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Mutation Status of Barrett's Esophagus Biopsies Indefinite for Dysplasia Correlates with Outcomes
AGA Abstracts
2003-2014. Most sites were community based practices (75%). Patients with GERD without alarm symptoms such as dysphagia, bleeding, vomiting, and weight loss were included. The primary study endpoint was endoscopic diagnosis of suspected Barrett's esophagus of length >2cm (sLSBE), which serves as a crude measure of the prevalence of Barrett's esophagus in this cohort. Prior studies have shown that about 75% of these patients will have histologic intestinal metaplasia consistent with Barrett's esophagus. Multivariate logistic regression analyses were used to generate odds ratios and an estimated number needed to evaluate (NNE) for sLSBE by age, gender, and race. Results Of the 73,535 patients whom underwent EGD for GERD without alarm symptoms, 4,122 (5.6%) had suspected Barrett's esophagus of any length. Of these, 963 (23.4%) had suspected Barrett's esophagus of unknown length, while 772 (18.7%) had sLSBE. Assuming the percentage of sLSBE remained consistent for those with unknown length of suspected Barrett's esophagus, 1.4% of our patients had sLSBE. Older age, men, and white patients were more likely to have sLSBE, with odds ratios shown in Table 1. The NNE grouped by age, race, and gender are shown in Table 2. The highest risk groups were white males age>50, but white males aged 40-49 are also at higher risk than any other age-race-gender grouping. Conclusion This is the largest study of endoscopic evaluation of GERD without alarm symptoms. We confirm previously suggested risk factors of older age, male gender, and white ethnicity for sLSBE, but also demonstrate a lower prevalence of sLSBE compared to prior studies. This low prevalence of sLSBE may be related to the inclusion of patients with alarm symptoms in prior studies, or potentially due to the increasing use of proton pump inhibitors to manage GERD during our study period. We identify the white male 40-49 age group as a potentially under-recognized group at risk, but this group would require 65 EGDs to identify one patient with sLSBE. In the highest risk group (white men >70 years), 37 EGDs would need to be performed to identify one patient with sLSBE. Therefore, in the absence of alarm symptoms, GERD is uncommonly associated with sLSBE. Multivariate risk of suspected Barrett's esophagus with length >2cm (sLSBE)
periodic surveillance endoscopy. We sought to evaluate the impact of BE screening/surveillance endoscopy on early-stage esophageal cancer detection and long-term survival. Methods: The Surveillance, Epidemiology, and End Results (SEER) database is a source of cancer and survival data based on the respective United States patient population. Pertinent data related to esophageal cancer was utilized to evaluate trends that corresponded to varying periods of BE screening and surveillance: 1989-1995 ("no" universal screening/surveillance), 19962004 ("early" universal screening/surveillance), and 2005-2011 ("current" universal screening/surveillance). We examined the incidence of esophageal cancer stratified by staging (localized and regional, distant and unstaged) as well as the corresponding five year survival for each respective time period. An effective screening/surveillance program should demonstrate an increase in early-stage cancers with a corresponding decrease in late-stage cancers, as well as a decrease in overall five-year mortality. Results: Between the three time periods ("no", "early", "current" BE screening/surveillance), there was a progressively increased incidence of esophageal cancer (5,744 vs 17,946 vs 20,668). There was also a corresponding improved five-year survival rate for esophageal cancer (12.3% vs 15.8% vs 17.9%) in all stages. During these time periods, the incidence of early-stage esophageal cancer (localized and regional staging) remained stable (50%, 54%, 52%). The percentage of late-stage esophageal cancer steadily rose (25%, 30%, 38%). These findings suggest that despite the installation of BE endoscopic screening/surveillance programs, esophageal cancers are not being increasingly diagnosed at earlier stages. Discussion: BE screening and surveillance programs have not led to increased detection rates of early-stage esophageal cancer nor decreased rates of late-stage cancer, despite improved overall survival in all stages of esophageal cancer. These findings suggest that improved survival in esophageal cancer is due to improved local and systemic therapy, and not due to Barrett's esophagus screening and surveillance programs.
