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P. Yang

Moderator of

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    O24 - Cancer Control and Epidemiology III (ID 134)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 6
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      O24.01 - Lung cancer risk attributable to occupation: in a case control study in black South Africans 2001-2008 (ID 3421)

      16:15 - 16:25  |  Author(s): C. Nattey

      • Abstract
      • Presentation
      • Slides

      Background
      Worldwide, lung cancer is the leading cause of death by cancer and most common cancer among occupational related cancers. Approximately 90% of men and 60% of women. developing lung cancer are smokers. Cancer Morbidity and the increase in cancer mortality in South Africa is well documented and has been attributed to different factors, including tobacco consumption, occupational exposures, infections, changing lifestyles, ageing population and environmental pollution The International Agency for Research on Cancer (IARC) has estimated that almost 40 000 deaths from cancer (58 000 cases) occur annually in South Africa. In men the leading causes of deaths were lung cancer (comprising 16% of all cancer deaths). Environmental and occupational risk factors contribute to the burden of lung cancer, but the extent of this contribution is still unclear in most settings especially in Africa, confirmed in a review by McCormack and Schuz Estimating the attributable fraction for specific risk factors helps to assess the potential impact the preventive interventions could have on the population. The proposed study will estimate lung cancer risk attributable to the different occupations and types of workplaces in black South African population represented in the data base while controlling for smoking and domestic fuel use. Identification of the role of occupation on the risk of lung cancer may enhance the ability to prevent the disease by permitting better focused occupational health and other preventive strategies in the fight against non-communicable diseases in black South Africans. There is very limited research on cancers and occupations in Africa; hence findings will contribute to the knowledge of lung cancer in relation to occupations in South Africa.

      Methods
      Data from the on-going Johannesburg Cancer Case-Control Study (JCCCS) of black African adult cancer patients (2001-2008) was used. Information from 579 lung cancer cases and 1120 frequency matched controls was analysed. Controls were randomly selected from cancers not known to be associated with the effects of tobacco, matched by sex and age (±5years). Usual occupation and/or workplace stated at interview were used as an indicator of occupational exposure. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression and attributable fraction (AF) by Miettinen’s formula, adjusted for smoking pack years, HIV status and domestic fuel type use.

      Results
      The mean age of cases and controls was 56.0 and 57.1 respectively. Among men the adjusted OR for lung cancer was 3.0 (95% CI 1.4-6.4) in miners and 1.7 (95% CI 1.3-3.2) in those working in transport occupations. In women working as domestic worker (maids, child minders etc) the adjusted OR was 7.3 (95% CI 1.7-11.3) whereas working in the food & beverage industry, the adjusted OR was 4.9 (95% CI 1.4-26.8). Occupation / workplace resulted in an AF of 14% in men and 26% in women.

      Conclusion
      Occupational risk factors for lung cancer in South Africa are gender-specific, having more impact in women than in men. Further studies are needed to assess possible specific exposures in the mining and transport industries for men, and food industry and private homes for women.

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      O24.02 - Lung cancer in South East Scotland, are we still making progress? (ID 1320)

      16:25 - 16:35  |  Author(s): S.C. Erridge, G. Kerr, C. Dodds, S. Campbell, J. Ironside, F. Little, M. Mackean, A. Price, J. Gysin, L. Bhatti, C. Selby

      • Abstract
      • Presentation
      • Slides

      Background
      South-East Scotland Cancer Network (SCAN) serves 1.4 million people using unified protocols collecting prospective data. We published population-based data from 1995 and 2002 (J Thorac Oncol. 2008;3(5):491-8) demonstrating increased cancer treatment and improved overall survival. This review investigates whether this has been sustained.

      Methods
      Patients were identified from Scottish Cancer Registry (SCR), SCAN audit and Edinburgh Cancer Centre databases to extract tumour characteristics, initial management (usually ≤6 months of diagnosis) and overall survival (OS). Missing data was sought from patients’ health records. Multivariate analysis (MVA) examined sex, age(<60,60-69,70-79,80+), deprivation, Healthboard of residence, performance status (PS), pathology and stage (localised, regional, metastatic) affecting use of any treatment, potentially curative treatment (PCT) defined as surgery (S) or potentially curative radiotherapy (PC-RT - ≥50Gy for NSCLC or ≥40Gy+chemo for SCLC) using Cox’s proportional hazards model to obtain factors affecting survival.

