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Original article
Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes
  1. David S Williams1,2,
  2. Dmitri Mouradov3,4,
  3. Robert N Jorissen3,4,
  4. Marsali R Newman1,
  5. Elham Amini5,
  6. David K Nickless6,
  7. Julie A Teague6,
  8. Catherine G Fang2,
  9. Michelle Palmieri3,4,
  10. Marie J Parsons4,
  11. Anuratha Sakthianandeswaren3,4,
  12. Shan Li4,
  13. Robyn L Ward7,
  14. Nicholas J Hawkins8,
  15. Ian Faragher9,
  16. Ian T Jones10,
  17. Peter Gibbs3,4,11,12,
  18. Oliver M Sieber3,4,13,14
  1. 1 Department of Pathology, Austin Health, Heidelberg, Victoria, Australia
  2. 2 Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
  3. 3 Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  4. 4 Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  5. 5 Clinipath Pathology, Sonic Healthcare, Perth, Western Australia, Australia
  6. 6 Australian Clinical Labs, The Northern Hospital, Epping, Victoria, Australia
  7. 7 Office of the Deputy Vice-Chancellor (Research), The University of Queensland, Brisbane, Queensland, Australia
  8. 8 Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
  9. 9 Department of Surgery, Western Health, Footscray, Australia
  10. 10 Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia
  11. 11 Department of Medical Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  12. 12 Department of Medical Oncology, Western Health, Footscray, Victoria, Australia
  13. 13 Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia
  14. 14 School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
  1. Correspondence to Dr Oliver M Sieber, Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; oliver.sieber{at}wehi.edu.au

Abstract

Objective Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear.

Design A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients.

Results Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) subtypes.

Conclusion TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

  • colorectal carcinoma
  • immune response
  • tumour markers
  • molecular pathology

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Footnotes

  • Contributors Conceptualisation: DSW, DM, RNJ and OMS; methodology and data acquisition: DSW,DM, RNJ, MRN, EA, DKN, JAT, CGF, MP, MJP, AS, SL and OMS; data curation and statistical analysis: DSW, DM, RNJ, RLW, NJH, IF, ITJ, PG and OMS; resources: DSW, RLW, NJH, IF, ITJ, PG and OMS; writing (original draft): DSW,DM, RNJ and OMS; writing (review and editing): MRN, EA, DKN, JAT, CGF, MP, MJP, AS, SL, RLW, NJH, IF, ITJ and PG; supervision: DSW and OMS; funding acquisition: DSW and OMS.

  • Funding This work was supported by a Cancer Australia Project Grant (APP1120882), a Cancer Council Victoria Grant-in-Aid (1060964), the Victorian Government’s Operational Infrastructure Support Program, a University of Melbourne Department of Pathology Career Development Award and an Austin Medical Research Foundation Project Grant. OMS is a NHMRC RD. Wright Biomedical Fellow (APP1062226). MP is supported by a Cancer Therapeutics CRC (CTx) Top Up PhD Scholarship and Australian Government Research Training Program Scholarship.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval WEHI HREC 12/19.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Not applicable.

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