Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy

Wendy Allen, Philip Dunne, Simon McDade, Enya Scanlon, Maurice Loughrey, Helen Coleman, Christopher McCann, Kristy McLaughlin, Zsuzsanna Nemeth, Najeeb Ashraf Syed, Puthen Veettil Jithesh, Ken Arthur, Richard Wilson, Victoria 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

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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<0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage II and III disease (p=0.0081 and p<0.0001 respectively), while CRIS-D significantly benefitted in stage III only (p=0.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk of relapse in both stage II and III disease (p=0.0031).

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
Pages (from-to)1-15
Journal JCO Precision Oncology
Volume2018
DOIs
Publication statusPublished - 13 Jun 2018

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Adjuvant Chemotherapy
Colorectal Neoplasms
Immunohistochemistry
Standard of Care
Neoplasms
Tumor-Infiltrating Lymphocytes
Recurrence
Drug Therapy

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Allen, Wendy ; Dunne, Philip ; McDade, Simon ; Scanlon, Enya ; Loughrey, Maurice ; Coleman, Helen ; McCann, Christopher ; McLaughlin, Kristy ; Nemeth, Zsuzsanna ; Syed, Najeeb Ashraf ; Jithesh, Puthen Veettil ; Arthur, Ken ; Wilson, Richard ; Coyle, Victoria ; McArt, Darragh ; Johnston, Patrick ; Murray, Graeme I ; Samuel, Leslie M ; Nuciforo, Paolo ; Jimenez, Jose ; Argiles, Guillem ; Dienstmann, Rodrigo ; Picariello, Lucia ; Nobili, Stefania ; Mini, Enrico ; Sheahan, Kieran ; Ryan, Elizabeth ; Tabernero, Josef ; Messerini, Luca ; Van Schaeybroeck, Sandra ; Lawler, Mark ; Longley, Daniel. / Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy. In: JCO Precision Oncology. 2018 ; Vol. 2018. pp. 1-15.
@article{62e6c8d9bb3f48759b757f29cbf6a0bd,
title = "Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy",
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<0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage II and III disease (p=0.0081 and p<0.0001 respectively), while CRIS-D significantly benefitted in stage III only (p=0.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk of relapse in both stage II and III disease (p=0.0031).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.",
author = "Wendy Allen and Philip Dunne and Simon McDade and Enya Scanlon and Maurice Loughrey and Helen Coleman and Christopher McCann and Kristy McLaughlin and Zsuzsanna Nemeth and Syed, {Najeeb Ashraf} and Jithesh, {Puthen Veettil} and Ken Arthur and Richard Wilson and Victoria Coyle and Darragh McArt and Patrick Johnston and Murray, {Graeme I} and Samuel, {Leslie M} and Paolo Nuciforo and Jose Jimenez and Guillem Argiles, and Rodrigo Dienstmann and Lucia Picariello and Stefania Nobili and Enrico Mini and Kieran Sheahan and Elizabeth Ryan and Josef Tabernero and Luca Messerini and {Van Schaeybroeck}, Sandra and Mark Lawler and Daniel Longley",
year = "2018",
month = "6",
day = "13",
doi = "10.1200/PO.17.00241",
language = "English",
volume = "2018",
pages = "1--15",
journal = "JCO Precision Oncology",
issn = "2473-4284",
publisher = "American Society of Clinical Oncology",

}

Allen, W, Dunne, P, McDade, S, Scanlon, E, Loughrey, M, Coleman, H, McCann, C, McLaughlin, K, Nemeth, Z, Syed, NA, Jithesh, PV, Arthur, K, Wilson, R, Coyle, V, McArt, D, Johnston, P, Murray, GI, Samuel, LM, Nuciforo, P, Jimenez, J, Argiles, G, Dienstmann, R, Picariello, L, Nobili, S, Mini, E, Sheahan, K, Ryan, E, Tabernero, J, Messerini, L, Van Schaeybroeck, S, Lawler, M & Longley, D 2018, 'Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy', JCO Precision Oncology, vol. 2018, pp. 1-15. https://doi.org/10.1200/PO.17.00241

Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy. / Allen, Wendy; Dunne, Philip; McDade, Simon; Scanlon, Enya; Loughrey, Maurice; Coleman, Helen; McCann, Christopher; McLaughlin, Kristy ; Nemeth, Zsuzsanna; Syed, Najeeb Ashraf ; Jithesh, Puthen Veettil ; Arthur, Ken; Wilson, Richard; Coyle, Victoria; McArt, Darragh; Johnston, Patrick; Murray, Graeme I; Samuel, Leslie M ; Nuciforo, Paolo ; Jimenez, Jose ; Argiles, Guillem ; Dienstmann, Rodrigo ; Picariello, Lucia; Nobili, Stefania ; Mini, Enrico; Sheahan, Kieran ; Ryan, Elizabeth; Tabernero, Josef; Messerini, Luca ; Van Schaeybroeck, Sandra; Lawler, Mark; Longley, Daniel.

In: JCO Precision Oncology, Vol. 2018, 13.06.2018, p. 1-15.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy

AU - Allen, Wendy

AU - Dunne, Philip

AU - McDade, Simon

AU - Scanlon, Enya

AU - Loughrey, Maurice

AU - Coleman, Helen

AU - McCann, Christopher

AU - McLaughlin, Kristy

AU - Nemeth, Zsuzsanna

AU - Syed, Najeeb Ashraf

AU - Jithesh, Puthen Veettil

AU - Arthur, Ken

AU - Wilson, Richard

AU - Coyle, Victoria

AU - McArt, Darragh

AU - Johnston, Patrick

AU - Murray, Graeme I

AU - Samuel, Leslie M

AU - Nuciforo, Paolo

AU - Jimenez, Jose

AU - Argiles,, Guillem

AU - Dienstmann, Rodrigo

AU - Picariello, Lucia

AU - Nobili, Stefania

AU - Mini, Enrico

AU - Sheahan, Kieran

AU - Ryan, Elizabeth

AU - Tabernero, Josef

AU - Messerini, Luca

AU - Van Schaeybroeck, Sandra

AU - Lawler, Mark

AU - Longley, Daniel

PY - 2018/6/13

Y1 - 2018/6/13

N2 - 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<0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage II and III disease (p=0.0081 and p<0.0001 respectively), while CRIS-D significantly benefitted in stage III only (p=0.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk of relapse in both stage II and III disease (p=0.0031).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.

AB - 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<0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage II and III disease (p=0.0081 and p<0.0001 respectively), while CRIS-D significantly benefitted in stage III only (p=0.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk of relapse in both stage II and III disease (p=0.0031).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.

U2 - 10.1200/PO.17.00241

DO - 10.1200/PO.17.00241

M3 - Article

C2 - 30088816

VL - 2018

SP - 1

EP - 15

JO - JCO Precision Oncology

JF - JCO Precision Oncology

SN - 2473-4284

ER -