Abstract 6411: The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors
Authors: Usyk Mykhaylo , Hayes Richard B. , Knight Rob , Gonzalez Antonio , Li Huilin , Osman Iman , Weber Jeffrey S. , Ahn Jiyoung 
Published: March 2024

Abstract
The gut microbiome (GMB) plays a crucial role in immune checkpoint blockade (ICB) therapy outcomes for metastatic melanoma patients, yet there remains a lack of consensus regarding the specific microbiota associated with clinical outcomes, particularly across different geographic regions. Furthermore, investigations into the relationship between GMB and melanoma outcomes in the adjuvant setting are notably absent. This highlights the pressing need for a comprehensive, large-scale study spanning diverse geographic locations within a well-controlled clinical trial environment. In this study, we conducted shotgun sequencing on pre-treatment stool samples collected from 674 melanoma patients participating in an international, randomized, double-blind, phase III adjuvant trial evaluating clinical outcomes following adjuvant nivolumab plus ipilimumab versus nivolumab. Our recruitment encompassed three continents and five geographically distinct regions. Given the significant influence of geographic region on GMB composition, we employed three analytical approaches: (a) region-specific analyses, (b) combined meta-analyses across regions, and (c) sub-set paired analyses involving subjects closely matched for overall GMB. Additionally, we assessed GMB stability by examining samples collected serially prior to therapy and at weeks 7 and 29 of ICB treatment. Through region-specific and meta-analyses, we identified ten pre-treatment gut bacterial markers, including Eubacterium, Ruminococcus, Clostridium, and Firmicutes, which exhibited associations with melanoma recurrence in the adjuvant setting. The predictive capacity of these microbial markers was directly proportion to GMB similarity (Spearman correlation = 0.86, p&lt;0.001 for AUC vs. beta-diversity). Notably, for closely matched patients in terms of their GMB composition, the prediction of recurrence using the recurrence-associated markers, in conjunction with clinical characteristics, yielded an AUC of 0.917 (95% CI: 0.825-1.00). Furthermore, GMB remained largely stable across serial samples collected before and after treatment (PERMANOVA R2 = 0.867, p-val&lt;0.001, at baseline, week 7, and week 29). This study underscores the remarkable stability of GMB during adjuvant ICB therapy for melanoma and identifies specific bacterial biomarkers that hold promise for predicting melanoma recurrence within the adjuvant treatment setting. The gut microbiome emerges as a potential source of microbial biomarkers for individualized prediction of melanoma recurrence in clinical practice.
Citation Format: Mykhaylo Usyk, Richard B. Hayes, Rob Knight, Antonio Gonzalez, Huilin Li, Iman Osman, Jeffrey S. Weber, Jiyoung Ahn. The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6411.