Transcriptional subtyping and CD8 immunohistochemistry identifies patients with stage II and III colorectal cancer with poor prognosis who benefit from adjuvant chemotherapy

Wendy L. Allen, Philip D. Dunne, Simon McDade, Enya Scanlon, Maurice Loughrey, Helen G. Coleman, Christopher McCann, Kristy McLaughlin, Zsuzsanna Nemeth, Najeeb Ashraf Syed, Puthen Veettil Jithesh, Ken Arthur, Richard Wilson, Vicky M. Coyle, Darragh McArt, Patrick Johnston, Graeme I. Murray, Leslie M Samuel, Paolo Nuciforo, Jose JimenezGuillem Argiles,, Rodrigo Dienstmann, Lucia Picariello, Stefania Nobili, Enrico Mini, Kieran Sheahan, Elizabeth Ryan, Josef Tabernero, Luca Messerini, Sandra Van Schaeybroeck, Mark Lawler, Daniel Longley

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)
367 Downloads (Pure)

Abstract

Purpose: Transcriptomic profiling of colorectal cancer (CRC) has led to identification of four consensus molecular subtypes (CMS1-4), which have prognostic value in stage II/III disease. More recently, the Colorectal Cancer Intrinsic Subtypes (CRIS) classification system has helped to define the biology specific to the epithelial component of colorectal tumors. However, the clinical value of these classifications in predicting response to standard-of-care adjuvant chemotherapy remains unknown.

Patients and Methods: Using samples from 4 European sites, we assembled a novel stage II/III CRC patient cohort and performed transcriptomic profiling on 156 samples, targeted sequencing and generated a tissue microarray to enable integrated "multi-omics" analyses. We also accessed data from 2 published stage II/III CRC patient cohorts: GSE39582 and GSE14333 (479 and 185 samples respectively).

Results: The epithelial-rich CMS2 subtype of CRC benefitted significantly from adjuvant chemotherapy treatment in both stage II and III disease (p = 0.02 and p < .001, respectively), whereas the CMS3 subtype significantly benefitted in stage III only (P = .001). After CRIS substratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from treatment with adjuvant chemotherapy in stage II and III disease (P = .0081 and P < .001, respectively), whereas the CRIS-D subtype significantly benefitted in stage III only (P = .0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk for relapse in both stage II and III disease (log-rank P = .0031; hazard ratio, 12.18 [95% CI, 1.51 to 98.58]).

Conclusion: Patient stratification using a combination of transcriptional subtyping and CD8 immunohistochemistry analyses is capable of identifying poor prognostic stage II/III patients who benefit from adjuvant standard-of-care chemotherapy. These findings are particularly relevant for stage II disease, where the overall benefit of adjuvant chemotherapy is marginal.

Original languageEnglish
Number of pages15
Journal JCO Precision Oncology
Volume2
Early online date13 Jun 2018
DOIs
Publication statusPublished - 01 Nov 2018

Fingerprint

Dive into the research topics of 'Transcriptional subtyping and CD8 immunohistochemistry identifies patients with stage II and III colorectal cancer with poor prognosis who benefit from adjuvant chemotherapy'. Together they form a unique fingerprint.

Cite this