Swallowable test developed for Barrett’s esophagus

Sanford Markowitz

An encapsulated balloon device combined with methylated DNA biomarkers demonstrated sensitivity and specificity higher than 90% for the detection of Barrett’s esophagus, a precursor to esophageal cancer.

Sanford Markowitz, MD, PhD, Markowitz-Ingalls professor of cancer genetics at Case Western Reserve University School of Medicine and co-leader of the cancer genetics program at Case Comprehensive Cancer Center, and colleagues performed genome-wide screening and identified high-frequency DNA methylation within the CCNA1 and VIM loci.

They first tested DNA methylation as a Barrett’s esophagus biomarker in cytology brushings of a study population of 173 individuals with or without Barrett’s esophagus. Investigators observed an area under the curve of 0.95 for distinguishing metaplasia and neoplasia in the patient population compared with healthy controls.

Results indicated a 95% sensitivity and a 91% specificity for the biomarker panel, with identical findings in a validation cohort of another 149 individuals. Moreover, the biomarkers performed nearly identically in 86 additional individuals who had nonendoscopic esophageal sampling with the swallowable balloon, with researchers reporting a 90.3% sensitivity and a 91.7% specificity.

HemOnc Today spoke with Markowitz about the encapsulated balloon approach and its potential benefits.

 

Question: Can you describe the need for new improved detection strategies?

Answer: Esophageal adenocarcinoma is the fastest growing cause of deaths from solid tumors among adult Americans and accounts for more deaths than ovarian cancer. It is highly aggressive, with patients having less than a 20% chance of survival 5 years after diagnosis. The best chance of reducing deaths is to detect individuals who harbor Barrett’s esophagus, which is the precursor lesion of esophageal adenocarcinoma and can be easily treated when progression or dysplasia are detected. The challenge is that Barrett’s esophagus is frequently silent, and the only way to detect it has been by endoscopy. The procedure is expensive and requires sedation, as well as a day off from work. The result is that most cases of Barrett’s esophagus remain undetected, and 95% of esophageal adenocarcinomas are diagnosed among individuals unaware that they harbored Barrett’s esophagus.

 

Question: How did the swallowable balloon approach come about?

A: Our group has had a long commitment to finding a better approach. We had pioneered methylated vimentin exon 1 as a DNA biomarker for detecting GI cancers, starting with colon cancer. This concept became the ColoSure stool DNA test (Exact Sciences), which was the forerunner of the Cologuard test (Exact Sciences) for detection of colon cancer. In 2012, we published our finding that methylated vimentin DNA is an even more sensitive and specific biomarker for the detection of Barrett’s esophagus and esophageal adenocarcinoma than for colon cancers. However, we needed a way to dispense with the endoscope, and we wanted the molecular test to be even better.

The impetus for this project was to develop a biomarker panel, which turned out to be methylated vimentin plus methylated CCNA1 DNAs, and to invent a simple, patient-friendly sampling device — the encapsulated balloon — that could replace the need for endoscopy.

The primary driver is that endoscopic screening is not being implemented for Barrett’s esophagus. The combination of cost and inconvenience results in reluctance of individuals and their physicians to undertake endoscopy even when an individual has gastroesophageal reflux disease (GERD), which is a major risk factor for Barrett’s esophagus. This is particularly the case if the GERD is controlled by proton pump inhibitors or other over-the-counter medications.

 

Q: Can you describe the effectiveness of this approach ?

A: The combination of a DNA biomarker panel and a swallowable balloon for sampling the esophagus creates a simple, 5-minute test with more than 90% accuracy — better than 90% sensitivity and 90% specificity — for identifying individuals who do or do not have Barrett’s esophagus. Screening for Barrett’s esophagus, and identifying individuals who are silent carriers, has the potential to prevent the development of and deaths from esophageal adenocarcinoma.

 

Q: How does the balloon device improve detection?

A: The biomarker panel of methylated DNAs from the VIM and CCNA1 genomic loci is an advance over our previous finding of methylated vimentin alone as a Barrett’s esophagus biomarker. The balloon concept builds on work of earlier investigators by improving the sampling characteristics of the balloon surface and, most importantly, by protecting the balloon inside a pill-shaped capsule, both before it is expanded and after it is retracted.

The protection means that the balloon can target only the region of the esophagus near the stomach where Barrett’s esophagus characteristically arises. This protects the DNA sample from dilution and contamination during the process of retrieving the balloon through the upper esophagus, throat and mouth, improving both sensitivity and specificity of the test. Shrinking the balloon back down also makes it more comfortable for the patient. These features are advantages of balloon-based devices as compared with sponge-based devices — which are also being tested in clinical trials — for sampling the esophagus.

 

Q: Are there any safety concerns?

A: No. The FDA has determined the balloon device is “non-significant risk.”

 

Q: What is the next step?

A: We hope that this technology will be practice-changing. We expect the next key step is to demonstrate the effectiveness of the technology compared with endoscopy in a population of individuals with GERD who have never received screening for Barrett’s esophagus. We expect to launch a national multicenter clinical trial in the second quarter of 2018 with support from the NCI BETRNet, SPORE, EDRN, and UH2/UH3 programs. – by Rob Volansky

 

Reference:

Moinova HR, et al. Sci Transl Med. 2018;doi:10.1126/scitranslmed.aao5848.

 

For more information:

Sanford Markowitz, MD, PhD, can be reached at Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106; email: axg844@case.edu.

 

Disclosure: Markowitz reports no relevant financial disclosures.

