Gastroenterology society guidelines recommend endoscopic surveillance as a means to detect early stage cancer in Barrett’s esophagus. However, the incidence of esophageal adenocarcinoma in Western countries continues to increase, suggesting that this strategy may be inadequate. Current surveillance methods rely on the endoscopist’s ability to identify suspicious areas of Barrett’s esophagus to biopsy, random biopsies, and on the histopathologic diagnosis of dysplasia. This review highlights the challenges of using dysplasia to stratify cancer risk and addresses the development and use of molecular biomarkers and in vivo molecular imaging to detect early neoplasia in Barrett’s esophagus.
Key points
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Gastroenterology society guidelines recommend endoscopic surveillance of Barrett’s esophagus using high-definition white-light endoscopy with 4-quadrant random biopsies to detect dysplasia and early cancers.
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The presence of dysplasia is the current gold standard biomarker for cancer risk in Barrett’s esophagus.
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Precision medicine and new biomarker development techniques have the potential to improve cancer risk assessment and response to treatment of patients with Barrett’s esophagus by identifying specific subtypes based on biomarker expression.
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Immunostaining for p53 is recommended by the British Society of Gastroenterology as an adjunct to histologic assessment of dysplasia in patients with Barrett’s esophagus.
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Early proof-of-principal studies demonstrate the promise of fluorescent-tagged molecular biomarkers to enhance the sensitivity and specificity of neoplasia detection during in vivo imaging for patients with Barrett’s esophagus.
Introduction
Barrett’s esophagus is an extremely common condition occurring in approximately 5.6% of adult Americans. The risk of esophageal adenocarcinoma for the general population of patients with nondysplastic Barrett’s esophagus is low, between 0.12% and 0.33% per year. For patients with high-grade dysplasia, the risk of esophageal adenocarcinoma is approximately 6% per year, whereas those patients with low-grade dysplasia (LGD) have a cancer incidence rate that lies between that of nondysplastic Barrett’s esophagus and high-grade dysplasia (HGD). Gastrointestinal society guidelines recommend endoscopic surveillance using high-definition white-light endoscopy with 4-quadrant random biopsies obtained every 1 to 2 cm, as a means to detect dysplasia and early cancers in Barrett’s esophagus. However, this strategy has limited effectiveness, as rates of esophageal adenocarcinoma have continued to increase. Among the challenges associated with our current cancer preventive strategy are the endoscopist’s ability to identify suspicious areas in the entire field of Barrett’s mucosa for targeted biopsies and the reliance on the histopathologic diagnosis of dysplasia. To overcome these challenges, new endoscopic imaging techniques are being explored that highlight neoplastic tissue. Some of the new techniques use fluorescent-tagged molecular biomarkers that bind to abnormal tissue and then are visualized during the imaging process. The combination of new imaging techniques and fluorescein-tagged molecular probes has been termed in vivo molecular imaging , an emerging technology that has garnered intense interest both for clinicians and scientists.
The following sections highlight the limitations of using dysplasia to stratify cancer risk for patients with Barrett’s esophagus, concepts regarding the development and use of biomarkers ex vivo and in vivo, and proof-of-principle studies demonstrating the potential of in vivo imaging using molecular biomarkers to detect early neoplasia in Barrett’s esophagus. This review focuses on current concepts supported by recently published key studies.
Introduction
Barrett’s esophagus is an extremely common condition occurring in approximately 5.6% of adult Americans. The risk of esophageal adenocarcinoma for the general population of patients with nondysplastic Barrett’s esophagus is low, between 0.12% and 0.33% per year. For patients with high-grade dysplasia, the risk of esophageal adenocarcinoma is approximately 6% per year, whereas those patients with low-grade dysplasia (LGD) have a cancer incidence rate that lies between that of nondysplastic Barrett’s esophagus and high-grade dysplasia (HGD). Gastrointestinal society guidelines recommend endoscopic surveillance using high-definition white-light endoscopy with 4-quadrant random biopsies obtained every 1 to 2 cm, as a means to detect dysplasia and early cancers in Barrett’s esophagus. However, this strategy has limited effectiveness, as rates of esophageal adenocarcinoma have continued to increase. Among the challenges associated with our current cancer preventive strategy are the endoscopist’s ability to identify suspicious areas in the entire field of Barrett’s mucosa for targeted biopsies and the reliance on the histopathologic diagnosis of dysplasia. To overcome these challenges, new endoscopic imaging techniques are being explored that highlight neoplastic tissue. Some of the new techniques use fluorescent-tagged molecular biomarkers that bind to abnormal tissue and then are visualized during the imaging process. The combination of new imaging techniques and fluorescein-tagged molecular probes has been termed in vivo molecular imaging , an emerging technology that has garnered intense interest both for clinicians and scientists.