      Results
      1117 patients were identified in the audit. 51.5% were men, median age 72 (range 31-98) years. 47.3% were from the two most deprived quintiles. 49.5% had WHO PS 0-1, 23.5% WHO2, 24.2% WHO3-4. 58.5% NSCLC (23.5% Stage I-II, 25.7% III, 48.8% IV), 13% SCLC (37.9% stage I-III, 61.4 stage IV) and 28.5% radiology-only diagnosis (24.5% Stage I-II, 19.5% III, 52.8% IV). 59.9% received some form of treatment; 28.4% with PCT ((126 S+/-chemo(C) = 19% of NSCLC), 190 PC-RT +/- C), and 31.5% palliatively. 467 (41.8%) received any RT, 268 (24%) any C. MVA showed age >70, PS≥2, metastatic disease, ‘not-SCLC’, but not sex, deprivation or Healthboard, were associated (all p<0.01) with lower treatment delivery, and only age > 80, PS≥2, radiology-only diagnosis and non-localised disease (all p<0.01) with reduced PCT. Median survival was 5.03 months (95%CI 4.3-5.8) with 46.8% alive at 6 months, 32.0% 12 and 17.7% 24 months following diagnosis. Male sex, PS≥2 and non-localised disease were associated with increased HR for death (all p<0.01). Comparison with the 2002 cohort (n= 971, Dumfries excluded from both cohorts) showed similar age and pathology profile, but increased women, residents from most deprived quintile and metastatic disease. Uni-variate analysis showed a similar proportion received treatment (62.3% 2002 v. 59.9% 2010 p=0.14) but more received PCT (23.6% v. 28.2% p=0.02) principally through increased use of PC-RT (13.1% v. 17.1% p=0.01). On MVA (without PS) the use of any treatment reduced (OR 0.73 (0.59-0.92) however, use of PCT increased (OR 1.84 (1.37-2.47) due to more PC-RT (1.57 (1.18-2.08)), but not surgery. Median (5.16 v. 4.90 months p=0.65), 1 year (29.0% (31.9-26.1) v. 31.4% (34.3-28.5) and 2 year (14.9% (17.3-12.5) v. 17.4% (19.8-15.0) survival were unchanged.

      Conclusion
      In the last 8 years in SCAN, there has been an increase in the number of women with lung cancer along with a worsening deprivation profile and increased identification of stage IV disease, possibly through improved staging. There has been an increase in potentially curative, but reduction in all therapy delivered without any apparent impact on survival. This analysis demonstrates the challenges of improving population-based outcomes in a disease where most present with advanced disease and are often unfit for treatment .

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      O24.03 - Lung cancer incidence trends among Asian-American ethnic populations in the United States, 1990-2010 (ID 1969)

      16:35 - 16:45  |  Author(s): S. Lin Gomez, I. Cheng, K. Gali, M.I. Patel, R. Haile, A. Noone, H. Wakelee

      • Abstract
      • Presentation
      • Slides

      Background
      In the United States (US), anti-smoking policies have resulted in a population-wide decline in lung cancer rates over the past decade. However, little is known about how lung cancer incidence trends vary among Asian-American ethnic populations, the largest growing population in the US.

      Methods
      For the first time, annual population estimates for Asian-American ethnic populations were developed for the regions in the Surveillance, Epidemiology, and End Results program, comprising half of the total U.S. Asian-American population. From 1990-2010, incidence rates and average annual percentage change (APC) were computed for each racial/ethnic group for lung cancer overall and by gender and histology.

      Results
      Among Asian-American males, trends were either stable or declining in all groups (Figure 1). The declines were statistically significant among Koreans (APC = -3.0), Hawaiians (APC = -2.3), Vietnamese (APC = -1.4), Filipino (APC = -1.9 from 1996-2010), and Chinese (APC = -1.5). Among Asian-American females, declining trends were seen among Hawaiians (APC = -5.9 from 2002-2010) and Vietnamese (APC = -1.5). In contrast, increasing trends were seen among Japanese (APC = 1.7) and Filipinas (APC = 1.5). Among Asian-American males, all histologies exhibited stable or declining trends with the exception adenocarcinoma, which increased among Chinese males from 1997-2010, appearing independent of the decrease in NOS, which occurred much later in this group. Among Asian-American females, declining or stable trends were seen for most histologies, with the exception of adenocarcinoma among Filipina and Korean females (APC = 2.5 and 3.0, respectively), and squamous cell carcinoma among Japanese females (APC = 2.4). Figure 1

      Conclusion
      To the extent that Asian-Americans have distinct primary and second-hand smoking profiles, unique environmental exposures , and population-specific genetic predisposition, analysis of incidence trends by histology suggests that, among Asian-American females, additional risk factors beyond primary and perhaps secondary smoking may be important for lung cancer etiology. The continued increase of lung cancer incidence among Filipina, Korean, and Japanese American females, especially in adenocarcinomas and squamous cell carcinomas, warrants further attention.