Sanford Markowitz

An encapsulated balloon device combined with methylated DNA biomarkers demonstrated sensitivity and specificity higher than 90% for the detection of Barrett’s esophagus, a precursor to esophageal cancer.

Sanford Markowitz, MD, PhD, Markowitz-Ingalls professor of cancer genetics at Case Western Reserve University School of Medicine and co-leader of the cancer genetics program at Case Comprehensive Cancer Center, and colleagues performed genome-wide screening and identified high-frequency DNA methylation within the CCNA1 and VIM loci.

They first tested DNA methylation as a Barrett’s esophagus biomarker in cytology brushings of a study population of 173 individuals with or without Barrett’s esophagus. Investigators observed an area under the curve of 0.95 for distinguishing metaplasia and neoplasia in the patient population compared with healthy controls.

Results indicated a 95% sensitivity and a 91% specificity for the biomarker panel, with identical findings in a validation cohort of another 149 individuals. Moreover, the biomarkers performed nearly identically in 86 additional individuals who had nonendoscopic esophageal sampling with the swallowable balloon, with researchers reporting a 90.3% sensitivity and a 91.7% specificity.

HemOnc Today spoke with Markowitz about the encapsulated balloon approach and its potential benefits.

 

Question: Can you describe the need for new improved detection strategies?

Answer: Esophageal adenocarcinoma is the fastest growing cause of deaths from solid tumors among adult Americans and accounts for more deaths than ovarian cancer. It is highly aggressive, with patients having less than a 20% chance of survival 5 years after diagnosis. The best chance of reducing deaths is to detect individuals who harbor Barrett’s esophagus, which is the precursor lesion of esophageal adenocarcinoma and can be easily treated when progression or dysplasia are detected. The challenge is that Barrett’s esophagus is frequently silent, and the only way to detect it has been by endoscopy. The procedure is expensive and requires sedation, as well as a day off from work. The result is that most cases of Barrett’s esophagus remain undetected, and 95% of esophageal adenocarcinomas are diagnosed among individuals unaware that they harbored Barrett’s esophagus.

 

Question: How did the swallowable balloon approach come about?

A: Our group has had a long commitment to finding a better approach. We had pioneered methylated vimentin exon 1 as a DNA biomarker for detecting GI cancers, starting with colon cancer. This concept became the ColoSure stool DNA test (Exact Sciences), which was the forerunner of the Cologuard test (Exact Sciences) for detection of colon cancer. In 2012, we published our finding that methylated vimentin DNA is an even more sensitive and specific biomarker for the detection of Barrett’s esophagus and esophageal adenocarcinoma than for colon cancers. However, we needed a way to dispense with the endoscope, and we wanted the molecular test to be even better.

The impetus for this project was to develop a biomarker panel, which turned out to be methylated vimentin plus methylated CCNA1 DNAs, and to invent a simple, patient-friendly sampling device — the encapsulated balloon — that could replace the need for endoscopy.

The primary driver is that endoscopic screening is not being implemented for Barrett’s esophagus. The combination of cost and inconvenience results in reluctance of individuals and their physicians to undertake endoscopy even when an individual has gastroesophageal reflux disease (GERD), which is a major risk factor for Barrett’s esophagus. This is particularly the case if the GERD is controlled by proton pump inhibitors or other over-the-counter medications.

 

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Q: Can you describe the effectiveness of this approach ?

A: The combination of a DNA biomarker panel and a swallowable balloon for sampling the esophagus creates a simple, 5-minute test with more than 90% accuracy — better than 90% sensitivity and 90% specificity — for identifying individuals who do or do not have Barrett’s esophagus. Screening for Barrett’s esophagus, and identifying individuals who are silent carriers, has the potential to prevent the development of and deaths from esophageal adenocarcinoma.

 

Q: How does the balloon device improve detection?

A: The biomarker panel of methylated DNAs from the VIM and CCNA1 genomic loci is an advance over our previous finding of methylated vimentin alone as a Barrett’s esophagus biomarker. The balloon concept builds on work of earlier investigators by improving the sampling characteristics of the balloon surface and, most importantly, by protecting the balloon inside a pill-shaped capsule, both before it is expanded and after it is retracted.

The protection means that the balloon can target only the region of the esophagus near the stomach where Barrett’s esophagus characteristically arises. This protects the DNA sample from dilution and contamination during the process of retrieving the balloon through the upper esophagus, throat and mouth, improving both sensitivity and specificity of the test. Shrinking the balloon back down also makes it more comfortable for the patient. These features are advantages of balloon-based devices as compared with sponge-based devices — which are also being tested in clinical trials — for sampling the esophagus.

 

Q: Are there any safety concerns?

A: No. The FDA has determined the balloon device is “non-significant risk.”

 

Q: What is the next step?

A: We hope that this technology will be practice-changing. We expect the next key step is to demonstrate the effectiveness of the technology compared with endoscopy in a population of individuals with GERD who have never received screening for Barrett’s esophagus. We expect to launch a national multicenter clinical trial in the second quarter of 2018 with support from the NCI BETRNet, SPORE, EDRN, and UH2/UH3 programs. – by Rob Volansky

 

Reference:

Moinova HR, et al. Sci Transl Med. 2018;doi:10.1126/scitranslmed.aao5848.

 

For more information:

Sanford Markowitz, MD, PhD, can be reached at Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106; email: axg844@case.edu.

 

Disclosure: Markowitz reports no relevant financial disclosures.