Figure 1. Esophageal cancer incidence stratified by cancer staging and BE screening/surveillance time periods.
Su1049 MUTATION STATUS OF BARRETT'S ESOPHAGUS BIOPSIES INDEFINITE FOR DYSPLASIA CORRELATES WITH OUTCOMES Stephen M. Lagana, Elena Komissarova, Sarawut Kongkarnka, Jorge L. Sepulveda, Antonia R. Sepulveda Background: Intestinal metaplasia of the esophagus (Barrett's intestinal metaplasia, BIM) is thought to progress to adenocarcinoma (EAC) through a step-wise process of dysplasia (DYS). Some cases are classified as indefinite for dysplasia (BIM-I) because of overlapping histology between reactive atypia (RA) and dysplasia, necessitating a shorter follow-up interval. In other cases, dysplasia is suspected, but unequivocal diagnostic features cannot be identified by histology. We hypothesized that mutation detection in genes involved in esophageal carcinogenesis by next-generation sequencing (NGS) may help categorize BIMI cases as RA vs. DYS. Methods: We tested endoscopic biopsy samples in 15 BIM-I cases, consisting of 9 BIM-I patients with no progression to subsequent dysplasia with an average follow up of 55 months (range 11-96), (BIM-I-NP, presumably RA) and 6 with concurrent high-grade DYS or EAC in other biopsies (BIM-I-C). Median age of BIM-I-NP, BIM-I-C, and BIM-NP patients was 73, 64, and 65 years, respectively. The diagnosis was confirmed by 2 gastrointestinal pathologists. 30 cases of never dysplastic BIM (BIM-NP) followed for at least 2 years were used as controls. Formalin-fixed paraffin-embedded (FFPE) biopsy tissues were used for DNA extraction. Next generation sequencing (NGS) was performed with the TruSeq cancer panel (Illumina) to interrogate mutational hotspots within 48 cancer genes. Sequencing data were analyzed with NextGENe software (SoftGenetics) and with a pipeline using the Integrative Genomics Viewer platform. Results: Recurrent mutations in TP53 and CDKN2A were detected in BIM samples. Mutations in TP53 or CDKN2A were not detected in any of the 9 BIM-I-NP whereas 3 of 6 cases (50%) of BIM-I-C showed mutations in TP53 and/or CDKN2A (p=.044). Only 2 of 30 (6.6%) control cases of BIM-NP showed TP53 or CDKN2A mutations (p=.024 vs. BIM-I-C). Conclusions: TP53 / CDKN2A mutations may be detected in Barrett's intestinal metaplasia indefinite for dysplasia. Biopsies with a diagnosis of indefinite for dysplasia and negative TP53/CDKN2A mutation status show outcomes similar to patients with Barrett's IM who never developed DYS/EAC. In contrast, the presence of TP53/CDKN2A mutation in a biopsy diagnosed as indefinite for dysplasia raises concern for a high-risk lesion and the possibility of endoscopically missed HGD/EAC, warranting closer surveillance. The results suggest that NGS mutational testing may be a useful ancillary test in risk stratification of BE patients found to have IND on endoscopy.
