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; Christophe McCann; Kristy McLaughlin; Zsuzsanna Nemeth; Najeeb Ashraf Syed; Puthen Veettil Jithesh; Ken Arthur; Richard Wilson; Vicky M. Coyle; Darragh McArt; Graeme L. Murray; Leslie Samuel; Paolo Nuciforo; Jose Jimenez; Guillem Argiles; Rodrigo Dienstmann; Josef Tabernero; Lucia Picariello; Luca Messerini; Stefania Nobili; Enrico Mini; Kieran Sheahan; Elizabeth Ryan; Patrick G.  Johnston; Sandra Van Schaeybroeck; Mark Lawler; Daniel B.  Longley

doi: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

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

^*Corresponding author for this work

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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 classification systems 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 (156 samples) and performed transcriptomic profiling, 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 (log rank p=0.0031; Hazard ratio=12.18, 95%CI 1.51-98.58).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 language	English
Pages (from-to)	1-15
Number of pages	15
Journal	JCO Precision Oncology
Volume	2
Early online date	13 Jun 2018
DOIs	https://doi.org/10.1200/PO.17.00241
Publication status	Published - 13 Jun 2018

Bibliographical note

This work was funded by Cancer Research UK: C212/A13721 and C11884/A24387

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Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy
© 2018 by American Society of Clinical Oncology Licensed under the Creative Commons Attribution 4.0 License: http://creativecommons.org/licenses/by/4.0/
Final published version, 1.09 MBLicence: CC BY

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Allen, W. L., Dunne, P. D., McDade, S., Scanlon, E., Loughrey, M., Coleman, H. G., McCann, C., McLaughlin, K., Nemeth, Z., Syed, N. A., Jithesh, P. V., Arthur, K., Wilson, R., Coyle, V. M., McArt, D., Murray, G. L., Samuel, L., Nuciforo, P., Jimenez, J., ... Longley, D. B. (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, 2, 1-15. https://doi.org/10.1200/PO.17.00241

Allen, WL, Dunne, PD, McDade, S, Scanlon, E, Loughrey, M, Coleman, HG, McCann, C, McLaughlin, K, Nemeth, Z, Syed, NA, Jithesh, PV, Arthur, K, Wilson, R, Coyle, VM, McArt, D, Murray, GL, Samuel, L, Nuciforo, P, Jimenez, J, Argiles, G, Dienstmann, R, Tabernero, J, Picariello, L, Messerini, L, Nobili, S, Mini, E, Sheahan, K, Ryan, E, Johnston, PG, Van Schaeybroeck, S, Lawler, M & Longley, DB 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. 2, pp. 1-15. https://doi.org/10.1200/PO.17.00241

@article{a637df6798704c9a999ccce4c8d63f49,

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 classification systems 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 (156 samples) and performed transcriptomic profiling, 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 (log rank p=0.0031; Hazard ratio=12.18, 95%CI 1.51-98.58).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.",

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

note = "This work was funded by Cancer Research UK: C212/A13721 and C11884/A24387",

year = "2018",

month = jun,

day = "13",

doi = "10.1200/PO.17.00241",

language = "English",

volume = "2",

pages = "1--15",

journal = "JCO Precision Oncology",

issn = "2473-4284",

publisher = "American Society of Clinical Oncology",

}

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 L.

AU - Dunne, Philip D.

AU - McDade, Simon

AU - Scanlon, Enya

AU - Loughrey, Maurice

AU - Coleman, Helen G.

AU - McCann, Christophe

AU - McLaughlin, Kristy

AU - Nemeth, Zsuzsanna

AU - Syed, Najeeb Ashraf

AU - Jithesh, Puthen Veettil

AU - Arthur, Ken

AU - Wilson, Richard

AU - Coyle, Vicky M.

AU - McArt, Darragh

AU - Murray, Graeme L.

AU - Samuel, Leslie

AU - Nuciforo, Paolo

AU - Jimenez, Jose

AU - Argiles, Guillem

AU - Dienstmann, Rodrigo

AU - Tabernero, Josef

AU - Picariello, Lucia

AU - Messerini, Luca

AU - Nobili, Stefania

AU - Mini, Enrico

AU - Sheahan, Kieran

AU - Ryan, Elizabeth

AU - Johnston, Patrick G.

AU - Van Schaeybroeck, Sandra

AU - Lawler, Mark

AU - Longley, Daniel B.

N1 - This work was funded by Cancer Research UK: C212/A13721 and C11884/A24387

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 classification systems 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 (156 samples) and performed transcriptomic profiling, 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 (log rank p=0.0031; Hazard ratio=12.18, 95%CI 1.51-98.58).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.

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 classification systems 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 (156 samples) and performed transcriptomic profiling, 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 (log rank p=0.0031; Hazard ratio=12.18, 95%CI 1.51-98.58).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.

U2 - 10.1200/PO.17.00241

DO - 10.1200/PO.17.00241

M3 - Article

C2 - 30088816

SN - 2473-4284

VL - 2

SP - 1

EP - 15

JO - JCO Precision Oncology

JF - JCO Precision Oncology

ER -

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

Abstract

Bibliographical note

UN SDGs

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