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

S:CORT Consortium; 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

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

S:CORT Consortium, 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 WestManuel 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

Applied Health Research

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

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 : an official journal of the American Association for Cancer Research
Volume	27
Issue number	1
Early online date	24 Nov 2020
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-3237
Publication status	Published - 1 Jan 2021

Bibliographical note

Keywords

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols/pharmacology
Biological Assay/methods
Biomarkers, Tumor/genetics
Chemotherapy, Adjuvant/methods
Colorectal Neoplasms/genetics
DNA Damage/drug effects
DNA Mutational Analysis
Female
Fluorouracil/pharmacology
Gene Expression Profiling
Humans
Leucovorin/pharmacology
Male
Microsatellite Instability
Middle Aged
Mutation
Neoadjuvant Therapy/methods
Organoplatinum Compounds/pharmacology
Progression-Free Survival
Randomized Controlled Trials as Topic

UN SDGs

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

Access to Document

10.1158/1078-0432.CCR-20-3237Licence: None: All rights reserved

https://eprints.whiterose.ac.uk/166051/Licence: None: All rights reserved

Cite this

S:CORT Consortium, 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., ... Dunne, P. D. (2021). In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(1), 288-300. https://doi.org/10.1158/1078-0432.CCR-20-3237

@article{350bb31b7da24004b1a23e7ef7b5d282,

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 = "Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Biological Assay/methods, Biomarkers, Tumor/genetics, Chemotherapy, Adjuvant/methods, Colorectal Neoplasms/genetics, DNA Damage/drug effects, DNA Mutational Analysis, Female, Fluorouracil/pharmacology, Gene Expression Profiling, Humans, Leucovorin/pharmacology, Male, Microsatellite Instability, Middle Aged, Mutation, Neoadjuvant Therapy/methods, Organoplatinum Compounds/pharmacology, Progression-Free Survival, Randomized Controlled Trials as Topic",

author = "{S:CORT Consortium} and 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}",

note = "{\textcopyright}2020 American Association for Cancer Research.",

year = "2021",

month = jan,

day = "1",

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

language = "English",

volume = "27",

pages = "288--300",

journal = "Clinical cancer research : an official journal of the American Association for Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research",

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S:CORT Consortium, 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 2021, 'In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 27, no. 1, pp. 288-300. https://doi.org/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. / S:CORT Consortium; Malla, Sudhir B; Fisher, David J et al.
In: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 27, No. 1, 01.01.2021, p. 288-300.

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

TY - JOUR

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

AU - S:CORT Consortium

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

PY - 2021/1/1

Y1 - 2021/1/1

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 - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology

KW - Biological Assay/methods

KW - Biomarkers, Tumor/genetics

KW - Chemotherapy, Adjuvant/methods

KW - Colorectal Neoplasms/genetics

KW - DNA Damage/drug effects

KW - DNA Mutational Analysis

KW - Female

KW - Fluorouracil/pharmacology

KW - Gene Expression Profiling

KW - Humans

KW - Leucovorin/pharmacology

KW - Male

KW - Microsatellite Instability

KW - Middle Aged

KW - Mutation

KW - Neoadjuvant Therapy/methods

KW - Organoplatinum Compounds/pharmacology

KW - Progression-Free Survival

KW - Randomized Controlled Trials as Topic

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

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

M3 - Article

C2 - 33028592

SN - 1078-0432

VL - 27

SP - 288

EP - 300

JO - Clinical cancer research : an official journal of the American Association for Cancer Research

JF - Clinical cancer research : an official journal of the American Association for Cancer Research

IS - 1

ER -

S:CORT Consortium, Malla SB, Fisher DJ, Domingo E, Blake A, Hassanieh S et al. In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jan 1;27(1):288-300. Epub 2020 Nov 24. 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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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