Co-mutations of DNA damage response system as predictive biomarker for immune checkpoint blockades
Invited conference paper presented and published in conference proceedings

香港中文大學研究人員

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摘要Abstract Background: Selecting appropriate biomarkers for immune checkpoint blockades (ICBs) remains a clinical challenge. Quantitative biomarkers, for instance, PD-L1 expression or tumor mutation burden, are limited by their vague cut-off value, intra-tumor heterogeneity distribution and dynamic alterations. Qualitative biomarkers, including dMMR/MSI-H, are potent predictors, but merely a minority of patients harbor this abnormality. Therefore, a more prevalent biomarker would be highly desirable. In humans, DNA damage response (DDR) system is indispensable in maintaining genomic integrity. We hypothesize genetic mutations of DDR pathways may increase genomic instability and manifest as up-regulated neoantigen load and TMB, contributing to higher susceptibility to immune checkpoint blockades (ICBs). Methods: Whole-exome sequencing data from 8552 solid tumors, across 29 cancer types from The Cancer Genome Atlas were included for analysis. The expression signatures of immune genes were compared across distinct DDR subgroups. Statistics concerning the correlation between DDR pathway mutations and treatment outcomes were evaluated in four cohorts treated with ICBs. Results: Co-mutations of HRR-MMR or HRR-BER pathways (defined as co-mut +) were correlated with higher neoantigen load and TMB. Co-mut + exhibited anabatic levels of immune gene expression signatures, including genes related to T-effector, IFNγ pathway, T cell receptors and tumor micro-environment. In these four validation cohorts, the progression-free survival (PFS) was longer in co-mut + patients with non-small cell lung cancer (NSCLC) than co-mut – (median, not reached vs. 4.1 months, P = 0.02) and the overall survival was longer in co-mut + melanoma patients than co-mut – (median, 32.4 vs. 10.8 months, P = 0.04). Subgroup analysis of NSCLC cohort demonstrated that co-mut + is predictive to longer PFS in patients with PD-L1 expression < 50% (median, 8.3 vs. 2.7 months, P = 0.03) or low TMB (median, not reached vs. 3.8 months, P = 0.04). Conclusions: Co-mutations of HRR-MMR or HRR-BER are a potential prognostic biomarker for ICBs immunotherapy, and warrant future prospective investigations.
著者Zhijie Wang, Jing Zhao, Guoqiang Wang, Fan Zhang, Yuzi Zhang, Hua Dong, Xiaochen Zhao, Jianchun Duan, Hua Bai, Yanhua Tian, Rui Wan, Lei Xiong, Shangli Cai, Tony Mok, Jie Wang
會議名稱ASCO Annual Meeting 2018
會議開始日01.06.2018
會議完結日05.06.2018
會議地點Chicago, IL
會議國家/地區美國
會議論文集題名Journal of Clinical Oncology
系列標題Developmental Therapeutics-Immunotherapy; Poster session (Board #238)
叢書冊次suppl; abstr 3024
出版年份2018
月份5
卷號36
期次15 suppl
國際標準期刊號0732-183X
電子國際標準期刊號1527-7755
語言英式英語
關鍵詞Co-mutations

上次更新時間 2018-30-10 於 15:38