Skip to main content
NCBI home page
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2021 Jan;25(2):1–32. doi: 10.3310/hta25020

Intratumoural immune signature to identify patients with primary colorectal cancer who do not require follow-up after resection: an observational study.

John N Primrose, Siân A Pugh, Gareth Thomas, Matthew Ellis, Karwan Moutasim, David Mant
PMCID: PMC7812416  PMID: 33416473

Abstract

BACKGROUND

Following surgical and adjuvant treatment of primary colorectal cancer, many patients are routinely followed up with axial imaging (most commonly computerised tomography imaging) and blood carcinoembryonic antigen (a tumour marker) testing. Because fewer than one-fifth of patients will relapse, a large number of patients are followed up unnecessarily.

OBJECTIVES

To determine whether or not the intratumoural immune signature could identify a cohort of patients with a relapse rate so low that follow-up is unnecessary.

DESIGN

An observational study based on a secondary tissue collection of the tumours from participants in the FACS (Follow-up After Colorectal Cancer Surgery) trial.

SETTING AND PARTICIPANTS

Formalin-fixed paraffin-embedded tumour tissue was obtained from 550 out of 1202 participants in the FACS trial. Tissue microarrays were constructed and stained for cluster of differentiation (CD)3+ and CD45RO+ T lymphocytes as well as standard haematoxylin and eosin staining, with a view to manual and, subsequently, automated cell counting.

RESULTS

The tissue microarrays were satisfactorily stained for the two immune markers. Manual cell counting proved possible on the arrays, but manually counting the number of cores for the entire study was found to not be feasible; therefore, an attempt was made to use automatic cell counting. Although it is clear that this approach is workable, there were both hardware and software problems; therefore, reliable data could not be obtained within the time frame of the study.

LIMITATIONS

The main limitations were the inability to use machine counting because of problems with both hardware and software, and the loss of critical scientific staff. Findings from this research indicate that this approach will be able to count intratumoural immune cells in the long term, but whether or not the original aim of the project proved possible is not known.

CONCLUSIONS

The project was not successful in its aim because of the failure to achieve a reliable counting system.

FUTURE WORK

Further work is needed to perfect immune cell machine counting and then complete the objectives of this study that are still relevant.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN41458548.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 2. See the NIHR Journals Library website for further project information.

Plain language summary

Bowel cancer (also known as colorectal cancer) is the fourth commonest cancer in the UK. When the cancer is confined to the bowel and/or the surrounding lymph nodes (early bowel cancer), it is typically treated with an operation to remove the cancer with or without the addition of chemotherapy. Following this treatment, many patients will be cured, but in approximately one in five patients the cancer may come back (recur) either in the bowel or in another organ (e.g. the liver). Consequently, after treatment of early bowel cancer, clinicians often follow up patients in the hope of detecting any recurrent cancer at an early and treatable stage. For the four out of five patients whose cancer will never recur, this follow-up is unnecessary and burdensome on both the NHS and the patients. Better markers are needed to inform which patients do and do not need to undergo this surveillance. Over the last decade, evidence has accumulated to show that the way that a patient's immune system responds to a cancer influences the likelihood of the cancer recurring. It is plausible that those with the most immune cells in their cancer have such a small chance of recurrence that follow-up is not necessary. To validate this in an accurately followed-up population of patients with bowel cancer, we collected cancer tissue specimens from 701 patients in the Follow-up After Colorectal Surgery (FACS) trial and developed methods to count the number of immune cells in their cancers. At present, methods are still under development to automate the process. Indeed, if this were ever to become part of routine practice in NHS laboratories, then automation would be essential.

Full text of this article can be found in Bookshelf.

