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
1908 - Androgen Receptor (AR) Aberrations in Patients (Pts) With Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Treated With Apalutamide (APA) Plus Androgen Deprivation Therapy (ADT) in TITAN
Presenter: Kim Chi
Session: Poster Display session 3
Resources:
Abstract
4058 - 68Ga-PSMA guided bone biopsies for molecular diagnostics in metastatic castration resistant prostate cancer patients
Presenter: Anouk de Jong
Session: Poster Display session 3
Resources:
Abstract
2226 - Spatial-Temporal Change in Quantitative Total Bone Imaging (QTBI) and Circulating Tumor Cells (CTCs) in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide (ENZA)
Presenter: Glenn Liu
Session: Poster Display session 3
Resources:
Abstract
5795 - Efficacy of Enzalutamide in Hormone-sensitive Metastatic Prostate Cancer: Clinical Utility of 18F-Choline PET and Whole Body MRI.
Presenter: Susanne Osanto
Session: Poster Display session 3
Resources:
Abstract
899 - Urine extracellular vesicle GATA2 mRNA alone and in a multigene test predicts initial prostate biopsy result
Presenter: Jungreem Woo
Session: Poster Display session 3
Resources:
Abstract
3094 - Circulating tumor cell (CTC) genomic landscape in neuroendocrine prostate cancer (NEPC) by single cell copy number analysis
Presenter: Vincenza Conteduca
Session: Poster Display session 3
Resources:
Abstract
2527 - Circulating Tumor Cells (CTC) count and Prostate-Specific Antigen (PSA) response measures in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients (pts) treated with Docetaxel (Doc)
Presenter: Rebeca Lozano Mejorada
Session: Poster Display session 3
Resources:
Abstract
6106 - Assessing the clinical relevance of drug–drug interactions (DDI) with darolutamide (DARO)
Presenter: Christian Zurth
Session: Poster Display session 3
Resources:
Abstract
2237 - KEYNOTE-921: phase 3 study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone (abi)-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Presenter: Daniel Petrylak
Session: Poster Display session 3
Resources:
Abstract
2241 - KEYNOTE-641: Phase 3 Study of Pembrolizumab (pembro) Plus Enzalutamide for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Presenter: Julie Graff
Session: Poster Display session 3
Resources:
Abstract