In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer

Sudhir B. Malla; David J Fisher; Enric Domingo; Andrew Blake; Sylvana Hassanieh; Keara L. Redmond; Susan D. Richman; Michael Youdell; Steven M. Walker; Gemma E. Logan; Aikaterina Chatzipli; Raheleh Amirkhah; Matthew P. Humphries; Stephanie G. Craig; Ultan McDermott; Matthew T. Seymour; Dion G. Morton; Philip Quirke; Nicholas P. West; Manuel Salto-Tellez; Richard D. Kennedy; Patrick G. Johnston; Ian Tomlinson; Viktor H. Koelzer; Letitia Campo; Richard S. Kaplan; Daniel B. Longley; Mark Lawler; Timothy S. Maughan; Louise C. Brown; Philip D. Dunne; The S:CORT Consortium; Graeme Murray

doi:10.1158/1078-0432.CCR-20-3237

In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer

Sudhir B. Malla, David J Fisher, Enric Domingo, Andrew Blake, Sylvana Hassanieh, Keara L. Redmond, Susan D. Richman, Michael Youdell, Steven M. Walker, Gemma E. Logan, Aikaterina Chatzipli, Raheleh Amirkhah, Matthew P. Humphries, Stephanie G. Craig, Ultan McDermott, Matthew T. Seymour, Dion G. Morton, Philip Quirke, Nicholas P. West, Manuel Salto-TellezRichard D. Kennedy, Patrick G. Johnston, Ian Tomlinson, Viktor H. Koelzer, Letitia Campo, Richard S. Kaplan, Daniel B. Longley, Mark Lawler, Timothy S. Maughan^* (Corresponding Author), Louise C. Brown, Philip D. Dunne, The S:CORT Consortium, Graeme Murray

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

Original language	English
Pages (from-to)	288-300
Number of pages	13
Journal	Clinical Cancer Research
Volume	27
Issue number	1
Early online date	7 Oct 2020
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-3237
Publication status	Published - Jan 2021

Keywords

BREAST
CELLS
CHEMOTHERAPY
COLON
MICROSATELLITE INSTABILITY
PATHWAYS
REPAIR DEFICIENCY
SUBTYPES
TUMORS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Malla, S. B., Fisher, D. J., Domingo, E., Blake, A., Hassanieh, S., Redmond, K. L., Richman, S. D., Youdell, M., Walker, S. M., Logan, G. E., Chatzipli, A., Amirkhah, R., Humphries, M. P., Craig, S. G., McDermott, U., Seymour, M. T., Morton, D. G., Quirke, P., West, N. P., ... Murray, G. (2021). In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer. Clinical Cancer Research, 27(1), 288-300. https://doi.org/10.1158/1078-0432.CCR-20-3237

Malla, SB, Fisher, DJ, Domingo, E, Blake, A, Hassanieh, S, Redmond, KL, Richman, SD, Youdell, M, Walker, SM, Logan, GE, Chatzipli, A, Amirkhah, R, Humphries, MP, Craig, SG, McDermott, U, Seymour, MT, Morton, DG, Quirke, P, West, NP, Salto-Tellez, M, Kennedy, RD, Johnston, PG, Tomlinson, I, Koelzer, VH, Campo, L, Kaplan, RS, Longley, DB, Lawler, M, Maughan, TS, Brown, LC, Dunne, PD, The S:CORT Consortium & Murray, G 2021, 'In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer', Clinical Cancer Research, vol. 27, no. 1, pp. 288-300. https://doi.org/10.1158/1078-0432.CCR-20-3237

@article{b50b26913e9747b6b3446f0cc72e81f7,

title = "In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer",

abstract = "Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.",

keywords = "BREAST, CELLS, CHEMOTHERAPY, COLON, MICROSATELLITE INSTABILITY, PATHWAYS, REPAIR DEFICIENCY, SUBTYPES, TUMORS",

author = "Malla, {Sudhir B.} and Fisher, {David J} and Enric Domingo and Andrew Blake and Sylvana Hassanieh and Redmond, {Keara L.} and Richman, {Susan D.} and Michael Youdell and Walker, {Steven M.} and Logan, {Gemma E.} and Aikaterina Chatzipli and Raheleh Amirkhah and Humphries, {Matthew P.} and Craig, {Stephanie G.} and Ultan McDermott and Seymour, {Matthew T.} and Morton, {Dion G.} and Philip Quirke and West, {Nicholas P.} and Manuel Salto-Tellez and Kennedy, {Richard D.} and Johnston, {Patrick G.} and Ian Tomlinson and Koelzer, {Viktor H.} and Letitia Campo and Kaplan, {Richard S.} and Longley, {Daniel B.} and Mark Lawler and Maughan, {Timothy S.} and Brown, {Louise C.} and Dunne, {Philip D.} and {The S:CORT Consortium} and Graeme Murray",

