583P - COMPReS study: Multiomic profiling reveals organ-specific differences in metastases and identifies novel predictive biomarkers in relapsed localized colon cancer

Background

Metastatic progression presents considerable treatment challenges in colon cancer. Despite localized CC (LCC) patients’ prognosis improvements, about 40% eventually experience relapse. Thus, understanding resistance mechanisms and the host tissue microenvironment is crucially needed. Our aim is to perform a multiomic analysis of high-risk primary tumors and metastatic lesions in order to discover new biomarkers and improve personalized therapies.

Methods

In the COMPReS study at Hospital Clínico Universitario of Valencia, Spain, we conducted multiomic profiling on 100 FFPE tissue samples from 61 patients with LCC. Samples included non-relapsed (NR) primary tumors (PTs) and relapsed (RL) PTs and their paired metastases (METs). Genomic, transcriptomic, and proteomic analyses were performed using whole exome sequencing (WES), RNAseq, and LC-MS/MS-SWATH, respectively. Functional enrichment via GSEA utilized a significance threshold of FDR<0.05.

Results

WES analysis uncovered early evolutionary changes in APC, KRAS, and TP53 in both PTs and METs, along with late mutations exclusive to METs, including NOTCH3, FOXO1 or STAT1. Distinct genomic profiles were noted across different metastatic sites, with mutation enrichment in E2F targets observed solely in liver METs. Moreover, specific mutational signatures were seen in the comparison of RL and NR PTs, featuring mutations in Wnt β-Catenin, PI3K-AKT-mTOR, or TGFβ pathways in RL patients. RNAseq and SWATH identified DE genes and proteins between PTs and METs, as well as a unique proteotranscriptomic profile in liver lesions. Additionally, DE genes and proteins between RL and NR PTs were pinpointed, such as the TGFβ target ACVR1, which were overexpressed in RL PTs. A Cox survival analysis linked DE proteins in RL PTs with a poor outcome, unveiling novel predictive biomarkers and potential therapeutic targets, including IWS1 or DPYSL4.

Conclusions

Comprehensive multiomic characterization of LCC reveals specific signatures for METs, particularly in liver lesions, and RL PTs. This indicates TGFβ pathway changes playing a pivotal role in relapse mechanisms, enabling the discovery of new biomarkers and therapeutic targets.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

INCLIVA, CIBERONC, ISCIII, MM, TTD.

Disclosure

V. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer, Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. S. Rosello Keranen: Financial Interests, Personal, Advisory Board: Pierre Fabre, Servier, Sirtex, Amgen; Financial Interests, Personal, Invited Speaker: Servier, MSD, Amgen; Financial Interests, Institutional, Local PI: 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; Financial Interests, Personal, Invited Speaker, Invited as a speaker in an educational session.: Bristol, Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in an educational session: Bristol, MSD, Lilly, Roche; Financial Interests, Personal, Advisory Board, update on the state of the art: AstraZeneca; Financial Interests, Personal, Advisory Board, Update on the state of the art: MSD; Financial Interests, Personal, Advisory Board, update on the state of the art of gastric cancer tumors: Amgen; Non-Financial Interests, Principal Investigator, PI of SURPASS-2 study: Adapt Immune; Non-Financial Interests, Principal Investigator, PI of a clinical trial in GEA tumors: Daichii- Sanyo; Non-Financial Interests, Principal Investigator, PI of a clinical trial: BeiGene; Non-Financial Interests, Principal Investigator, Matterhorn clinical trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Fortitude 102: Amgen. M. Huerta: Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Invited Speaker: Servier. A. Cervantes: Financial Interests, Institutional, Advisory Board: Merck Serono, Amgen, Roche, Transgene, AnHeart Therapeutics, Abbvie, GSK; 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 in Chief: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, BeiGene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda, Affimed, Roche, Seamless, Gilead, Janssen, F. STAR Therapeutics, Ribon Therapeutics; Non-Financial Interests, Other, Scientific Director: INCLIVA Biomedical Research Institute. N. Tarazona Llavero: Financial Interests, Personal, Advisory Board: MERCK, Guardant Health, Grifols; Financial Interests, Personal, Invited Speaker: MERCK, Pfizer, Servier, Amgen; Financial Interests, Institutional, Funding: Natera Inc, Guardant Health; Non-Financial Interests, Member: SEOM Committee. All other authors have declared no conflicts of interest.