References

  1. Bastiaenen VP, Hovdenak Jakobsen I, Labianca R, Martling A, Morton DG, Primrose JN, et al. Consensus and controversies regarding follow-up after treatment with curative intent of nonmetastatic colorectal cancer: a synopsis of guidelines used in countries represented in the European Society of Coloproctology. Colorectal Dis 2019;21:392–416. https://doi.org/10.1111/codi.14503 doi: 10.1111/codi.14503. [DOI] [PubMed]
  2. National Institute for Health and Care Excellence (NICE). Colorectal Cancer: Diagnosis and Management. Clinical Guideline 131. London: NICE; 2011. URL: nice.org.uk/guidance/cg131 (accessed July 2020).
  3. Glimelius B, Tiret E, Cervantes A, Arnold D, ESMO Guidelines Working Group. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl. 6):vi81–8. https://doi.org/10.1093/annonc/mdt240 doi: 10.1093/annonc/mdt240. [DOI] [PubMed]
  4. Labianca R, Nordlinger B, Beretta GD, Mosconi S, Mandalà M, Cervantes A, Arnold D, ESMO Guidelines Working Group. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl. 6):vi64–72. https://doi.org/10.1093/annonc/mdt354 doi: 10.1093/annonc/mdt354. [DOI] [PubMed]
  5. Pugh SA, Shinkins B, Fuller A, Mellor J, Mant D, Primrose JN. Site and stage of colorectal cancer influence the likelihood and distribution of disease recurrence and postrecurrence survival: data from the FACS randomized controlled trial. Ann Surg 2016;263:1143–7. https://doi.org/10.1097/SLA.0000000000001351 doi: 10.1097/SLA.0000000000001351. [DOI] [PubMed]
  6. Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 2012;4:283–301. https://doi.org/10.2147/CLEP.S34285 doi: 10.2147/CLEP.S34285. [DOI] [PMC free article] [PubMed]
  7. Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2007;1:CD002200. https://doi.org/10.1002/14651858.CD002200.pub2 doi: 10.1002/14651858.CD002200.pub2. [DOI] [PubMed]
  8. Rosati G, Ambrosini G, Barni S, Andreoni B, Corradini G, Luchena G, et al. A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma. Ann Oncol 2016;27:274–80. https://doi.org/10.1093/annonc/mdv541 doi: 10.1093/annonc/mdv541. [DOI] [PubMed]
  9. Primrose JN, Perera R, Gray A, Rose P, Fuller A, Corkhill A, et al. Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial. JAMA 2014;311:263–70. https://doi.org/10.1001/jama.2013.285718 doi: 10.1001/jama.2013.285718. [DOI] [PubMed]
  10. Wille-Jørgensen P, Syk I, Smedh K, Laurberg S, Nielsen DT, Petersen SH, et al. Effect of more vs less frequent follow-up testing on overall and colorectal cancer-specific mortality in patients with stage II or III colorectal cancer: the COLOFOL randomized clinical trial. JAMA 2018;319:2095–103. https://doi.org/10.1001/jama.2018.5623 doi: 10.1001/jama.2018.5623. [DOI] [PMC free article] [PubMed]
  11. Jass JR, Ajioka Y, Allen JP, Chan YF, Cohen RJ, Nixon JM, et al. Assessment of invasive growth pattern and lymphocytic infiltration in colorectal cancer. Histopathology 1996;28:543–8. https://doi.org/10.1046/j.1365-2559.1996.d01-467.x doi: 10.1046/j.1365-2559.1996.d01-467.x. [DOI] [PubMed]
  12. George S, Primrose J, Talbot R, Smith J, Mullee M, Bailey D, et al. Will Rogers revisited: prospective observational study of survival of 3592 patients with colorectal cancer according to number of nodes examined by pathologists. Br J Cancer 2006;95:841–7. https://doi.org/10.1038/sj.bjc.6603352 doi: 10.1038/sj.bjc.6603352. [DOI] [PMC free article] [PubMed]
  13. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960–4. https://doi.org/10.1126/science.1129139 doi: 10.1126/science.1129139. [DOI] [PubMed]
  14. Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009;27:5944–51. https://doi.org/10.1200/JCO.2008.19.6147 doi: 10.1200/JCO.2008.19.6147. [DOI] [PubMed]
  15. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, et al. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol 2014;232:199–209. https://doi.org/10.1002/path.4287 doi: 10.1002/path.4287. [DOI] [PMC free article] [PubMed]
  16. Van den Eynde M, Mlecnik B, Bindea G, Fredriksen T, Church SE, Lafontaine L, et al. The link between the multiverse of immune microenvironments in metastases and the survival of colorectal cancer patients. Cancer Cell 2018;34:1012–26.e3. https://doi.org/10.1016/j.ccell.2018.11.003 doi: 10.1016/j.ccell.2018.11.003. [DOI] [PubMed]
  17. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018;391:2128–39. https://doi.org/10.1016/S0140-6736(18)30789-X doi: 10.1016/S0140-6736(18)30789-X. [DOI] [PubMed]
  18. Maby P, Tougeron D, Hamieh M, Mlecnik B, Kora H, Bindea G, et al. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res 2015;75:3446–55. https://doi.org/10.1158/0008-5472.CAN-14-3051 doi: 10.1158/0008-5472.CAN-14-3051. [DOI] [PubMed]
  19. BBC. Citizen Science. URL: www.bbc.co.uk/programmes/articles/4BZZdHm64S051q2lnZ1Nr7p/citizen-science (accessed June 2019).
  20. Carl Zeiss. URL: www.zeiss.com/microscopy/int/products/imaging-systems/axio-scan-z1.html (accessed June 2019).
  21. Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: Open source software for digital pathology image analysis. Sci Rep 2017;7:16878. https://doi.org/10.1038/s41598-017-17204-5 doi: 10.1038/s41598-017-17204-5. [DOI] [PMC free article] [PubMed]
  22. Mant D, Gray A, Pugh S, Campbell H, George S, Fuller A, et al. A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent. Health Technol Assess 2017;21(32). https://doi.org/10.3310/hta21320 doi: 10.3310/hta21320. [DOI] [PMC free article] [PubMed]
  23. Pugh SA, Moutasim K, Jenkins NM, Shinkins B, Thomas G, Mant D, et al. Association between density of tumor infiltrating lymphocytes and disease-free survival (DFS) in patients with resected stage I-III colorectal cancer in the FACS randomized trial. J Clin Oncol 2018;36:3573.

RESOURCES