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

W. L. Allen, P. D. Dunne, S. McDade, E. Scanlon, Maurice Loughrey, Helen Coleman, C. McCann, K. McLaughlin, Z. Nemeth, N. Syed, P. Jithesh, K. Arthur, R. Wilson, Vicky Coyle, Darragh McArt, Graeme Murray, Leslie Samuel, P. Nuciforo, J. Jimenez, G. Argiles & 12 others R. Dienstmann, J. Tabernero, L. Picariello, L. Messerini, S. Nobili, E. Mini, K. Sheahan, E. Ryan, P. G. Johnston, S. Van Schaeybroeck, Mark Lawler, D. B. 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 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 languageEnglish
Pages (from-to)1-15
Number of pages15
JournalJCO Precision Oncology
Volume2018
Issue number2
Early online date13 Jun 2018
DOIs
Publication statusPublished - 2018

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

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Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy. / Allen, W. L.; Dunne, P. D.; McDade, S.; Scanlon, E.; Loughrey, Maurice; Coleman, Helen; McCann, C.; McLaughlin, K.; Nemeth, Z.; Syed, N.; Jithesh, P.; Arthur, K.; Wilson, R.; Coyle, Vicky; McArt, Darragh; Murray, Graeme; Samuel, Leslie; Nuciforo, P.; Jimenez, J.; Argiles, G.; Dienstmann, R.; Tabernero, J.; Picariello, L.; Messerini, L.; Nobili, S.; Mini, E.; Sheahan, K.; Ryan, E.; Johnston, P. G. ; Van Schaeybroeck, S.; Lawler, Mark; Longley, D. B. .

In: JCO Precision Oncology, Vol. 2018, No. 2, 2018, p. 1-15.

Research output: Contribution to journalArticle

Allen, WL, Dunne, PD, McDade, S, Scanlon, E, Loughrey, M, Coleman, H, McCann, C, McLaughlin, K, Nemeth, Z, Syed, N, Jithesh, P, Arthur, K, Wilson, R, Coyle, V, McArt, D, Murray, G, 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 poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy', JCO Precision Oncology, vol. 2018, no. 2, pp. 1-15. https://doi.org/10.1200/PO.17.00241
Allen, W. L. ; Dunne, P. D. ; McDade, S. ; Scanlon, E. ; Loughrey, Maurice ; Coleman, Helen ; McCann, C. ; McLaughlin, K. ; Nemeth, Z. ; Syed, N. ; Jithesh, P. ; Arthur, K. ; Wilson, R. ; Coyle, Vicky ; McArt, Darragh ; Murray, Graeme ; Samuel, Leslie ; Nuciforo, P. ; Jimenez, J. ; Argiles, G. ; Dienstmann, R. ; Tabernero, J. ; Picariello, L. ; Messerini, L. ; Nobili, S. ; Mini, E. ; Sheahan, K. ; Ryan, E. ; Johnston, P. G. ; Van Schaeybroeck, S. ; Lawler, Mark ; Longley, D. B. . / Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy. In: JCO Precision Oncology. 2018 ; Vol. 2018, No. 2. pp. 1-15.
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title = "Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients 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, {W. L.} and Dunne, {P. D.} and S. McDade and E. Scanlon and Maurice Loughrey and Helen Coleman and C. McCann and K. McLaughlin and Z. Nemeth and N. Syed and P. Jithesh and K. Arthur and R. Wilson and Vicky Coyle and Darragh McArt and Graeme Murray and Leslie Samuel and P. Nuciforo and J. Jimenez and G. Argiles and R. Dienstmann and J. Tabernero and L. Picariello and L. Messerini and S. Nobili and E. Mini and K. Sheahan and E. Ryan and Johnston, {P. G.} and {Van Schaeybroeck}, S. and Mark Lawler and Longley, {D. B.}",
note = "This work was funded by Cancer Research UK: C212/A13721 and C11884/A24387",
year = "2018",
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",
number = "2",

}

TY - JOUR

T1 - Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy

AU - Allen, W. L.

AU - Dunne, P. D.

AU - McDade, S.

AU - Scanlon, E.

AU - Loughrey, Maurice

AU - Coleman, Helen

AU - McCann, C.

AU - McLaughlin, K.

AU - Nemeth, Z.

AU - Syed, N.

AU - Jithesh, P.

AU - Arthur, K.

AU - Wilson, R.

AU - Coyle, Vicky

AU - McArt, Darragh

AU - Murray, Graeme

AU - Samuel, Leslie

AU - Nuciforo, P.

AU - Jimenez, J.

AU - Argiles, G.

AU - Dienstmann, R.

AU - Tabernero, J.

AU - Picariello, L.

AU - Messerini, L.

AU - Nobili, S.

AU - Mini, E.

AU - Sheahan, K.

AU - Ryan, E.

AU - Johnston, P. G.

AU - Van Schaeybroeck, S.

AU - Lawler, Mark

AU - Longley, D. B.

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

PY - 2018

Y1 - 2018

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

VL - 2018

SP - 1

EP - 15

JO - JCO Precision Oncology

JF - JCO Precision Oncology

SN - 2473-4284

IS - 2

ER -