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 journalArticlepeer-review

13 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 languageEnglish
Pages (from-to)288-300
Number of pages13
JournalClinical Cancer Research
Volume27
Issue number1
Early online date7 Oct 2020
DOIs
Publication statusPublished - Jan 2021

Bibliographical 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.

Keywords

  • BREAST
  • CELLS
  • CHEMOTHERAPY
  • COLON
  • MICROSATELLITE INSTABILITY
  • PATHWAYS
  • REPAIR DEFICIENCY
  • SUBTYPES
  • TUMORS

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