594P - Genetic and transcriptomic analyses of Early-Onset Colon Cancer (EOCC): A post-hoc analysis of 2973 patients (pts) from two adjuvant randomized trials

Background

Although colon cancer (CC) incidence is decreasing, an inverse trend is being registered since late 90s in pts <50 years possibly due to lifestyle-related factors/exposome. However, it is still unclear if they represent a distinct biological entity with a different prognosis. Large clinical, biological datasets together with gene expression–based subtyping could allow a better characterization.

Methods

Clinical and molecular data from stage III CC pts enrolled in PETACC-8 and IDEA-France were collected and analyzed according to two age groups (<50=EOCC; >50=Late-Onset CC (LOCC)). Mismatch repair deficiency (dMMR) and mutational status were analyzed on prospectively collected tumor blocks. Consensus Molecular Subtype (CMS) was determined from 3’RNA sequencing.

Results

A total of 2,973 pts, including 2,607 LOCC (88%) and 366 EOCC (12%) were analyzed. Compared with LOCC pts, EOCC pts were more likely to have ECOG-PS 0 (85 vs 78%), intestinal obstruction/perforation (24 vs 18%) and a high-risk stage III tumor (54 vs 44%). Considering molecular profiling, EOCC were more often dMMR (17 vs 8%), RAS wild type (57 vs 50%), and PTEN (8.5 vs 3.8%), CTNNB1 (6.3 vs 2.5%), ERBB2 (3 vs 1%) and DDR2 (3 vs 0.6%) mutated. After 3’RNA-seq, CMS1 was more frequent in EOCC (24 vs 15%). In terms of prognosis, time to recurrence (TTR) was similar among the two groups. However, in CMS1 (487 pts), TTR was halved in EOCC as compared to LOCC. As the interaction test between age and MMR status was significant for TTR (p=0.03), we analyzed separately p and dMMR pts. A better TTR was seen in pMMR CMS1 EOCC vs LOCC (3y TTR rate 82 vs 63%) (p=0.041), but not in dMMR CMS1 EOCC pts. No significant difference in TTR between LOCC and was observed for CMS2-3-4 pts.

