Microbes in the digestive tract help tailor treatment for melanoma patients

The specific mix of bacteria living in a person's gut can predict the chances that melanoma will recur after surgery and immunotherapy, which helps immune cells target cancer cells. This is according to a new study led by researchers from NYU Langone Health and its Perlmutter Cancer Center.

Past studies showed that 25 % to 40 % of melanoma patients see their cancer return despite these two standard approaches, but predicting which patients will see cancer return has been a challenge.

Publishing online April 17 in the journal Cell, the study in 674 patients enrolled a global clinical trial revealed that differences in the amount of key bacterial groups (taxa) in in the gut predicted cancer recurrence with up to 94% accuracy when patients were analyzed in a new way. The taxa associated most with changes in recurrence risk were Eubacterium, Ruminococcus, Firmicutes, and Clostridium.

"Our study identified for the first time gut bacterial types that can serve as markers of increased recurrence risk in these specific patients, which will help to tailor treatment," said study senior author Jiyoung Ahn, PhD, a professor in the Department of Population Health at NYU Grossman School of Medicine, and associate director of Population Research at NYU Langone's Perlmutter Cancer Center.

The current results revolve around the gut microbiome, the community of trillions of bacteria that live in the human digestive tract. There they train the immune system to tell apart dangerous bacteria, which should be attacked, from bacteria that help humans to digest food, which should be tolerated. Past studies have found that the study taxa interact with immune cells (e.g., natural killer cells, T cells) in ways that change a patient's response to immunotherapies. Such bacteria may also affect the sugar supply that serves as fuel for cancer cell growth.

Geography matters

The new study analyzed the gut bacterial species from an international clinical trial called CheckMate 915. Researchers analyzed bacteria in stool samples from patients with melanoma who had their tumors surgically removed. Patients from five geographic regions (e.g., North America, Eastern Europe, Western Europe, Australia, and the rest of the world) then received either a combination of immunotherapies, nivolumab and ipilimumab, or nivolumab alone.

The research team discovered that the gut microbiome is a powerful predictor of melanoma recurrence but with a twist. The bacterial markers that most accurately signal recurrence risk varied depending on where a patient lived.

By first matching patients based on the overall similarity of their gut microbiomes regardless of where they lived, the research team was then able to find bacterial "fingerprints" that predict cancer recurrence accurately in each region. Reading the sequence or order of DNA building blocks in all the bacterial species in patients' guts, the researchers created a list of which species were present or not when melanoma recurred.

Using a standard measurement of microbial similarity, the team found that a signature derived from North American patients, for example, could accurately predict recurrence in patients from other parts of the world, but only if those patients had a similar fingerprint. Levels of these markers were found to predict cancer recurrence ranging from 83 to 94 percent accuracy, depending on the geographical region.

"Past studies have struggled because the gut bacteria that predict treatment success seemed to change from one region to another," said Ahn. "Our study provides a new method that overcomes this barrier, showing that these markers are indeed generalizable if we account for the person's underlying microbiome."

Finally, the research team also found that the gut microbiome remained remarkably stable in patients during their year-long course of immunotherapy.

"This means that a single pre-treatment microbiome test could provide a reliable forecast of a patient's risk," said study author Richard Hayes, DDS, MPH, PhD, a professor in the Department of Population Health at NYU Langone.

The next step is to validate this matching approach in other cancers and to build the diverse databases needed to make this approach clinically feasible. In the future we envision analyzing a patient's microbiome before treatment, comparing it to a global database, and providing a reliable prognosis that guides therapy from the start."

Richard Hayes, Department of Population Health, NYU Grossman School of Medicine

Along with Ahn and Hayes, study authors from NYU Langone Health were Mykhaylo Usyk, Huilin Li, Iman Osman, and the late Jeffrey Weber. Also authors were Rob Knight and Antonio Gonzalez of the Departments of Pediatrics, Computer Science & Engineering, and Bioengineering, at the University of California, San Diego.