Image-Based Consensus Molecular Subtyping Refines Prognostication in Stage II/III Colorectal Cancer: A Retrospective Analysis of the SCOT Trial
Purpose Risk stratification in localized colorectal cancer (CRC) remains inadequate. Transcriptome-based classifiers such as consensus molecular subtyping (CMS) improve this, but are challenging to implement. We determined the performance of a novel image-based method for CRC CMS subtyping (imCMS) using routine pathology images from the SCOT trial and investigated association of imCMS subtypes with clinicopathologic and tumor molecular and immune factors, treatment benefit, and survival. Methods We applied a novel imCMS classifier to stage II/III CRCs from the SCOT trial (ISRCTN59757862) which examined 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy following curative-intent surgery. We determined correlates of imCMS subgroups and investigated imCMS prognostic and predictive value for CRC recurrence-free interval, overall survival (OS), and survival after CRC recurrence (SAR) by univariable and multivariable Cox regression. Results A total of 2,816 cases were informative for imCMS classification, of which 664 (24%) were imCMS1 (immune), 987 (35%) imCMS2 (canonical), 433 (15%) imCMS3 (metabolic), 653 (23%) imCMS4 (mesenchymal), and 79 (3%) of mixed subtype. Analysis confirmed expected associations of imCMS1 with deficient DNA mismatch repair (dMMR) and imCMS3 with KRAS mutation and revealed substantially lower intraepithelial CD8 + and intrastromal FoxP3 + T-cell infiltrate (CD8 IE -FoxP3 IS ) in imCMS4 tumors. imCMS classification was strongly prognostic independent of clinicopathologic factors, dMMR, and CD8 IE -FoxP3 IS in multivariable analysis but did not predict differential benefit from chemotherapy duration or regimen. The combination of imCMS with CD8 IE -FoxP3 IS groups defined CRC subgroups with substantially different recurrence risk. Analysis of OS and SAR revealed notable discordance in imCMS3 and imCMS4 prognostic value before and after relapse. Conclusion imCMS classification improves CRC prognostication beyond existing tumor factors and is potentially deliverable in clinical practice. imCMS prediction of therapeutic benefit requires further study.
Authors
- Viktor Hendrik Koelzer (ORCID: https://orcid.org/0000-0001-9206-4885)
- Claire Palles (ORCID: https://orcid.org/0000-0002-9670-2263)
- Paul D. Harkin
- T. Maughan
- Celina Whalley (ORCID: https://orcid.org/0000-0001-7183-5388)
- Richard Adams (ORCID: https://orcid.org/0000-0003-3915-7243)
- Jens Rittscher (ORCID: https://orcid.org/0000-0002-8528-8298)
- Leslie M. Samuel (ORCID: https://orcid.org/0000-0002-8402-8670)
- Andrea Harkin (ORCID: https://orcid.org/0000-0002-8831-7381)
- Korsuk Sirinukunwattana (ORCID: https://orcid.org/0000-0002-3603-4435)
- Tim Maughan
- Mark P. Saunders (ORCID: https://orcid.org/0000-0002-7195-4712)
- Ian P.M. Tomlinson (ORCID: https://orcid.org/0000-0003-3037-1470)
- Kathryn L. Gilroy (ORCID: https://orcid.org/0000-0003-4607-194X)
- Manuel Salto‐Tellez (ORCID: https://orcid.org/0000-0001-8586-282X)
- Nicholas Paul West (ORCID: https://orcid.org/0000-0002-0346-6709)
- Susan M. Richman
- G. Higgins
- David Sebag‐Montefiore (ORCID: https://orcid.org/0000-0002-5978-9259)
- Richard S. Kaplan (ORCID: https://orcid.org/0000-0002-0189-8348)
- Timothy J. Iveson (ORCID: https://orcid.org/0000-0002-4681-2712)