Conclusions

In this large genomic and transcriptomic analysis of stage III CC pts, EOCC presented with a more severe disease, a better ECOG-PS and slightly different mutational profiles. Although no major differences were seen between EO and LOCC considering CMS groups, CMS1 was more frequent in EOCC. TTR was significantly better in EO pts compared to LO pts, only in the subgroup of pMMR CMS1 pts, by contrast to dMMR CMS1 pts.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Gallois: Financial Interests, Institutional, Invited Speaker: Sanofi Genzyme; Financial Interests, Institutional, Advisory Board: Servier, Pierre Fabre, Merck; Financial Interests, Institutional, Other, french congress invitation: MSD; Financial Interests, Institutional, Other, Congress invitation: Amgen. C. Lepage: Financial Interests, Personal, Advisory Board: AAA; Financial Interests, Personal, Invited Speaker: AMGEN, Pierre Fabre, IPSEN. R. Guimbaud: Financial Interests, Personal, Advisory Board: ADACAP, BMS; Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Bayer, Esteve, Pierre Fabre, Merck. B. Chibaudel: Financial Interests, Personal, Advisory Board: Amgen, Bayer, BeiGene, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Roche, SeqOne, Sanofi, Servier, Takeda. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Ivited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020: Clovis; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in a symposium in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposium in 2020: Servier; Financial Interests, Personal, Advisory Board, Consultant with personal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposium Lecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded)Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022: Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023: Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022: BMS; Financial Interests, Personal, Advisory Board, Contract 2021: Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Writing Engagement, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merck Serono; Financial Interests, Personal, Other, Educational in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, Gilead Sciences Global GI Advisory Board on January 18, 2023: Aptitude Health, Gilead; Financial Interests, Personal, Other, Consultant like member of the SGNTUC-029 Steering Committee (the “Steering Committee”) Services related to the Company’s Study titled “An Open-label Randomized Phase 3 Study of Tucatinib in Combination with Trastuzumab and mFOLFOX6 versus mFOLFOX6 given with or without either Cetuximab or Bevacizumab as First-line Treatment for Subjects with HER2+ Metastatic Colorectal Cancer” (collectively, the “Services”).Including teleconferences and board preparation befor the board (6h)Participation of the Board on September 2022 inParis, September 10, 2022 MOUNTAINEER-03 Steering Committee Meeting during ESMO: Seagen; Financial Interests, Personal, Other, Consultant like member of the to be a member of the Colorectal Program Scientific Advisory Committee (SAC). In charges for reviewing V940 Pembro on Engagezone (as per your contract in ref).and also an interview about Pembrolizumab for MSI/dMMR metstatic colorectal 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, but also formation for the Takeda team, and consultant for Takeda Contract beetween 1 sept 2023 and 15 October 2024: Takeda; Financial Interests, Personal, Advisory Board, Board Meeting (October 19, 2023): Abbvie; Financial Interests, Personal, Invited Speaker, Emerging Role of Biomarkers in Gastrointestinal Cancers Webcast Engagement reference: Wenibar: MSD; Financial Interests, Personal, Invited Speaker, Preparation and presentation at the Seagen ESMO GI 2023 Scientific Exchange HER2 as an emerging target for the treatment of mCRC in the context MOUNTAINEER03: Seagen; Financial Interests, Personal, Advisory Board, Fruquitinib: Takeda; Financial Interests, Personal, Invited Speaker, Oral speaker in a Symposium 2 and 3 February 2024, GI cancer MSI: MSD; Financial Interests, Personal, Invited Speaker, Management of CRC: Aptitude Health; Financial Interests, Personal, Invited Speaker, Symposium JFHOD GI CancerPARIS15 03-2024: Servier; Financial Interests, Institutional, Coordinating PI, PI Garnet study: GSK; Financial Interests, Institutional, Coordinating PI, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Coordinating PI, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Coordinating PI, SPOTLIGHT study: Astellas; Financial Interests, Personal, Steering Committee Member, and international PI (trial chair Solstice study): Servier; Financial Interests, Personal, Steering Committee Member, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Financial Interests, Institutional, Local PI, a randomized, open-label, phase 2 study of botensilimab (agen1181) as monotherapy and in combination with balstilimab (agen2034) or investigator’s choice standard of care (regorafenib or trifluridine and tipiracil) for the treatment of refractory metastatic colorectal cancer: Agenus; Financial Interests, Institutional, Local PI, Study with trastuzumab deruxtecan in mCRC C study: Daichi; Non-Financial Interests, Member of Board of Directors, Investigator: Gercor group; Non-Financial Interests, Member of Board of Directors, President since October 2022: ARCAD Foundation; Other, DMC Meeting by Teleconference on November 7, 2023 5member of Steering Committee of A randomized Phase 2 Study of ompenaclid versus placebo in combination with FOLFIRI plus bevacizumab in patients withpreviously treated RAS mutant advanced or metastatic colorectal cancer (RGX-202-002): Inspira. P. Laurent-Puig: Financial Interests, Personal, Invited Speaker: Amgen, Sanofi; Financial Interests, Personal, Advisory Board: Biocartis, Pierre Fabre; Financial Interests, Personal, Ownership Interest: Methys DX; Financial Interests, Institutional, Research Grant, PI of translational research: Federation Francophone de Cancerologie Digestive; Non-Financial Interests, Leadership Role: President of Canceropole Ile de France. J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Astellas, Merck, Servier, Pierre Fabre, Amgen, BMS, Novartis, Pfizer, Sanofi, Rottapharm, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, BMS, Merck, MSD, Novartis; Financial Interests, Personal, Invited Speaker, symposia: Astellas; Financial Interests, Personal, Other, Steering Committee of clinical trial: Novartis; 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); Non-Financial Interests, Other, Steering Committee of clinical trials: Pfizer, Servier. All other authors have declared no conflicts of interest.