Association of Short-Chain Fatty Acids in the Gut Microbiome With Clinical Response to Treatment With Nivolumab or Pembrolizumab in Patients With Solid Cancer Tumors

• DOI: 10.1001/jamanetworkopen.2020.2895
• Publication Date: 2020-04-16T18:31:01Z
• Authors: Motoo Nomura; Ryosuke Nagatomo; Keitaro Doi; Juko Shimizu; Kiichiro Baba; Tomoki Saito; Shigemi Matsumoto; Koichi Inoue; Manabu Muto
• Keywords: Adult; Aged, 80 and over; Male; 0303 health sciences; Middle Aged; Antibodies, Monoclonal, Humanized; Fatty Acids, Volatile; Gastrointestinal Microbiome; 3. Good health; 03 medical and health sciences; Antineoplastic Agents, Immunological; Nivolumab; Japan; Neoplasms; Humans; Female; Prospective Studies; Original Investigation; Aged

Immunotherapy using immune checkpoint inhibitors has been remarkably effective for treating multiple cancer types, and the gut microbiome is a possible factor affecting immune checkpoint inhibitor efficacy. However, the association between the gut microbiome and immune status of the tumor microenvironment remains unclear. Short-chain fatty acids (SCFAs) are major end product metabolites produced by the gut microbiota and have wide-ranging impacts on host physiology.To evaluate fecal and plasma SCFAs in patients with solid cancer tumors treated with programmed cell death-1 inhibitors (PD-1i).This was a prospective cohort biomarker study of patients with cancer who planned therapy with PD-1i at Kyoto University Hospital between July 2016 and February 2019. Data were analyzed from October 2019 to February 2020.Patients who were treated with nivolumab or pembrolizumab were classified into 2 groups based on their treatment response using Response Evaluation Criteria in Solid Tumors version 1.1: responders who achieved an objective response and nonresponders. Dietary information in terms of intake frequency was obtained. Concentrations of SCFAs in fecal and plasma samples collected before PD-1i administration were measured using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry.The concentration of SCFAs and progression-free survival.Among 52 patients enrolled, the median (range) patient age was 67 (27-84) years, and 23 (44%) were women. Median (range) duration of follow-up of the survivors after administration of PD-1i was 2.0 (0.4-4.1) years. The overall response rate was 28.8%. High concentrations of some SCFAs were associated with longer progression-free survival. These included fecal acetic acid (hazard ratio [HR], 0.29; 95% CI, 0.15-0.54), propionic acid (HR, 0.08; 95% CI, 0.03-0.20), butyric acid (HR, 0.31; 95% CI, 0.16-0.60), valeric acid (HR, 0.53; 95% CI, 0.29-0.98), and plasma isovaleric acid (HR, 0.38; 95% CI, 0.14-0.99).Results of this study suggest that fecal SCFA concentrations may associated with PD-1i efficacy; thus, SCFAs may be the link between the gut microbiota and PD-1i efficacy. Because fecal examinations are completely noninvasive, they may be applicable for routine monitoring of patients.