Related Experiment Video
Updated: Dec 6, 2025
Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
Published on: February 24, 2023
In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in
Sudhir B Malla1, David J Fisher2, Enric Domingo3
1Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom.
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.
Insights
The DNA damage immune response (DDIR) assay does not predict oxaliplatin chemotherapy response in colorectal cancer. However, DDIR may identify tumors suitable for immune checkpoint blockade therapy.
Area of Science:
- Oncology
- Cancer Immunology
- Genomics
Background:
- The DNA damage immune response (DDIR) assay is established for predicting platinum-based chemotherapy response in breast and esophageal cancers.
- DDIR is linked to homologous recombination and Fanconi anemia pathway deficiencies.
- Currently, no validated biomarker predicts oxaliplatin response in colorectal cancer.
Purpose of the Study:
- To evaluate the DDIR assay's predictive value for oxaliplatin-based chemotherapy in colorectal cancer.
- To characterize the biological features of DDIR-positive colorectal cancer.
Main Methods:
- Analysis of DDIR status in colorectal cancer patients from the FOCUS (n=361, stage IV) and FOxTROT (n=97, stage II/III) trials.
- Assessment of whole transcriptome, mutation, and IHC data to interrogate DDIR biology.
- Refinement of the DDIR signature based on IFN-related chemokine signaling.
Main Results:
- DDIR-negative patients showed a trend toward improved outcomes with oxaliplatin chemotherapy compared to DDIR-positive patients.
- DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1.
- The refined DDIR assay did not predict oxaliplatin response in colorectal cancer.
Conclusions:
- DDIR positivity does not predict improved response to oxaliplatin in colorectal cancer.
- The DDIR assay may identify immune-rich tumors potentially responsive to immune checkpoint blockade, complementing MSI status.
