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


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AbstractAbstract 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.
All Author(s) ListZhijie 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
Name of ConferenceASCO Annual Meeting 2018
Start Date of Conference01/06/2018
End Date of Conference05/06/2018
Place of ConferenceChicago, IL
Country/Region of ConferenceUnited States of America
Proceedings TitleJournal of Clinical Oncology
Series TitleDevelopmental Therapeutics-Immunotherapy; Poster session (Board #238)
Number in Seriessuppl; abstr 3024
Year2018
Month5
Volume Number36
Issue Number15 suppl
ISSN0732-183X
eISSN1527-7755
LanguagesEnglish-United Kingdom
KeywordsCo-mutations

Last updated on 2018-30-10 at 15:38