Abstract:
Background and aims: Oesophageal adenocarcinoma (OAC) incidence continues to rise in developed countries. Despite advances in deciphering cancer genomes and oncogenic pathways, precision therapies for OAC remain limited.
Methods: We selected 109 actionable and/or potentially actionable genes based on pan-cancer drug information from open-source compendia and clinical trials for curation of genomic alterations. We determined the prevalence of alterations within these 109 genes using whole genome sequencing data of tumor DNA from n=217 OAC patients to discover approved treatments and potentially targetable alterations (PTAs). Additionally, matching RNA-seq from 210 of the patients was interrogated for select immune checkpoint inhibitor (ICI) targets (n=59), with expression findings validated in an independent OAC cohort (n=114).
Results: Approved actionable targets were revealed in 22.1% of patients; including HER-2 and MET antagonists, and immunotherapy directed by microsatellite instability and high tumor mutation burden. PTAs were noted in a further 72.8% of patients, with highest frequency in TP53; others were noted in APC, ARID1A, BRCA1, BRCA2, CCNE1, CDKN2A, EGFR, KRAS, MDM2, PIK3CA, PTEN, SMARCB1 and TSC2. Candidate co-occurring alterations included co-occurrence of PTEN loss and ERBB2 amplification and co-occurring variants in KRAS and TP53. For the remaining 5.1% of patients, no PTAs were detected. We identified and validated high expression of four genes encoding candidate ICI targets for OAC: CD24, VEGFA, PVR, and SLC3A2.
Conclusion: These PTAs and ICI targets will help to inform future clinical trials. Precision therapy may become available for all OAC in the near future.