The following sections highlight the limitations of using dysplasia to stratify cancer risk for patients with Barrett’s esophagus, concepts regarding the development and use of biomarkers ex vivo and in vivo, and proof-of-principle studies demonstrating the potential of in vivo imaging using molecular biomarkers to detect early neoplasia in Barrett’s esophagus. This review focuses on current concepts supported by recently published key studies.
Limitations with using dysplasia to stratify cancer risk in Barrett’s esophagus
Histologic analysis of biopsies to identify dysplasia is the current gold standard for assessing cancer risk in patients with Barrett’s esophagus. However, there are several limitations when relying on the grading of dysplasia to risk stratify patients with Barrett’s esophagus. Four-quadrant random biopsies may not detect areas of dysplasia, leading to sampling error and missed cases of dysplasia. Assuming adequate biopsies are taken, technical or processing artifact of the tissue can hinder accurate determine of dysplasia. Histologic interpretation of biopsies is more challenging when active inflammation and ulceration are present, which is not uncommon in patients with Barrett’s esophagus. Inflammation induces regenerative changes in the Barrett’s epithelium, and these regenerative changes can mimic dysplasia. This mimicry can lead to diagnostic uncertainty and may result in a biopsy specimen labeled indefinite for dysplasia, leading to the need for repeat endoscopy with biopsies. This issue of inflammation mimicking dysplasia is the rationale underlying the recommendation in the American College of Gastroenterology’s (ACG) guidelines, which advise against taking biopsies in areas of erosive esophagitis until after intensive antisecretory therapy has healed any mucosal injury.
Even without the presence of inflammation, histologic interpretation of dysplasia is challenging. There are no scientifically validated morphologic features to distinguish LGD from HGD, leading to variations in interpretation between pathologists. In addition to the difficulties in distinguishing low-grade from high-grade dysplasia, there is also a substantial disagreement among pathologists when distinguishing HGD from intramucosal cancer. To compound the problem, there is a high degree of interobserver and intraobserver variability in the diagnosis and grading of dysplasia in Barrett’s esophagus, which has been seen in multiple studies. In studies in which expert gastrointestinal pathologists reviewed histopathology slides from cases of nondysplastic and dysplastic (both LGD and HGD) Barrett’s esophagus, the interobserver agreement for nondysplastic Barrett’s esophagus was fair to moderate, with a kappa statistic (K) of 0.2 to 0.58, higher for HGD/carcinoma (K = 0.43–0.65) and lower for LGD (K = 0.11–0.4). These findings among expert gastrointestinal pathologists with a research interest in Barrett’s esophagus emphasize the limitations of using dysplasia to stratify the risk of cancer in patients with Barrett’s esophagus. As dysplasia is an imperfect measure of cancer risk, new techniques are needed to improve the identification of patients who may progress from nondysplastic Barrett’s esophagus to cancer.
Biomarker development: cancer hallmarks
Biomarkers have been used in multiple diseases to assess risk of cancer, predict response to treatment, and estimate prognosis. Many of these biomarkers are derived from cellular and tissue features specific to cancer. In 2000, Hanahan and Weinberg proposed the concept that genetic alterations of different molecular pathways alter normal cellular physiologic function, allowing cells to acquire essential cancer hallmarks that enable them to transform into malignant cells ( Fig. 1 ). These essential cancer hallmarks are core physiologic attributes allowing cells to proliferate without exogenous stimulation, resist growth-inhibitory signals, avoid apoptosis, resist cell senescence, develop new vascular supplies (angiogenesis), and invade and metastasize. In 2011, the same investigators proposed 2 additional requisite physiologic hallmarks: cancer cells must reprogram their energy metabolism to support their malignant proliferation and cancer cells must evade destruction by immune cells, including T and B lymphocytes, macrophages, and natural killer cells (see Fig. 1 ). Finally, the acquisition of these cancer attributes is accelerated by 2 enabling features, including genome instability and mutation, which facilitates the genetic alterations essential for tumorigenesis, and tumor-promoting inflammation, which supports the capabilities endowed by the core hallmarks. Many of these cancer hallmarks have been developed into biomarkers for different diseases. This circumstance is also a factor in Barrett’s esophagus, as some of these cancer hallmarks are present in metaplastic Barrett’s cells even before they exhibit the histologic features of dysplasia. In the future, molecular biomarkers may become better predictors of neoplastic progression than dysplasia.
