Gut Microbiome Study Yields Clues to Melanoma Development, Progression

A comparative analysis of fecal bacteria revealed distinct differences between patients with melanoma and healthy volunteers and between patients with early- versus late-stage melanoma.

Patients with melanoma had a higher abundance of Fusobacterium as compared with the volunteers. Fecal microbiota of patients with early-stage melanoma had a higher alpha diversity and a higher abundance of Roseburia versus specimens obtained from patients with late-stage melanoma. Additionally, functional pathways had different degrees of enrichment among the various patient groups.

The analysis showed no relationship between fecal microbiota and disease recurrence in patients with stage III melanoma treated with immunotherapy, reported Kelly C. Nelson, MD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors in JAMA Dermatology.

"These findings suggest that gut dysbiosis may be linked to melanomagenesis and disease progression," the authors concluded. "Further investigation is needed to confirm these findings and determine whether modifying the gut microbiome could influence melanoma development and progression."

The findings relative to early- versus late-stage melanoma support the concept that loss of diversity is associated with disease progression, as well as with disease development, observed Amrit K. Greene, MD, and Amanda M. Nelson, PhD, of Penn State College of Medicine and Penn State Health in Hershey, Pennsylvania, in an accompanying editorial.

"In aggregate, [the findings] provide additional evidence that gut bacterial profiles vary between melanoma stages and that a loss of diversity is associated with late-stage disease," Greene and Nelson wrote. "The questions now include (1) defining gut dysbiosis and how it may affect melanoma progression and (2) how this information can benefit patients prognostically, therapeutically, or both."

"The gut microbiome is a crucial piece of the puzzle in our health, therapy responses, and treatment outcomes," they added. "[These findings] provide another piece of this puzzle by identifying key features of gut dysbiosis in patients with melanoma. In this era of precision medicine, research is beginning to unlock the therapeutic potential of this complex ecosystem."

Multiple studies have provided evidence that the gut microbiome may influence cancer initiation, disease progression, drug toxicity, and treatment response, the study authors noted in their introduction. With respect to melanoma, preclinical and clinical studies have shown an association between specific gut microbes and response to immunotherapy. However, limited data exist regarding the relationship between microbiome composition in patients with localized or early-stage melanoma or whether differences exist versus individuals without melanoma.

Immunotherapy has significantly improved survival in some patients with melanoma. However, many patients do not respond or are unable to receive treatment with immune checkpoint inhibitors, the authors continued. Ongoing studies seek to gain insight into how modulation of the gut microbiome might optimize immunotherapy response.

The authors performed a case-control study to compare fecal microbiota -- including diversity, composition, and function -- between healthy volunteers and patients with melanoma. They also compared the microbiomes of patients with localized, early-stage melanoma (stages 0 to II) and metastatic late-stage melanoma (stage III or IV). Finally, they examined baseline gut microbiota for associations with outcomes in patients with stage III melanoma treated with immunotherapy.

The study included 49 healthy volunteers and 179 patients with melanoma, comprising 38 with early-stage disease and 141 with late-stage disease. Within the melanoma cohort, the late- and early-stage patients were matched 2:1 with respect to age, sex, body mass index, and race/ethnicity. The matched groups were comparable with respect to medication use, except for antibiotics, which were more common among the late-stage subgroup (43.3% vs 10.5%, P<0.001).

Comparison of microbiome features in patients with melanoma and the volunteers showed a greater diversity of species (alpha diversity) in the control group (median 16.7 vs 11.4, P=0.06). An analysis of the variability between different samples within a group (beta diversity) showed that controls formed distinct or distant communities as compared with patients who had melanoma (P<0.001).

An analysis of diversity differences between the controls and the patients showed greater abundance of the bacterial phyla Actinomycetota and Firmicutes in the control group. The bacterial genus Fusobacterium, implicated in colorectal cancer and gut inflammation, was more abundant in the melanoma group by univariate analysis (P<0.001) but not after adjustment for medication use and other factors (P=0.09).

Investigators then compared microbiome features between patients with early-stage melanoma and the matched patients with late-stage disease without exposure to systemic therapy. The results showed a significantly higher alpha diversity in association with early-stage disease (median 14.6 vs 10.8, P=0.003). The two subgroups also had significant differences in beta diversity (P=0.03).

Samples from patients with early-stage disease had a greater abundance of Roseburia (2.4% vs 1.2%, P<0.001), but the difference was no longer significant after covariate adjustment. The functional analysis showed that multiple pathways were differentially enriched in early- and late-stage samples.

The investigators analyzed fecal microbiota from 66 patients with stage III melanoma treated with adjuvant therapy. During follow-up, 20 patients had recurrence. Patients with recurrence had a significantly higher alpha diversity (15.1 vs 11.4, P=0.008), but patients with and without recurrence did not differ with respect to beta diversity. Additionally, they had no significant differences in abundance of specific bacterial taxa.

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