Abstract 2314
Background
Immune checkpoint inhibitors (ICIs) elicits durable responses in non–small cell lung cancer (NSCLC), but only a fraction of patients responded. TP53 and ATM co-mutation may lead to genomic instability and hypermutation. However, the prevalence and utility of a TP53/ATM co-mutation as a biomarker to ICIs are not fully understood.
Methods
This was a multiple cohort pooled study, 2020 NSCLC samples from Geneplus Institute, 1031 samples from TCGA, 1567 samples from MSKCC, 853 samples from POLAR/OAK databases were statically analyzed. Next-generation sequencing assays were performed in the Geneplus Institute. Genomic, transcriptomic and clinical data were obtained from the TCGA, MSKCC, POLAR/OAK databases. Comprehensive profiling was performed to determine the prevalence of TP53/ATM co-mutation and correlation with the prognosis and the response to ICIs.
Results
TP53/ATM co-mutation sites were found to be scattered throughout the genes and we did not observe any significant difference in TP53/ATM co-mutated frequency within the histologic subtypes and driver genes. In five independent NSCLC cohorts, TP53/ATM co-mutation contributed to significantly higher tumor mutation burden (TMB) compared to both the sole mutation and both wild type groups. Furthermore, in the MSKCC-IO cohort, a TP53/ATM co-mutation was associated with better OS than sole mutation and both wild type groups, especially in pan-cancer (P=.241, NSCLC and P<.0001, Pan-cancer). Similar results were shown in the POLAR/OAK cohort, the disease control benefit rate, and progression free survival (PFS) and OS were all greater in patients with the TP53/ATM co-mutation compared with the other three groups. GSEA showed that IFN-α response, IFN-γ response, IL6/JAK/STAT3 signaling, and TNF-α signaling pathways had higher levels of activation and there was greater PD-L1 expression in the co-mutated group, compared with solely mutated and both wild type group.
Conclusions
Our findings suggest that patients with TP53/ATM co-mutation comprise a special subgroup of NSCLC patients and correlate with increasing TMB and responses to ICIs. It may have implications for potential predictive biomarker in guiding ICIs immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Jian Ji Pan.
Funding
National Natural Science Foundation of China (Grant No. U1705282).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2963 - Analytical performance of the Resolution-HRD plasma assay used to identify mCRPC patients with biallelic disruption of DNA repair genes for treatment with niraparib
Presenter: Ira Pekker
Session: Poster Display session 3
Resources:
Abstract
3523 - Results of a global external quality assessment scheme for EGFR testing on liquid biopsy
Presenter: Nicola Normanno
Session: Poster Display session 3
Resources:
Abstract
3295 - Clinical impact of plasma Next-Generation Sequencing (NGS) in advanced Non-small cell lung cancer (aNSCLC)
Presenter: Laura Bonanno
Session: Poster Display session 3
Resources:
Abstract
5632 - Feasibility study of a ctEGFR prototype assay on the fully automated Idylla™ platform
Presenter: Martin Reijans
Session: Poster Display session 3
Resources:
Abstract
3614 - Enhanced Access to EGFR Molecular Testing in NSCLC using a Cell-Free DNA Tube for Liquid Biopsy
Presenter: Theresa May
Session: Poster Display session 3
Resources:
Abstract
5664 - Analysis of circulating tumor DNA in paired plasma and sputum samples of EGFR-mutated NSCLC patients
Presenter: Christina Grech
Session: Poster Display session 3
Resources:
Abstract
4945 - Liquid biopsy and Array Comparative Genomic Hybridization (aCGH)
Presenter: Panagiotis Apostolou
Session: Poster Display session 3
Resources:
Abstract
5746 - Next-generation sequencing panel verification to detect low frequency single nucleotide and copy number variants from mixing cell line studies
Presenter: Rocio Rosas-Alonso
Session: Poster Display session 3
Resources:
Abstract
5901 - Automated rarefaction analysis for precision B and T cell receptor repertoire profiling from peripheral blood and FFPE-preserved tumor
Presenter: Luca Quagliata
Session: Poster Display session 3
Resources:
Abstract
2027 - A Heptamethine cyanine dye is a potential diagnostic marker for Myeloid-Derived Suppressor Cells
Presenter: Chaeyong Jung
Session: Poster Display session 3
Resources:
Abstract