Biomarker development for Barrett’s esophagus in the precision medicine era
The US Precision Medicine Initiative, announced by President Barack Obama during the 2015 State of the Union Address, aspires to improve health by collecting clinical and biomarker data from patients with the same disease and then integrating these findings to reclassify the disease into subtypes ( Fig. 2 ). The goal of the precision medicine approach is the development of better biomarkers for disease; however, the magnitude of data collected and the speed of analysis have been substantially accelerated by this initiative. The idea is to determine which pieces of data from the large quantity of collected data (ie, histology, RNA, protein, and so forth) are the best predictors of disease risk, treatment response, and/or prognosis, and quickly move these data forward into the biomarker development pipeline.
Classification of tumor subtypes is already underway, with the discovery of mutations and targeted therapies that impact treatment of certain tumor subtypes. For example, colorectal cancers with mutant Ras respond to different chemotherapy than colorectal cancers negative for the Ras mutation. Categorization of breast cancers has led to targeted chemotherapy, as tumors with the human epidermal growth factor receptor 2 (HER2) mutation respond to specific chemotherapy targeted to the mutation, whereas other breast cancers do not.
Incredible technological advances have now accelerated biomarker discovery and development. DNA, RNA, proteins, cell metabolites, microbial products, and host cell products are being measured by omics techniques, such as genomics and metabolomics. The profiles derived from these omics techniques can then be used to identify viable biomarkers. Specifically, over the last 10 years, The Cancer Genome Atlas collaborative initiative has performed omic profiling of advanced stage tumors using multiple platforms, such as DNA sequencing for mutations and RNA sequencing for micro-RNA expression, to gain insight into the molecular alterations associated with cancer. This effort has uncovered several hundred genes that are potential drivers of cancer formation. In addition, performance of multiple omics arrays has allowed recategorization of several tumor types. For example, low-grade gliomas are traditionally classified based on histology; but this classification suffers from large intraobserver and interobserver variability and does not adequately predict clinical outcomes. By combining data from multiple omics profiles from low-grade gliomas, a new classification was developed, composed of 3 molecular subtypes strongly associated with overall survival, outperforming histologic classification for prediction of survival. Similar to the study of gliomas, the histologic classification in Barrett’s esophagus suffers from the same issues, as histologic classification does not always accurately predict clinical outcomes. Using the precision medicine approach to categorize molecular subtypes of Barrett’s esophagus holds promise for the future of biomarker development (see Fig. 2 ).
Using a precision medicine-type approach, Stachler and colleagues performed whole-exome sequencing on DNA extracted from esophageal adenocarcinoma and Barrett’s esophagus from the same patient. Using complex bioinformatics analyses, they found that most esophageal adenocarcinomas harbored a p53 mutation and that the same p53 mutation could be detected in the nondysplastic Barrett’s metaplasia of patients who progressed to cancer. Interestingly, this study found 2 general pathways for neoplastic transformation in Barrett’s esophagus ( Fig. 3 ). They found a minority of tumors progressed along the traditional pathway of carcinogenesis, involving the stepwise accumulation of alterations in the p53 and p16 tumor suppressor genes, followed by oncogene activation, and then development of genomic instability. In contrast, most tumors in the study developed through a different pathway, called the genome-doubled pathway. In this pathway, the cell first acquired a p53 mutation that gave that cell a growth advantage and allowed it to expand throughout the mucosa. These p53-mutant cells then underwent whole-genome doubling, an alteration that was primarily detected in areas of dysplasia. Whole-genome doubling was then followed by genomic instability and oncogene amplification, resulting in malignancy. The investigators proposed that the genome-doubled pathway may be a more rapid pathway to cancer development in Barrett’s esophagus and may possibly explain the failure of endoscopic surveillance strategies to stem the increasing incidence of esophageal adenocarcinoma. Using the precision medicine approach, perhaps Barrett’s esophagus could be stratified into molecular subtypes, based on p53 immunostaining with or without whole-genome doubling. This stratification could potentially improve our ability to risk stratify neoplastic progression and guide treatment decisions for patients with Barrett’s esophagus (see Fig. 2 ).
Related posts:
New Directions in Barrett’s Esophagus
The Troublesome Epidemiology of Barrett’s Esophagus and Esophageal Adenocarcinoma
Who Deserves Endoscopic Screening for Esophageal Neoplasia?
Radiofrequency Ablation of Barrett’s Esophagus
The Role of Endoscopic Ultrasound in the Management of Patients with Barrett’s Esophagus and Superficial Neoplasia
Radiofrequency Ablation of Barrett’s Esophagus
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