note = "Acknowledgements We are grateful to all the patients and their families who participated in the FOCUS and FOxTROT clinical trials and gave consent to further research on their samples. We are also grateful to the Trial Management Groups and Trial Steering Committees for FOCUS and FOxTROT trials who allowed this work to proceed. This work was originally led by Paddy Johnston from Queen's University Belfast. Sadly, soon after the project commenced Paddy passed away and we would like to dedicate this work tohim. The stratification in colorectal cancer consortium (S:CORT) is funded by a UK Medical Research Council (MRC) Stratified Medicine Consortium programme grant (grant ref MR/M016587/1) and co-funded by Cancer Research-UK. L.C. Brown, D.J. Fisher, and R.S. Kaplan are partially funded by an MRC Core funding grant for the MRC Clinical Trials Unit at UCL (grant code 12023/20). This work was supported by a Cancer Research UK programme grant (to P.D. Dunne, D.B. Longley, P.G. Johnston; C212/A13721). Sample collection for FOxTROT was funded by Yorkshire Cancer Research.",

year = "2021",

month = jan,

doi = "10.1158/1078-0432.CCR-20-3237",

language = "English",

volume = "27",

pages = "288--300",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "1",

}

TY - JOUR

T1 - In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer

AU - Malla, Sudhir B.

AU - Fisher, David J

AU - Domingo, Enric

AU - Blake, Andrew

AU - Hassanieh, Sylvana

AU - Redmond, Keara L.

AU - Richman, Susan D.

AU - Youdell, Michael

AU - Walker, Steven M.

AU - Logan, Gemma E.

AU - Chatzipli, Aikaterina

AU - Amirkhah, Raheleh

AU - Humphries, Matthew P.

AU - Craig, Stephanie G.

AU - McDermott, Ultan

AU - Seymour, Matthew T.

AU - Morton, Dion G.

AU - Quirke, Philip

AU - West, Nicholas P.

AU - Salto-Tellez, Manuel

AU - Kennedy, Richard D.

AU - Johnston, Patrick G.

AU - Tomlinson, Ian

AU - Koelzer, Viktor H.

AU - Campo, Letitia

AU - Kaplan, Richard S.

AU - Longley, Daniel B.

AU - Lawler, Mark

AU - Maughan, Timothy S.

AU - Brown, Louise C.

AU - Dunne, Philip D.

AU - The S:CORT Consortium

AU - Murray, Graeme

N1 - Acknowledgements We are grateful to all the patients and their families who participated in the FOCUS and FOxTROT clinical trials and gave consent to further research on their samples. We are also grateful to the Trial Management Groups and Trial Steering Committees for FOCUS and FOxTROT trials who allowed this work to proceed. This work was originally led by Paddy Johnston from Queen's University Belfast. Sadly, soon after the project commenced Paddy passed away and we would like to dedicate this work tohim. The stratification in colorectal cancer consortium (S:CORT) is funded by a UK Medical Research Council (MRC) Stratified Medicine Consortium programme grant (grant ref MR/M016587/1) and co-funded by Cancer Research-UK. L.C. Brown, D.J. Fisher, and R.S. Kaplan are partially funded by an MRC Core funding grant for the MRC Clinical Trials Unit at UCL (grant code 12023/20). This work was supported by a Cancer Research UK programme grant (to P.D. Dunne, D.B. Longley, P.G. Johnston; C212/A13721). Sample collection for FOxTROT was funded by Yorkshire Cancer Research.

PY - 2021/1

Y1 - 2021/1

N2 - Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

AB - Purpose: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

KW - BREAST

KW - CELLS

KW - CHEMOTHERAPY

KW - COLON

KW - MICROSATELLITE INSTABILITY

KW - PATHWAYS

KW - REPAIR DEFICIENCY

KW - SUBTYPES

KW - TUMORS

UR - http://www.scopus.com/inward/record.url?scp=85100349573&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-20-3237

DO - 10.1158/1078-0432.CCR-20-3237

M3 - Article

VL - 27

SP - 288

EP - 300

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -

In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer

Abstract

Keywords

UN SDGs

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