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, Louise C Brown, Philip D Dunne, S Cort Consortium

Research output: Contribution to journalArticlepeer-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 languageEnglish
Pages (from-to)288-300
JournalClinical Cancer Research
Volume27
Issue number1
Early online date07 Oct 2020
DOIs
Publication statusPublished - 01 Jan 2021

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