Abstract 379P
Background
Despite the use of standard adjuvant treatment (ACT) based on fluoropyrimidines plus oxaliplatin, up to 80% of patients with localized colorectal cancer (CC) presents detectable circulating tumor DNA (ctDNA) related with relapse. No biomarkers of response and resistance to ACT have been clarified and the molecular mechanisms of relapse remain unknown. Our aim is to identify the dynamic molecular changes at relapse, intratumoral heterogeneity (ITH) and potential novel therapeutic approaches to eradicate residual disease.
Methods
Whole exome sequencing (WES) of matched primary tumor, plasma ctDNA at relapse and white blood cells of 25 CC patients was performed. From 12 of them, plasma ctDNA at diagnosis was also available. Oncogenic variants were annotated according to COSMIC, OncoKB and an in-house database. Functional enrichment analyzes have been done by GSEA and cancer hallmarks selecting processes with FDR < 0.05. Tumor mutational burden (TMB) was correlated with the ratio of non-synonymous to synonymous mutations (dN/dS). Patient-derived organoids (PDO) were treated with matched therapy based on WES analysis.
Results
33.9% of variants were exclusively observed in plasma at diagnosis, suggesting tissue ITH. At time of relapse, 26.5% of alterations linked to cellular stress response and WNT pathways were detected, suggesting an aggressive phenotype. An enrichment in the number of mutations across genes related to immune evasion, as a parallel event consequence was detected. While on baseline not correlation in TMB and dN/dS ratio was found, at time of relapse dN/dS ratio related with high TMB values (p = 0.023). At least 1 potentially actionable mutation was detected in 80% of patients. In one PDO, the molecular matched therapy with adavosertib showed a significant decrease in cells viability (p < 0.05).
Conclusions
ctDNA genomic profiling in CC patients (1) identifies mechanisms of progression based on immune evasion and evolutionary selection of mutation load, showing the potential role for immunotherapy and, (2) detects targeted alterations with therapeutic value which could eliminate residual disease more efficiently than ACT. PDOs may help in personalizing ACT.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
A. Cervantes Ruipérez.
Funding
Health Institute Carlos III (ISCIII).
Disclosure
S. Rosello Keranen: Financial Interests, Personal, Advisory Board: Pierre Fabre, Servier, Sirtex, Amgen; Financial Interests, Personal, Invited Speaker: Servier, MSD, Amgen; Financial Interests, Institutional, Invited Speaker: Novartis, Roche, Pfizer, Pierre Fabre, Astellas, Seagen, Menarini, Hutchinson, Mirati, G1 Therapeutics, Ability Pharmaceuticals. T.C. Fleitas: Financial Interests, Personal, Invited Speaker, Update on the ongoing treatment strategies for GEA: Servier; Financial Interests, Personal, Invited Speaker, The clinical impact of NRTK strategies in GI tumors: Bayer. A. Cervantes: Financial Interests, Institutional, Advisory Board: MerckSerono, Amgen, Roche, Transgene, AnHeart Therapeutics; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, Beigene, Bayer, Astra Zeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda; Non-Financial Interests, Other, General and Scientific Director: INCLIVA Biomedical Research Institute. N. Tarazona Llavero: Financial Interests, Personal, Advisory Board: MERCK; Financial Interests, Personal, Invited Speaker: MERCK, Pfizer; Financial Interests, Institutional, Funding: Natera Inc; Non-Financial Interests, Member: SEOM Committee. All other authors have declared no conflicts of interest.