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      O24.04 - Risk of second primary lung cancer (SPLC) in patients (pts) with previously treated lung cancer: Analysis of the Surveillance, Epidemiology and End Results (SEER) data (ID 2204)

      16:45 - 16:55  |  Author(s): A.J. Wozniak, A. Schwartz, F.D. Vigneau, R.D. Shore, M.K. Islam, S. Gadgeel

      • Abstract
      • Presentation
      • Slides

      Background
      BACKGROUND: Second primary lung cancer (SPLC) in patients who have been treated for a prior lung cancer is a recognized phenomenon. There has been an improvement in the staging and treatment of lung cancer in the last several decades resulting in longer survival for pts and affording an opportunity for the development of SPLCs. The objective of this study was to establish the frequency of SPLCs and to characterize the demographics, histology and stage at presentation, time interval between diagnoses, and cumulative risks of developing a SPLC in this pt population.

      Methods
      METHODS: The pts were identified from population-based SEER-9 Registries Data Base. All pts with a primary lung cancer between 1973 and 2004 were included with follow-up to 2009. The histology and stage of the SPLCs were evaluated in comparison to the initial primary lung cancer (IPLC). The incidence of SPLCs was compared to the expected incidence by calculating multiple primary-standardized incidence ratios (MP-SIRs) using the SEER Stat program. Selected cohorts were stratified by sex, race, age at diagnosis, and date of diagnosis. Sex-specific cumulative risks of developing SPLCs were calculated using the Kaplan-Meier method.

      Results
      RESULTS: 208,486 pts had an IPLC diagnosed from 1973-2004. No smoking history was available. Patient Characteristics at time of IPLC: 60.4% male; 84.3% white; 8.5% (20-49 yr), 55.9% (50-69 yr), 35.6% (≥ 70 yr); 84% non-small cell lung cancer (NSCLC); 33.8% distant disease, 23.5% regional, 29.9% local. 5,302 pts developed SPLC. The majority were male (56.6%), white (84.9%), and in the 50-69 yr age group (68%). Females had the highest SIR values across all ethnicities and age groups particularly in the youngest cohort (20-49 yr) where the SIR was 8.58. The SIR values were ≥ 2 for all cohorts expect for males ≥ 70 yr (SIR=1.65). The predominant histologic types for IPLCs were adenocarcinoma (ADC) and squamous cell cancer and the associated SPLCs were usually of the same histology. IPLC ADC and BAC pts were most likely to develop a SPLC. Most SPLCs (50%) presented with regional or distant disease, while only 37% were localized at diagnosis. The median time to development of SPLCs was 68 mo for males and 74 mo for females. The risk of developing a SPLC continually increased as a function of time for both sexes.

      Conclusion
      CONCLUSION: Patients with a history of IPLC are at high risk for developing SPLC and this risk increases over time. This is especially true of females who are diagnosed at an early age with their initial lung cancer. The majority of SPLCs present late and at a more advanced stage. These findings could have major implications with regard to the length and type of surveillance in pts who survive their initial lung cancer diagnosis.

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      O24.05 - The impact of body mass index on survival in stage 3 and 4 lung cancer (ID 663)

      16:55 - 17:05  |  Author(s): K.M. Wong, S. Cuffe, L. Coate, O. Espin-Garcia, K. Boyd, R. Feld, N. Leighl, F.A. Shepherd, W. Xu, G. Liu

      • Abstract
      • Presentation
      • Slides

      Background
      Obesity has been shown to be an adverse prognostic factor in several cancers, including breast, colorectal, endometrial, ovarian, pancreatic and prostate. However, studies of body mass index (BMI) and outcomes in lung cancer are lacking. Understanding the clinical impact of body weight on cancer outcomes is important given the high prevalence of obesity globally. We retrospectively evaluated the distribution of BMI at diagnosis and its effects on survival in stage 3 and 4 lung cancer patients.

