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
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
DOI:
10.1001/jamanetworkopen.2020.2895
Publication Date:
2020-04-16T18:31:01Z
AUTHORS (9)
ABSTRACT
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.
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