Abstract 321P
Background
The development at reasonable cost of 3’RNA seq from paraffin embedded tissues opens new avenues for elaborating new prognostic signatures in colon cancer (CC). We applied this approach to a large series of stage III CC to establish a predictive model of the risk of recurrence, based on clinical-pathological features and genomic signatures.
Methods
3’RNAseq was performed in 1,734 FFPE samples from the PETACC8 trial including patients with stage III CC and treated with FOLFOX +/- cetuximab. Stromal and immune signatures of cancer-associated fibroblasts (CAF), macrophages (M1 and M2), B-cells, plasma cells, NK cells, T-cells infiltration, CXCL13 and the Oncotype signature derived from Oncotype Dx© Colon recurrence score (RS), were measured. A multivariate Cox proportional hazard model was built using variables known to be associated with prognosis and signatures selected by the stepwise regression for the prediction of recurrence-free survival (RFS).
Results
The best performing model included the signatures of macrophages M2, a type of myofibroblastic CAF named “wound-myCAF”, CXCL13, T-cells infiltration, and the Oncotype signature, with a C-index of 0.73. The variables independently associated with RFS were: T and N stage, RAS mutation status, bad prognosis CMS combinations and all the signatures included in the model (Table). The AUC of time-dependent ROC curve at 3 years was 0.77. Dividing the population into quartiles based on this RS (RS 1 to RS 4), the 3-year RFS rate was 95%, 87%, 76.1% and 52%, respectively.
Conclusions
This predictive model, based on known prognostic variables, stromal/immune signatures and the Oncotype signature, is able to effectively predict the risk of recurrence for patients with stage III CC by dividing them into 4 RS. Our study paves the way towards personalized care according to the estimation of this risk of recurrence, especially for the decision of adjuvant chemotherapy. Table: 321P
The predictive model
| adjusted HR | p-value | |
| Male gender | 1.0 | 0.7 |
| ECOG-PS 1-2 | 1.3 | 0.07 |
| Bowel obstruction and/or perforation | 1.2 | 0.07 |
| T4 stage | 2.0 | <10 -4 |
| N2 stage | 2.5 | <10 -4 |
| Grade 3-4 | 1.1 | 0.5 |
| RAS mutation | 1.3 | 0.01* |
| BRAF mutation | 1.4 | 0.06 |
| dMMR | 0.9 | 0.7 |
| Interaction BRAF/MMR | 0.4 | 0.045 |
| CMS major.minor : CMS4.CMS1/CMS1.CMS4/CMS1.CMS3/CMS3.CMS4 | 1.7 | <10 -4 |
| Signatures | ||
| T-cells infiltration | 0.3 | 0.0002 |
| macrophages M2 | 3.6 | 0.002 |
| wound-myCAF | 0.2 | 0.001 |
| Oncotype | 1.02 | 0.0007 |
| CXCL13 | 0.8 | 0.008 |
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Gallois: Non-Financial Interests, Institutional, Other, congress invitation: Amgen, MSD; Non-Financial Interests, Institutional, Advisory Board: Servier; Non-Financial Interests, Institutional, Invited Speaker: Sanofi. C. de la Fouchardiere: Financial Interests, Personal, Advisory Board: Merck, Roche, Lilly, Bayer, Amgen, MSD, Servier, Pierre Fabre Oncologie, Bristol-Myers Squibb, Incyte; Financial Interests, Personal, Invited Speaker: Ipsen, Eisai; Financial Interests, Institutional, Invited Speaker: Pierre Fabre Oncologie, Servier. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daichii Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Avvinity, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, Pfizer, MedImmune, Menarini, Merus N V, Mirati; Non-Financial Interests, Invited Speaker, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Invited Speaker, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., Hutchinson Medipharma, HalioDX SAS, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Roche, Merck, Servier, Pierre Fabre, Amgen, BMS, Novartis; Financial Interests, Personal, Invited Speaker: Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, Servier; Non-Financial Interests, Leadership Role, President of the scientific committee of the ARCAD foundation until end 2022: ARCAD Foundation; Non-Financial Interests, Leadership Role, Chair of the ARCAD pancreas research group: ARCAD Foundation; Non-Financial Interests, Leadership Role, Member of the administrative council, the scientific committee, the executive board and responsible for the international relationships /partnership for FFCD in the prodige intergroup: Federation Francophone de Cancerologie Digestive (FFCD). P. Laurent-Puig: Financial Interests, Personal, Invited Speaker: Amgen, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Biocartis, Pierre Fabre; Financial Interests, Personal, Ownership Interest: Methys DX; Financial Interests, Institutional, Research Grant: Federation francophone de cancerologie digestive; Non-Financial Interests, Leadership Role: President of canceropole ile de france. All other authors have declared no conflicts of interest.