review will focus on the commonly utilized models of adenocarcinoma (ADC) and squamous cell carcinoma(SCC). ADC: Multiple, well-characterized models of murine adenocarcinoma are available in which pulmonary adenomas progress to adenocarcinomas. These progression models also allow for the study of pre-malignant airway lesions. The most commonly studied models include initiator-promoter carcinogenesis(1), mutant KRAS(2) or EGFR(3) and the use of complete carcinogens. Urethane, a component of cigarette smoke, is a complete carcinogen because it leads to tumor development without the need for other carcinogens or promoters(4). 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) , another tobacco smoke carcinogen, is a chemically-induced model where the NNK is typically administered in drinking water or injected intraperitoneally. Tobacco smoke models also exist and they can reproducibly induce pulmonary adenocarcinomas, but they are fairly labor-intensive and do not result in robust tumor multiplicity(5). There are also multiple two-stage murine models of lung tumor promotion. Several of them use 3-methlycholanthrene (3-MCA), a polycyclic aromatic hydrocarbon, as the initiator at a low dose, followed by multiple doses of butylated hydroxytoluene (BHT). BHT is a well known antioxidant found in processed foods and packaging, however it is also an oxidant and well characterized promoter. In addition, genetically modified animal models, in which viral oncogenes or transforming ras mutants are selectively expressed in lung tissue, have been developed and extensively investigated. While there are differences between the human and murine respiratory tracts, the murine tumors derived from these models have many similarities to human adenocarcinoma, ranging from specific markers to gene expression patterns(6). SCC: Models of squamous cell lung cancer have also been developed, but they are much fewer in number. The most commonly utilized SCC model involves NTCU (N-nitroso-tris-chloroethylurea), which is applied topically and histopathological analysis of serial lung sections in this model revealed a range of lung pathology, including squamous-cell carcinoma, carcinoma in situ, and varying levels of bronchial dysplasia(7). Immunohistochemical studies on the premalignant lesions show staining that corresponds to analogous human lesions(8), and the NTCU model also induces dysplastic lesions that are similar to those found during bronchoscopy and can therefore be used to evaluate one proposed surrogate endpoint in pre-clinical studies (endobronchial dysplasia). Several positive murine chemoprevention studies examining ginseng, pomegranate fruit extract, and aerosolized budesonide +/- pioglitazone have also used NTCU (reviewed in (9)). Additional SCC models have been developed, the first consisting of a kinase dead IKKα knockin mouse (Ikkα[K44A/K44A], Ikkα[KA/KA]) that develop spontaneous SCC and marked pulmonary inflammation(10). A recently described model involved biallelic inactivation of LKB1 and PTEN in mouse lung leads to SCC that expresses the squamous markers keratin 5, p63, and SOX2(11). Chemopreventive interventions have been assessed in many of the murine preclinical models. This includes (but is not limited to): inhaled and systemic glucocorticoids; myoinositol; overexpression of prostacyclin synthase; dietary administration of the prostacyclin agonist iloprost; PPARγ overexpression; dietary administration of pioglitazone; COX inhibitors; the VEGF inhibitor vandetanib; and the anti-estrogen fulvestrant. The effect of COX inhibitors on lung cancer prevention has also been tested in murine models. It is likely the chemoprevention world will take a cue from lung cancer therapeutics by determining the altered pathways in specific premalignant lesions and employing targeted (or ‘precision’) chemoprevention in the next generation of trials. Reference List (1) Malkinson AM, Koski KM, Evans WA, Festing MF. Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene. Cancer Res 1997;57:2832-4. (2) Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410:1111-6. (3) Regales L, Balak MN, Gong Y, Politi K, Sawai A, Le C, et al. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS One 2007;2:e810. (4) Malkinson AM. Primary lung tumors in mice: an experimentally manipulable model of human adenocarcinoma. Cancer Res 1992;52:2670s-6s. (5) Witschi H. Tobacco smoke as a mouse lung carcinogen. Exp Lung Res 1998;24:385-94. (6) Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA, Jr., et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol 2005;167:1763-75. (7) Wang Y, Zhang Z, Yan Y, Lemon WJ, LaRegina M, Morrison C, et al. A chemically induced model for squamous cell carcinoma of the lung in mice: histopathology and strain susceptibility. Cancer Res 2004;64:1647-54. (8) Hudish TM, Opincariu LI, Mozer AB, Johnson MS, Cleaver TG, Malkoski SP, et al. N-nitroso-tris-chloroethylurea induces premalignant squamous dysplasia in mice. Cancer Prev Res (Phila) 2012;5:283-9. (9) Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013;10:334-43. (10) Xiao Z, Jiang Q, Willette-Brown J, Xi S, Zhu F, Burkett S, et al. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 2013;23:527-40. (11) Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 2014;25:590-604.
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ORAL 23 - Prevention and Cancer Risk (ID 121)
- Event: WCLC 2015
- Type: Oral Session
- Track: Prevention and Tobacco Control
- Presentations: 2
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ORAL23.02 - Pioglitazone for the Chemoprevention of Lung Cancer (ID 2419)
10:56 - 11:07 | Author(s): R.L. Keith
- Abstract
- Presentation
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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ORAL23.03 - Role of Inflammatory Infiltrates in Promoting Persistence or Regression of Bronchial Dysplasia (ID 3026)
11:07 - 11:18 | Author(s): R.L. Keith
- Abstract
- Presentation
Background:
Inflammatory infiltrates show differing capacities to eliminate malignant cells. This capacity is related to the polarization of key inflammatory cells in tumor infiltrates. A pathway analysis of genes that are differentially expressed between persistent and regressive bronchial dysplasia (BD) identified 13 pathways associated with persistence of which 8 were related to inflammation. We have hypothesized that differences in inflammatory infiltrate polarization may contribute to lung carcinogenesis and have employed gene expression and in situ analyses to characterize differences in inflammatory infiltrates related to persistence and regression of pre-malignant BD.