      Methods
      1,121 patients with stage 3 or 4 lung cancer from a single institution were analyzed. Clinicopathologic data were collected retrospectively. Adjusted hazard ratios (aHR) for overall survival (OS) and progression-free survival (PFS) were generated by Cox regression for each BMI (kg/m[2]) category (underweight: <18.5, normal: 18.5-24.9, overweight: 25.0-29.9, obese: ≥30), after adjusting for age, gender, Charlson Comorbidity Index, performance status (PS), clinical stage and treatment regimen.

      Results
      In this cohort (n=1,121), the frequencies of stage 3A, 3B and 4 lung cancers were 35%, 32% and 33%, respectively. There were 633 (57%) adenocarcinomas, 238 (21%) squamous cell carcinomas, 38 (3%) small cell lung cancers, and 210 (19%) other histologies. Patients had variable BMI: 82 (7%) underweight, 550 (49%) normal weight, 333 (30%) overweight, 156 (14%) obese. Being overweight/obese was associated with older age (p=0.002) and stage 3A disease (p=0.001); underweight patients were more likely current smokers (p<0.001). OS was significantly decreased with age ≥65, males, PS 2-3, stage 4, and lack of systemic treatment (p<0.001). Median OS in underweight, normal weight, overweight and obese patients were 14, 23, 24 and 26 months, respectively. Compared with BMI ≥18.5, being underweight was associated with significantly poorer OS (aHR 1.33, 95% CI 1.01-1.77, p=0.045), but not PFS (aHR 1.12, 95% CI 0.86-1.46, p=0.414). The magnitude of this association was greatest among those aged less than 65 years (aHR 1.57, 95% CI 1.11-2.22, p=0.011).

      Conclusion
      In stage 3 and 4 lung cancer, being underweight at diagnosis is associated with significantly poorer OS, especially in patients younger than 65 years of age. Lower BMI is mostly observed in current smokers, while above normal BMI is seen in older patients and stage 3A disease. Unlike other malignancies, obesity does not increase mortality in this population. The BMI-survival relationship in lung cancer requires further study.

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      O24.06 - DISCUSSANT (ID 4001)

      17:05 - 17:20  |  Author(s): I.N. Olver

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO05.01 - Validation of gene expression biomarker panels in non-small cell lung cancer (ID 2928)

      16:15 - 16:20  |  Author(s): P. Yang

      • Abstract
      • Presentation
      • Slides

      Background
      Many studies in the literature have suggested that gene expression biomarkers may guide patient classification and clinical management in NSCLC. Despite minimal external validation and no clinical trial evidence, gene expression biomarker panels have been proposed as tools for making treatment decisions. Recent controversy surrounding the validity of such data and its potential applicability to clinical practice led us to perform an external validation study of published gene expression biomarker panels.

      Methods
      We performed gene expression profiling for a total of 209 patients with both Affymetrix whole transcriptome U133Plus2 arrays in addition to a NSCLC-specific array constructed by our group for assessment of mRNA expression in frozen tumor specimens of NSCLC. Clinical outcome data were collected and analyzed for correlations of gene expression with disease-free and overall survival. Cox proportional hazard models were used to test significance of individual genes and for gene sets defined by each panel. Panels tested included those previously published from Michigan, Mayo Clinic, Taiwan, Toronto, and UCSF.

      Results
      Expression profiling data were generated for a total of 209 patients with NSCLC. This included U133Plus2 arrays of 242 tumor samples and 105 matched surrounding normal lung tissue, as well as 111 tumor profiles using the NSCLC-specific array. There were 98 women and 111 men in the study cohort, with 120 patients having Stage I NSCLC (57.4%), 38 with Stage II (18.2%), 50 with Stage III (23.9%), and one patient with Stage IV disease (0.5%). Mean follow-up time after surgical resection was 62.4 ± 48 months. Seventy-four patients (35.1%) developed post-resection recurrence after a mean of 53.3 ± 49.3 months, of which 62 patients died (83.8%). Known clinical predictors such as TNM stage, histology, and tumor grade were predictive of survival. Although many genes within the published biomarker panels were significantly correlated with disease-free and overall survival, none provided additive prognostic value beyond standard clinical predictors.

      Conclusion
      Although a number of individual gene expression biomarkers have prognostic significance in univariate models, published biomarker panels perform poorly in external validation studies such as this. The additive prognostic value beyond standard, known clinical predictors in the TNM staging system casts doubt as to whether such information will be useful in clinical practice. Despite the success of gene expression biomarkers for molecular subtyping in other cancers, our data suggests that this information has a low likelihood of clinical translation in NSCLC for unselected patients.

