Will Spatial Genomics Help Identify Barrett’s Esophagus Patients at High Risk of Esophageal Cancer?

A Keck Medicine of USC expert explains how next-generation genetic analysis could help stratify patients’ cancer risk — and guide treatment decisions.

Barrett’s esophagus is a precancerous change in the esophagus caused by acid reflux that can eventually lead to esophageal cancer. Not everyone who develops Barrett’s esophagus will progress to esophageal cancer, but determining which patients are at high risk is critical to determining the best treatment course.

How do genetics increase the risk of developing Barrett’s esophagus or esophageal cancer? As Lipham explains, “There’s definitely a genetic link, not only to what causes acid reflux but to what puts patients at risk for developing Barrett’s esophagus or esophageal cancer.”

In short: Acid reflux is a mechanical problem caused by a weak lower esophageal sphincter (LES) that fails to prevent acid from the stomach from entering the esophagus. Genetics can predispose a person to having a weak LES. For these individuals, continued acid reflux can turn dangerous. In the long term, acid, bile and digestive enzymes from the stomach can damage the inside of the esophagus, causing ulcerations, bleeding or a stricture.

“This damage can lead to precancerous changes in the esophagus in about 15% of people,” Lipham says. “That precancerous change is called Barrett’s esophagus. It’s when the inside of the esophagus changes to a different type of lining that has a much higher risk of developing esophageal cancer. So, ultimately, reflux can lead to esophageal cancer.”

And while it’s true that lifestyle choices, such as the food one eats, can worsen acid reflux, genetics can’t be overcome. “As the weak LES worsens due to the underlying genetic or connective tissue disorder, we get to a point when it doesn’t even matter what someone eats or does,” Lipham says. “The LES becomes a wide-open door, and everything comes up no matter what you eat.”

Treating Barrett’s esophagus

Once a patient is diagnosed with Barrett’s esophagus, doctors must determine what treatment course to take. In general, there are two options.

One is to manage Barrett’s esophagus through medication that addresses reflux — such as proton pump inhibitors — and to conduct regular endoscopy checkups to monitor any dysplasia progression.

“Many patients can go their whole life with reflux and not develop esophageal cancer,” Lipham says. “Only a small percentage of people with Barrett’s esophagus will progress to cancer. If we know a patient’s risk level is low based on their genetic profile, we may opt to manage them with a proton pump inhibitor instead of performing surgery.”

The other option is to endoscopically ablate the part of the esophagus afflicted with Barret’s esophagus, such as with radiofrequency ablation or cryoablation, with the hope of lowering the risk of developing cancer. “Patients in the intermediate- or high-risk category are the ones we’re going to be more aggressive with treating by recommending ablation,” Lipham says.

The challenge, however, is determining whether a Barrett’s esophagus patient is at low, medium or high risk. This is where a newer type of genetic profiling, called spatial genomics, could help.

Spatial genomics: a new frontier in genomic testing

Spatial genomics is an emerging field of genetic profiling that evaluates cellular behavior based on the location of cells. It considers where cells are positioned within tissue relative to other cells, and through this context it studies how cells interact and behave.

In the case of Barrett’s esophagus, “spatial omics” companies are developing spatial genomics technologies to analyze biopsies of esophageal tissue to identify molecular changes that precede dysplasia, helping to identify Barrett’s esophagus cases that are more likely to progress to cancer. New testing technologies from spatial omics companies are making it possible to study and analyze cells in their natural architecture in intact tissue.

Spatial omics in practice

The enhanced ability to stratify patient risk enables a more personalized approach to care, Lipham says: “Ultimately, the genetic profile will help us to decide which treatment will work best for a patient to help prevent cancer.”

He continues: “To me it’s been a game changer in how we treat not just reflux patients but, more importantly, the Barrett’s patients. Before, we treated them all the same. If you had Barrett’s esophagus, we would just monitor you very closely, meaning you had to have an endoscopy every one to three years. But now, with our ability to stratify patients’ risk, we can tell a patient, ‘You’re at low risk. You probably don’t need to come back for another endoscopy for five years, if not more.’ And if it’s a high-risk patient, we can move to ablation and/or surgery.”

Lipham has already seen the benefits in action. In one instance, he and his colleagues were diagnosing a patient who had developed a small area of Barrett’s esophagus. A biopsy sent to a standard pathology lab classified the patient as non-dysplastic and low risk. Lipham and his colleagues, however, had also sent a biopsy to a spatial omics testing lab. The spatial omics technology deemed the patient very high risk, with a 25% risk of progressing to cancer.

Based on the spatial omics results, Lipham says, “We elected to do additional endoscopy and biopsies to make sure we weren’t missing anything. Indeed, in those additional biopsies, we ended up fing an early cancer that we couldn’t see with the naked eye. Luckily, it was caught early enough that we were able to treat the patient endoscopically, ablating the Barrett’s area away so that they didn’t have to undergo a major surgery like esophagectomy for cancer.”

Lipham predicts that spatial omics will become the standard of care for Barrett’s esophagus patients. “This has been the biggest game changer I’ve seen so far in terms of diagnostics and trying to decrease esophageal cancer mortality or development. Not only does it help us identify the patients who are at risk of developing cancer, the patients who need intervention sooner than later, but it also identifies the patients who are at low risk who don’t need more drastic intervention. It allows us to deescalate their care so they can just be treated with antacids and less-frequent checkups,” he says.

He adds, “When presented with a patient with bad reflux, Barrett’s esophagus or even early esophageal cancer, it’s important to send the patient to a place like the USC Digestive Health Institute which specializes in treatment, where we not only have a deep understanding of these conditions but also have access to some of these newer diagnostic tests and treatment options.”

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