Number of EGDs needed to evaluate uncomplicated GERD per finding of suspected Barrett's esophagus with length >2cm (sLSBE)
Su1048 BARRETT'S ESOPHAGUS SCREENING AND SURVEILLANCE IS NOT RESPONSIBLE FOR IMPROVED OUTCOMES IN ESOPHAGEAL CANCER Kartik Sampath, Stuart R. Gordon, Timothy B. Gardner Background: Esophageal adenocarcinoma (EA) is the most common esophageal cancer subtype in the United States and Barrett's esophagus (BE) is the premalignant condition to EA. Current guidelines recommend screening select patient populations for BE, with subsequent
AGA Abstracts
S-454
2003-2014. Most sites were community based practices (75%). Patients with GERD without alarm symptoms such as dysphagia, bleeding, vomiting, and weight loss were included. The primary study endpoint was endoscopic diagnosis of suspected Barrett's esophagus of length >2cm (sLSBE), which serves as a crude measure of the prevalence of Barrett's esophagus in this cohort. Prior studies have shown that about 75% of these patients will have histologic intestinal metaplasia consistent with Barrett's esophagus. Multivariate logistic regression analyses were used to generate odds ratios and an estimated number needed to evaluate (NNE) for sLSBE by age, gender, and race. Results Of the 73,535 patients whom underwent EGD for GERD without alarm symptoms, 4,122 (5.6%) had suspected Barrett's esophagus of any length. Of these, 963 (23.4%) had suspected Barrett's esophagus of unknown length, while 772 (18.7%) had sLSBE. Assuming the percentage of sLSBE remained consistent for those with unknown length of suspected Barrett's esophagus, 1.4% of our patients had sLSBE. Older age, men, and white patients were more likely to have sLSBE, with odds ratios shown in Table 1. The NNE grouped by age, race, and gender are shown in Table 2. The highest risk groups were white males age>50, but white males aged 40-49 are also at higher risk than any other age-race-gender grouping. Conclusion This is the largest study of endoscopic evaluation of GERD without alarm symptoms. We confirm previously suggested risk factors of older age, male gender, and white ethnicity for sLSBE, but also demonstrate a lower prevalence of sLSBE compared to prior studies. This low prevalence of sLSBE may be related to the inclusion of patients with alarm symptoms in prior studies, or potentially due to the increasing use of proton pump inhibitors to manage GERD during our study period. We identify the white male 40-49 age group as a potentially under-recognized group at risk, but this group would require 65 EGDs to identify one patient with sLSBE. In the highest risk group (white men >70 years), 37 EGDs would need to be performed to identify one patient with sLSBE. Therefore, in the absence of alarm symptoms, GERD is uncommonly associated with sLSBE. Multivariate risk of suspected Barrett's esophagus with length >2cm (sLSBE)
periodic surveillance endoscopy. We sought to evaluate the impact of BE screening/surveillance endoscopy on early-stage esophageal cancer detection and long-term survival. Methods: The Surveillance, Epidemiology, and End Results (SEER) database is a source of cancer and survival data based on the respective United States patient population. Pertinent data related to esophageal cancer was utilized to evaluate trends that corresponded to varying periods of BE screening and surveillance: 1989-1995 ("no" universal screening/surveillance), 19962004 ("early" universal screening/surveillance), and 2005-2011 ("current" universal screening/surveillance). We examined the incidence of esophageal cancer stratified by staging (localized and regional, distant and unstaged) as well as the corresponding five year survival for each respective time period. An effective screening/surveillance program should demonstrate an increase in early-stage cancers with a corresponding decrease in late-stage cancers, as well as a decrease in overall five-year mortality. Results: Between the three time periods ("no", "early", "current" BE screening/surveillance), there was a progressively increased incidence of esophageal cancer (5,744 vs 17,946 vs 20,668). There was also a corresponding improved five-year survival rate for esophageal cancer (12.3% vs 15.8% vs 17.9%) in all stages. During these time periods, the incidence of early-stage esophageal cancer (localized and regional staging) remained stable (50%, 54%, 52%). The percentage of late-stage esophageal cancer steadily rose (25%, 30%, 38%). These findings suggest that despite the installation of BE endoscopic screening/surveillance programs, esophageal cancers are not being increasingly diagnosed at earlier stages. Discussion: BE screening and surveillance programs have not led to increased detection rates of early-stage esophageal cancer nor decreased rates of late-stage cancer, despite improved overall survival in all stages of esophageal cancer. These findings suggest that improved survival in esophageal cancer is due to improved local and systemic therapy, and not due to Barrett's esophagus screening and surveillance programs.