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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.08 - Genomic alterations in pulmonary carcinoid tumors (ID 3162)

      16:55 - 17:00  |  Author(s): P. Yang

      • Abstract
      • Presentation
      • Slides

      Background
      Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize. Relatively little is known about bronchopulmonary carcinoid tumorigenesis, and understanding of these tumors has yet to benefit from the insight of genomic studies. This unfortunately has translated into relatively limited treatment options for these patients and no recent advances in therapy. We aimed to characterize genomic alterations in pulmonary carcinoid tumors under the hypothesis that a better molecular understanding may lead to improved therapeutic approaches and patient outcomes.

      Methods
      We characterized genomic alterations in pulmonary carcinoid tumors using whole genome, exome, and RNA sequencing, in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC. Fresh-frozen specimens from 54 patients with primary lung neuroendocrine tumors were obtained from our lung specimen registry and clinical data collected. This included a total of 31 typical and 11 atypical carcinoid tumors with associated normal tissue, and 12 SCLC. Whole transcriptome mRNA expression profiling and SNP genotyping for evaluating copy number variation was performed using Illumina array platforms. For a subset of tumors, whole genome sequencing was performed through Complete Genomics, and exome and RNA sequencing performed through BGI and the Mayo Clinic Genomics Facility. These data were correlated with the histologic subtype, stage and survival data available from this cohort of patients.

      Results
      Gene expression clearly identified distinct profiles differentiating carcinoid tumors from SCLC, though not between typical and atypical carcinoids. Copy number variations (CNV) were widely prevalent in SCLC, less frequent in AC, while TC had the lowest frequency of CNV. Validated sequencing data from exome and WGS platforms revealed a number of novel mutations for pulmonary carcinoid tumors, including ADNP, BRIP1, cyclin B3, CREBL2, GLI3, HERC1, IRAK3, NEDD4L, PRRX2, and ZDBF2, among others. RNA sequencing data did not reveal any novel fusions from analysis to date. Despite a low overall mutation frequency versus other forms of lung cancer, each carcinoid tumor had at least one potential driver mutation, suggesting possible targeted therapy opportunities for a disease where currently none exist.

      Conclusion
      Despite a low overall mutation frequency and an absence of frequently recurring mutations from the tumors sequenced to date, targeted therapy opportunities may exist through mutation profiling in broncopulmonary carcinoid tumors.

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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.02-003 - DNA methylation and expression patterns in adenocarcinomas of the lung of never-smokers with discordant methylation and expression patterns of homeobox related genes (ID 856)

      10:04 - 10:21  |  Author(s): P. Yang

      • Abstract

      Background
      Lung cancer occurs in a significant number of never-smokers. Epigenetic changes in lung cancer potentially represent important diagnostic, prognostic and therapeutic targets. Accordingly, we sought to determine if there are differences in DNA methylation between lung adenocarcinomas and adjacent non-malignant lung tissue in never-smokers.

      Methods
      Using the Illumina Infinium HumanMethylation27 BeadChip we compared the DNA methylation profiles of 28 adenocarcinomas of the lung of never-smokers with their paired adjacent non-malignant lung tissue. The β value represents each methylation data point as the ratio of fluorescent signals between the methylated sites and the sum of methylated and unmethylated sites, which ranges continuously from 0 (unmethylated) to 1 (fully methylated). We used the Mann Whitney U test to compare β values between groups using JMP (SAS Institute Inc. Cary, NC USA). Then, using the Illumina Human WG DASL beadchip, we correlated differential methylation changes with gene expression changes from the same 28 samples. We validated our findings with 24 samples of lung adenocarcinomas and paired non-malignant tissue from The Cancer Genome Atlas (TCGA). Database for Annotation, Visualization, and Integrated Discovery was used to determine gene enrichment.

