Analysis of Gut Microbiome Using Explainable Machine Learning Predicts Risk of Diarrhea Associated With Tyrosine Kinase Inhibitor Neratinib: A Pilot Study

• Main Authors: Chi Wah Wong, Susan E. Yost, Jin Sun Lee, John D. Gillece, Megan Folkerts, Lauren Reining, Sarah K. Highlander, Zahra Eftekhari, Joanne Mortimer, Yuan Yuan
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-03-01
• Series: Frontiers in Oncology
• Subjects: gut microbiota; breast cancer; neratinib; diarrhea; artificial intelligence; explainable machine learning
• Online Access: https://www.frontiersin.org/articles/10.3389/fonc.2021.604584/full

Neratinib has great efficacy in treating HER2+ breast cancer but is associated with significant gastrointestinal toxicity. The objective of this pilot study was to understand the association of gut microbiome and neratinib-induced diarrhea. Twenty-five patients (age ≥ 60) were enrolled in a phase II trial evaluating safety and tolerability of neratinib in older adults with HER2+ breast cancer (NCT02673398). Fifty stool samples were collected from 11 patients at baseline and during treatment. 16S rRNA analysis was performed and relative abundance data were generated. Shannon’s diversity was calculated to examine gut microbiome dysbiosis. An explainable tree-based approach was utilized to classify patients who might experience neratinib-related diarrhea (grade ≥ 1) based on pre-treatment baseline microbial relative abundance data. The hold-out Area Under Receiver Operating Characteristic and Area Under Precision-Recall Curves of the model were 0.88 and 0.95, respectively. Model explanations showed that patients with a larger relative abundance of Ruminiclostridium 9 and Bacteroides sp. HPS0048 may have reduced risk of neratinib-related diarrhea and was confirmed by Kruskal-Wallis test (p ≤ 0.05, uncorrected). Our machine learning model identified microbiota associated with reduced risk of neratinib-induced diarrhea and the result from this pilot study will be further verified in a larger study.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02673398.