Figure 1. Esophageal cancer incidence stratified by cancer staging and BE screening/surveillance time periods.
Su1049 MUTATION STATUS OF BARRETT'S ESOPHAGUS BIOPSIES INDEFINITE FOR DYSPLASIA CORRELATES WITH OUTCOMES Stephen M. Lagana, Elena Komissarova, Sarawut Kongkarnka, Jorge L. Sepulveda, Antonia R. Sepulveda Background: Intestinal metaplasia of the esophagus (Barrett's intestinal metaplasia, BIM) is thought to progress to adenocarcinoma (EAC) through a step-wise process of dysplasia (DYS). Some cases are classified as indefinite for dysplasia (BIM-I) because of overlapping histology between reactive atypia (RA) and dysplasia, necessitating a shorter follow-up interval. In other cases, dysplasia is suspected, but unequivocal diagnostic features cannot be identified by histology. We hypothesized that mutation detection in genes involved in esophageal carcinogenesis by next-generation sequencing (NGS) may help categorize BIMI cases as RA vs. DYS. Methods: We tested endoscopic biopsy samples in 15 BIM-I cases, consisting of 9 BIM-I patients with no progression to subsequent dysplasia with an average follow up of 55 months (range 11-96), (BIM-I-NP, presumably RA) and 6 with concurrent high-grade DYS or EAC in other biopsies (BIM-I-C). Median age of BIM-I-NP, BIM-I-C, and BIM-NP patients was 73, 64, and 65 years, respectively. The diagnosis was confirmed by 2 gastrointestinal pathologists. 30 cases of never dysplastic BIM (BIM-NP) followed for at least 2 years were used as controls. Formalin-fixed paraffin-embedded (FFPE) biopsy tissues were used for DNA extraction. Next generation sequencing (NGS) was performed with the TruSeq cancer panel (Illumina) to interrogate mutational hotspots within 48 cancer genes. Sequencing data were analyzed with NextGENe software (SoftGenetics) and with a pipeline using the Integrative Genomics Viewer platform. Results: Recurrent mutations in TP53 and CDKN2A were detected in BIM samples. Mutations in TP53 or CDKN2A were not detected in any of the 9 BIM-I-NP whereas 3 of 6 cases (50%) of BIM-I-C showed mutations in TP53 and/or CDKN2A (p=.044). Only 2 of 30 (6.6%) control cases of BIM-NP showed TP53 or CDKN2A mutations (p=.024 vs. BIM-I-C). Conclusions: TP53 / CDKN2A mutations may be detected in Barrett's intestinal metaplasia indefinite for dysplasia. Biopsies with a diagnosis of indefinite for dysplasia and negative TP53/CDKN2A mutation status show outcomes similar to patients with Barrett's IM who never developed DYS/EAC. In contrast, the presence of TP53/CDKN2A mutation in a biopsy diagnosed as indefinite for dysplasia raises concern for a high-risk lesion and the possibility of endoscopically missed HGD/EAC, warranting closer surveillance. The results suggest that NGS mutational testing may be a useful ancillary test in risk stratification of BE patients found to have IND on endoscopy.
Number of EGDs needed to evaluate uncomplicated GERD per finding of suspected Barrett's esophagus with length >2cm (sLSBE)
Su1048 BARRETT'S ESOPHAGUS SCREENING AND SURVEILLANCE IS NOT RESPONSIBLE FOR IMPROVED OUTCOMES IN ESOPHAGEAL CANCER Kartik Sampath, Stuart R. Gordon, Timothy B. Gardner Background: Esophageal adenocarcinoma (EA) is the most common esophageal cancer subtype in the United States and Barrett's esophagus (BE) is the premalignant condition to EA. Current guidelines recommend screening select patient populations for BE, with subsequent
AGA Abstracts
S-454