Please use this identifier to cite or link to this item: https://doi.org/10.1093/annonc/mdy550
Title: Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer
Authors: Sundar, R 
Huang, KK 
Qamra, A
Kim, K-M
Kim, ST
Kang, WK
Tan, ALK
Lee, J
Tan, P 
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
epigenetic alternate promoter
immune checkpoint inhibition
pembrolizumab
immunotherapy
gastric cancer
TUMORS
Issue Date: 1-Mar-2019
Publisher: OXFORD UNIV PRESS
Citation: Sundar, R, Huang, KK, Qamra, A, Kim, K-M, Kim, ST, Kang, WK, Tan, ALK, Lee, J, Tan, P (2019-03-01). Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer. ANNALS OF ONCOLOGY 30 (3) : 424-430. ScholarBank@NUS Repository. https://doi.org/10.1093/annonc/mdy550
Abstract: © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. Background Utilization of alternative transcription start sites through alterations in epigenetic promoter regions causes reduced expression of immunogenic N-terminal peptides, which may facilitate immune evasion in early gastric cancer. We hypothesized that tumors with high alternate promoter utilization would be resistant to immune checkpoint inhibition in metastatic gastric cancer. Patients and methods Two cohorts of patients with metastatic gastric cancer treated with immunotherapy were analyzed. The first cohort (N = 24) included patients treated with either nivolumab or pembrolizumab. Alternate promoter utilization was measured using the NanoString ® (NanoString Technologies, Seattle, WA, USA) platform on archival tissue samples. The second cohort was a phase II clinical trial of patients uniformly treated with pembrolizumab (N = 37). Fresh tumor biopsies were obtained, and transcriptomic analysis was carried out on RNAseq data. Alternate promoter utilization was correlated to T-cell cytolytic activity, objective response rate and survival. Results In the first cohort 8 of 24 (33%) tumors were identified to have high alternate promoter utilization (AP high), and this was used to define the AP high tertile of the second cohort (13 AP high of 37). AP high tumors exhibited decreased markers of T-cell cytolytic activity and lower response rates (8% versus 42%, P = 0.03). Median progression-free survival was lower in the AP high group (55 versus 180 days, P = 0.0076). In multivariate analysis, alternative promoter utilization was an independent predictor of immunotherapy survival [hazard ratio 0.29, 95% confidence interval 0.099-0.85, P = 0.024). Analyzing tumoral evolution through paired pre-treatment and post-treatment biopsies, we observed consistent shifts in alternative promoter utilization rate associated with clinical response. Conclusion A substantial proportion of metastatic gastric cancers utilize alternate promoters as a mechanism of immune evasion, and these tumors may be resistant to anti-PD1 immune checkpoint inhibition. Alternate promoter utilization is thus a potential mechanism of resistance to immune checkpoint inhibition, and a novel predictive biomarker for immunotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT#02589496
Source Title: ANNALS OF ONCOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/155022
ISSN: 0923-7534
1569-8041
DOI: 10.1093/annonc/mdy550
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