- Caroline Kelly (ORCID: https://orcid.org/0000-0002-5330-7888)
- Bengt L. G. Glimelius (ORCID: https://orcid.org/0000-0002-5440-791X)
- Gillies W. McKenna
- Aikaterini Chatzipli (ORCID: https://orcid.org/0000-0003-4775-3846)
- Richard P. Sullivan (ORCID: https://orcid.org/0000-0001-7176-1673)
- Owen James Sansom (ORCID: https://orcid.org/0000-0001-9540-3010)
- Joanne Edwards (ORCID: https://orcid.org/0000-0002-7192-6906)
- Jennifer R. Hay (ORCID: https://orcid.org/0000-0001-9973-4992)
- Simon Parkinson Bach (ORCID: https://orcid.org/0000-0001-8412-7241)
- David N. Church (ORCID: https://orcid.org/0000-0002-4617-962X)
- Graeme I. Murray (ORCID: https://orcid.org/0000-0003-3981-2420)
- Maxime W. Lafarge (ORCID: https://orcid.org/0000-0001-9235-783X)
- Jean‐Baptiste Cazier (ORCID: https://orcid.org/0000-0001-7581-9051)
- Noori Maka (ORCID: https://orcid.org/0009-0001-7402-5054)
- Ultan McDermott (ORCID: https://orcid.org/0000-0001-9032-4700)
- Gary Middleton
- Enric Domingo (ORCID: https://orcid.org/0000-0003-4390-8767)
- Tim Maughan (ORCID: https://orcid.org/0000-0002-0580-5065)
- Michael Youdell
- James Robineau
- Clare Orange (ORCID: https://orcid.org/0000-0001-9155-3468)
- Andrew Blake (ORCID: https://orcid.org/0000-0002-8154-6253)
- David J. Adams (ORCID: https://orcid.org/0000-0001-9490-0306)
- Karin A. Oien (ORCID: https://orcid.org/0000-0002-5237-275X)
- Ingrid Berg (ORCID: https://orcid.org/0000-0002-7058-1969)
- Dr philip dunne
- Jim Hill
- Emma Jaeger
- Hannah Morgan (ORCID: https://orcid.org/0009-0008-8275-6990)
- Dennis Horgan
- Mark Lawler
- Campbell Roxburgh
- Maxime Lafarge
- Ismail Gögenur (ORCID: https://orcid.org/0000-0002-3753-268X)
- Simon Leedham
- Philip Quirke
- Keara Redmond
- Richard Wilson
- Claire Hardy
- Rachel Kerr
- Jen Hay
- Andrew Beggs
- Dion Morton
- Steven Walker
- Bernard Hild (ORCID: https://orcid.org/0009-0001-7501-6109)
- Richard Kennedy
- Francesca Buffa
- Matthew Seymour
- Louise Brown
- Peter Campbell
- Christopher Holmes
- Chieh-Hsi Wu
Institutions
- University of Leeds (GB)
- University of Basel (CH)
- University of Zurich (CH)
- Cancer Research UK (GB)
- Wellcome Sanger Institute (GB)
- University Hospital of Basel (CH)
- University of Oxford (GB)
- University Hospital of Zurich (CH)
- The Christie NHS Foundation Trust (GB)
- Cancer Research UK Scotland Institute (GB)
- Oxford University Hospitals NHS Trust (GB)
- Queen Elizabeth University Hospital (GB)
- University of Southampton (GB)
- Varian Medical Systems (United States) (US)
- University of Glasgow (GB)
- Medical Research Council (GB)
Publication Details
- Journal
- Journal of Clinical Oncology
- Published
- 2026-11-06
- DOI
- https://doi.org/10.1200/jco-25-02761
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Amgen
- Bristol-Myers Squibb
- AstraZeneca
- GlaxoSmithKline
- Varian Medical Systems
- Universität Basel
- Ludwig Institute for Cancer Research
- Merck KGaA
- NHS Greater Glasgow and Clyde
- Moderna
- Cancer Research UK
- National Institute for Health and Care Research
- University of Southampton
- University of Oxford
- University of Glasgow
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Cancerfonden
- Leids Universitair Medisch Centrum
- Oxford University Hospitals NHS Foundation Trust
- Universität Zürich
- Uppsala Universitet
- Universitätsspital Zürich
- Sjællands Universitetshospital
- Medical Research Council
- NIHR Oxford Biomedical Research Centre