Source: Dr_Microbe/Getty Images
Source: Dr_Microbe/Getty Images

A scientist at Johns Hopkins has published a paper (“Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett’s Esophagus: A Prospective Validation Study”) in Clinical Cancer Research that he says could finally result in simple and inexpensive screening for esophageal cancer.

“Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for BE diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a BE detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB). We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We employed MOB to extract and bisulfite-convert DNA, followed by qMSP to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set. In the training set, 5 of 8 candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in BE patients than in controls,” wrote the investigators.

“We built a 4-biomarker-plus-age lasso regression model for BE diagnosis. The AUC was 0.894, with sensitivity 94.4% (95% CI 71%~99%) and specificity 62.2% (95% CI 44.6%~77.3%) in the training set. This model also performed with high accuracy for BE diagnosis in an independent test set: AUC= 0.929 (P<0.001, 95% CI 0.810~1), with sensitivity = 78.6% (95% CI 48.8%~94.3%) and specificity = 92.8% (95% CI 64.1%~99.6%). EsophaCap, in combination with an epigenetic biomarker panel and the MOB method, is a promising, well-tolerated, low-cost esophageal sampling strategy for BE diagnosis. This approach merits further prospective studies in larger populations.”

Stephen Meltzer, MD, a professor of medicine and oncology at the Johns Hopkins University School of Medicine, along with a team of researchers, clinicians, and biomedical engineers described the EsophaCap test that uses specific genetic biomarkers to detect dangerous changes in the cells that line the inside of the esophagus.

Previous studies have demonstrated Meltzer’s biomarkers’ ability to detect Barrett’s esophagus, which causes the body to replace the tissue that lines the organ with cells that can turn cancerous. But large-scale methods to deploy those biomarkers as a screening tool have been elusive until now, according to the researchers.

The principle behind the EsophaCap is simple, said Meltzer. The patient swallows a small capsule that has a long string attached to it. After the capsule makes its way down the esophagus and into the stomach, a process that reportedly takes a minute or so, the gelatin coating on the capsule begins to dissolve.

From that capsule emerges a 2-cm polyurethane sponge, still attached to the string, much of which still hangs from the patient’s mouth. The screener gently pulls the string and the sponge begins its journey, out of the stomach, into the esophagus and, finally, out of the patient’s mouth.

As it makes its way up, the sponge comes into contact with the entire length and breadth of the esophagus, collecting genetic material all along the way. Then, as the sponge nears the top, the screener gives a final gentle tug, popping the sponge past the organ’s upper sphincter muscle. The sponge emerges loaded with genetic material that holds the key to the patient’s esophageal health.

The sponge is then sent to a company that performs genetic tests on the material to determine the patient’s risk for esophageal cancer.

“Early detection is the whole ballgame when it comes to esophageal cancer,” Meltzer said. “Patients have a much better chance to treat it, or even prevent it, if they know their risk. We believe this little sponge can bring easy and inexpensive screening to people around the world.”

With nearly half a million new cases a year, esophageal cancer is the eighth most-common cancer worldwide, with the highest rates in parts of Africa and Asia.

In 2016, the United States saw nearly 17,000 new cases diagnosed and about 16,000 deaths from cancer of the esophagus. Those numbers have increased sharply in recent years. The five-year survival rate for people with cancer confined to the esophagus is 43%. When it spreads to nearby tissues or organs, that rate falls to 23%. And esophageal cancer that spreads to distant parts of the body offers a five-year survival rate of only 5%.

In previous research, Meltzer has performed testing on the set of genetic biomarkers he uses to diagnose Barrett’s esophagus. The gene combination of p16, NELL1, AKAP12, and TAC1 has yielded a sensitivity of nearly 92% and has offered reliable diagnoses, he explained, noting that medicine has never had routine screening methods for the disease. Both endoscopy and biopsy are less-than-ideal, since they’re inexact, expensive, and rely on random tissue samples, rather than material from the whole esophagus lining, continued Meltzer.

“It’s actually possible to miss early cancerous cells using endoscopy with biopsy and most patients with Barrett’s don’t ever undergo endoscopy,” said Meltzer. “Right now, we’re confident that we have the tools to identify this type of cancer. But we previously lacked a way to collect enough genetic material to confidently determine a patient’s diagnosis. We believe that EsophaCap now provides a solution to this serious problem.”

Meltzer administered the EsophaCap test to 94 people over the course of the study. Eighty-five percent of subjects were able to swallow the capsule, with 100% successful sponge retrieval. Endoscopic evaluation of the patients after EsophaCap administration, Meltzer reported, showed no evidence of bleeding, pain, trauma, or other adverse reactions to the test.

In the journal article, Meltzer reported that of the patients able to swallow the capsule, nearly half would be diagnosed with Barrett’s esophagus, a rate far higher than that of the general U.S. population. He notes that most patients enrolled in the study were being treated for gastrointestinal symptoms. “That may explain why we saw a rate of Barrett’s esophagus that was higher than in the general population,” he said.

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