      Results
      We observed a distinct separation in methylation profiles between tumor and adjacent nonmalignant lung tissue using principal component analysis. Tumors were generally hypomethylated (β=0.15) when compared to adjacent non-malignant tissue (β=0.17; p=0.02). There were 1906 differentially methylated (Bonferroni corrected p value <0.05) CpG sites between tumor and adjacent non-malignant lung tissue. Of these sites, 1198 were within classically defined CpG islands where tumors (median β=0.38) were hypermethylated compared to adjacent non-malignant tissue (median β=0.22; p<0.0001), and 708 sites were outside of CpG islands where tumors (β=0.49) were hypomethylated compared to adjacent non-malignant tissue (β=0.56; p<0.0001). When compared to a dataset of 24 lung adenocarcinomas and paired non-malignant tissue from TCGA, 1841 of these 1906 (96.6%) sites were also differentially methylated with the same direction of change between tumor and non-tumor lung tissue. We matched 1483 genes with the differentially methylated CpG sites and found that these genes were enriched with the terms glycoprotein, signal, plasma membrane part, homeobox in addition to a few other terms. There were significant differences in expression of 376 genes (Bonferroni corrected p<0.05) of the 1483 (25.4%) differentially methylated CpG sites. There was an inverse correlation between methylation and gene expression in 80% of these genes. Genes that were not significantly differentially expressed and were hypermethylated within CpG sites were enriched for homeobox genes (false discovery rate = 1.2E-27).

      Conclusion
      The methylation profiles of lung adenocarcinomas of never-smokers and their adjacent non-malignant lung tissue are significantly different. Differential methylation of a CpG site was associated with altered gene expression in approximately 25% of cases. Despite the differential methylation of homeobox genes, no significant changes in expression of these genes were detected.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-018 - Outcomes of lung adenocarcinoma patients with signet ring cell tumors: a three-way evaluation (ID 2884)

      09:30 - 09:30  |  Author(s): P. Yang

      • Abstract

      Background
      Pathologically, signet ring cells (SRC) describe singly dispersed tumor cells with intracytoplasmic mucin vacuoles, which eccentrically displace and compress the nucleus. SRCs are traditionally associated with adenocarcinoma of the gastrointestinal tract and are rare in lung adenocarcinoma (LACA). Patients with primary LACA with SRC features (SRC+) have been associated with poor clinical outcome and ALK gene rearrangement (ALK+). However, the impact of SRC+ on clinical outcome is not well delineated. We systematically studied LACA survival outcomes for the impact of SRC status.

      Methods
      Three distinct groups of surgically treated patients with LACA (n=763) that were followed for ≥5 years were reviewed: never smokers (n=266), 2006-2007 cohort (n=222), and smokers enriched for various degrees of lepidic growth pattern (LGP, n=275). Two pulmonary pathologists reviewed all cases; SRC+ tumors were defined as having >10% SRCs, agreed by both pathologists. SRC+ tumors were TTF1+, and generally cytoplasmic mucin+ and CDX2-. ALK immunostain was performed on all SRC+ cases, and ALK status was confirmed by FISH for cases with any degree of immunoreactivity. Impact of SRC+ on patients’ survival outcomes (overall and disease-free, OS and DFS) were analyzed using Cox models (by hazard ratio, HR) separately for the three groups, with careful evaluation of known prognostic factors: age at diagnosis; gender; smoking status; lung cancer history; tumor subtype; grade and stage; and treatment (surgery, chemotherapy and/or radiation).

      Results
      In the total of 763 patients (61% women, mean age at diagnosis 68 years), 53 (7%) were SRC+. In never smokers (73% women), 9% were SRC+; 33% of the SRC+ were ALK+ vs. 5% among the SRC- cases (p<0.0001). In the 2006-2007 cohort (55% women), 9% were SRC+; in LGP-smokers (54% women), 3% were SRC+. Across all three groups, SRC+ tumors were more likely to occur in men and have higher stage. Univariate analysis showed SRC+ never smokers had shorter survival: median DFS was 2.4 years (vs. 5.2 in SRC- never smokers, p=0.0004), and median OS was 3.7 years (vs. 7.6, p=0.0064). However, multivariate analysis did not confirm a significant impact of SRC+ on survival. In contrast, for the other two groups, crude 5-year survival was 6%-27% decreased in SRC+ cases compared to SRC- cases (none reached statistical significance); however, multivariate analysis revealed a 2-fold higher mortality (HR=2.30, 95% CI=1.01-5.27, p=0.048) for smokers with SRC+ tumors.

      Conclusion
      Based on results from three patient groups, we confirmed that SRC+ is significantly associated with ALK+. Worse survival in patients with SRC+ tumors was observed in never smokers by univariate analysis. A potential negative impact of SRC+ tumors on OS in LGP-smokers was only uncovered after adjusting for known prognostic factors. These results need to be furthered confirmed.