Methods:
Normalized gene expression levels (Affymetrix Hu 1.0) of selected genes related to inflammatory cell polarization features were analyzed to find differences associated with follow-up histology for BD. Validational analyses of these relationships were undertaken in studies of baseline biopsies selected to represent persistent (n=43) and regressive BD (n=39). These biopsies were analyzed by quantitative immunohistochemistry and dual immunofluorescence studies to characterize the overall proportion of subsets of T-lymphocytes and macrophages in each of the groups. Image analysis tools (Aperio) were used to characterize the density of inflammatory cell subsets in the stromal and epithelial compartments of biopsy tissue within defined areas.
Results:
Analysis of expression levels for a subset of inflammatory cell related genes assessed in a global gene expression analysis indicated significantly higher levels of expression of macrophage M1 markers HLA-DRA (p=0.01) and inducible nitric oxide synthetase (iNOS; p=0.02) and T-helper lymphocyte marker CD4 (p=0.04) in regressive BD compared to persistent BD. There was also a trend toward higher expression of cytotoxic T-lymphocyte marker CD8 in regressive BD (p=0.25). Expression of B-lymphocyte and neutrophil markers were not different between regressive and persistent BD. CD68 immunohistochemical stains (IHC) demonstrated a trend toward an increase in macrophages per area of combined dysplastic epithelium and underlying stroma with a mean increase in IHC positivity of 1.75-fold in regressive versus persistent BD (p=0.08). CD4 and CD8 IHC showed 1.36- and 1.19-fold increases, respectively, in regressive BD but these changes were not statistically significant (p=0.36 and p=0.43 respectively). Dual immunofluorescence was undertaken to determine if polarization specific subsets of macrophages correlated with regression or persistence of BD. Analysis of a preliminary subset of regressive (n=3) and persistent (n=3) BD demonstrates a wide range of M1 to M2 ratios (range = 0.84 – 4.82 for ratio of HLA-DRA-CD68 dual positive M1 to CD206-CD68 dual positive M2 macrophages per high power field, 400X). Additional analyses of macrophages are ongoing to determine if the polarization status is related to regression or persistence of BD, and analysis of markers of T-helper lymphocyte subsets are planned.
Conclusion:
Gene expression analyses indicate that increased expression of markers of M1 macrophages and T-helper lymphocytes are associated with regression, and in situ analyses suggest that differences in the amount of inflammatory cell subsets may be related to outcome in BD. These studies could have implications for predicting the behavior of premalignant disease and manipulating inflammatory activity in preventing progression of BD to invasive lung cancer.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-062 - Temporal Programming of Murine Pulmonary Macrophages in N-Nitroso-Tris-(2-Chloroethyl) Urea (NTCU)-Induced Squamous Dysplasia (ID 2955)
09:30 - 09:30 | Author(s): R.L. Keith
- Abstract
Background:
Continuous topical application of N-Nitroso-tris-(2-chloroethyl)urea (NTCU) twice per week for 32 weeks causes the development of squamous dysplasia and lung carcinoma (SCC) in certain strains of inbred mice including A/J and FVB mice. In A/J mice, short term/high dose topical application of NTCU induces higher grade squamous lung lesions at earlier times with less toxicity than the 32 week, continuous dosing model. In lung adenocarcinoma, alveolar macrophages become alternatively programmed shortly after carcinogen exposure, before lung lesions are detected indicating that inflammation may be important in lesion development. Herein we examine whether short term/high dose NTCU exposure produces squamous dysplastic lesions in FVB mice. In addition, we characterize macrophage programming as a function of time during lesion development.
Methods:
FVB/N mice were treated with 20mM NTCU twice/week for 2, 4, 8, or 32 weeks and lungs were harvested at 16, 20, 24, 28, and 32 weeks after the initial application. The appearance of squamous lesions was monitored by stereology at the later time point and by the appearance of cytokeratin 5-positive bronchial cells at the earlier time points. Inflammatory cell content was determined by flow cytometry at the 16, 20, 24, and 32 week time in the mice continuously exposed to NTCU and compared to vehicle control. Macrophage programming was assessed by immunofluorescent detection iNOS or arginase I expression .
Results:
Squamous dysplasia appeared in the tracheas of NTCU-treated mice after 16 continual weeks of NTCU exposure, but lung dysplasia was not evident until 8-10 weeks later. The appearance of cytokeratin 5 positive cells in the airways preceded the appearance of these lesions. In mice treated with 8 weeks of NTCU, cytokeratin 5 positive cells in the airways appeared at 24 weeks and dysplastic lesions were also detected. Alveolar macrophage numbers also increased at the 24 week time point in these mice. Data from 28 and 32 week time points is currently being analyzed. Alveolar macrophages displayed little change in iNOS or arginase I staining through 20 weeks, however there were isolated iNOS[+] and arginase I[+] macrophages at 24 weeks. There were also weakly activated macrophages present in mice treated with NTCU continuously for 32 weeks although alveolar macrophage numbers did not increase significantly.
Conclusion:
The short term/high dose NTCU treatment regimen is less toxic and produces dysplastic lesions at times similar to those in continuous exposure groups. Alveolar macrophage numbers also increase as a function of time in the short term/high dose model whereas there is less reproducibility of this increase in the continuous dosing model. Changes in alveolar macrophage programming occur during dysplastic lesion development, but not to the same extent as that seen in progression of adenomas and adenocarcinomas.
