Abstract 464P
Background
Plasma circulating tumor DNA (ctDNA) detects minimal residual disease and accurately monitors patients’ response to adjuvant chemotherapy (ACT) in localized colon cancer (CC). Up to 80% of patients with detectable ctDNA may not become negative after ACT. Our study analyses whole exome sequencing (WES) of ctDNA at relapse comparing with initial diagnosis to better understand dynamic mutation changes and potential targets for future therapies.
Methods
Patients diagnosed with localized CC were prospectively recruited at a single academic center between October 2015 and October 2017. WES of matched primary tumor, cell-free DNA and white blood cells in relapsing patients was performed to evaluate clonal evolution and to identify druggable alterations at relapse. Emerging alterations were matched with OncoKB levels of evidence for the choice of specific targeted therapies. Pathway enrichment analysis was conducted with KEGG database.
Results
Among 13 relapsing patients sequenced, 69% harbored at least 1 potentially actionable alteration, classified as a level 3B or 4. Pathogenic druggable germline variants involved in DNA damage repair (RAD54L) were identified in 15% of patients. 39% of patients had a high tumor mutation burden (TMB) at diagnosis and at first relapse. TMB was highest among patients with microsatellite instability and CDX2 loss. We also observed a mutation enrichment in the MUC family at relapse compared to baseline. Patients, who presented high clonal evolution, harbored mutations belonging to the VEGF signaling pathway (MAPK1,KRAS, CDC42…). At relapse, all patients who did not get ACT had mutations on CARD10 or WDRE33, which were not found in those receiving ACT. Parallel evolution in antigen processing and presentation pathways (HLA mutations) was observed as a distinct pattern of relapse.
Conclusions
Comprehensive genomic profiling of ctDNA in localized CC patients at relapse may be of interest because 1) it detects targeted alterations with therapeutic value; 2) it involves immune evasion mechanisms related to parallel evolution or angiogenesis pathways on clonal evolution and; 3) the observed mutational landscape may differ between patients treated or not with conventional ACT.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Andrés Cervantes.
Funding
-Spanish Society of Medical Oncology (SEOM) -Digestive Tumour Treatment Group (TTD-Group), Spain -Carlos III Health Institute, Spain.
Disclosure
N. Tarazona: Financial Interests, Personal, Invited Speaker: Merck; Servier; Pfizer; Amgen; Financial Interests, Institutional, Research Grant: Mutua Madrileña; TTD-Group; SEOM; AECC. A. Cervantes: Financial Interests, Personal, Advisory Role: Merck Serono; Roche; Servier; Takeda; Astellas; Financial Interests, Institutional, Funding: Merck Serono; Genentech; BMS; Roche; Lilly; Bayer; Novartis; Takeda; NATERA; MSD; Astellas; Beigene; Fibrogen. All other authors have declared no conflicts of interest.