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Translational relevance:Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with around 1.3 million cases diagnosed each year. Efforts to develop biomarkers of prognosis and response to chemotherapy in CRC have resulted in stratification systems based on components of the tumour microenvironment (TME), highlighting the importance of characterising both molecular and pathological features. The DNA Damage Immune Response (DDIR) transcriptional assay was developed as a predictive biomarker for identifying breast cancer (BC) patients that benefit from DNA-damaging chemotherapy, based on signalling associated with defective homologous recombination DNA repair. Here we show that the DDIR signature does not predict outcomes from oxaliplatin based chemotherapy for localised or metatastic CRC patients in clinical trials. We show that although this predictive assay identifies tumours enriched for defects in the DNA mismatch repair machinery, it primarily identifies immune-rich, albeit exhausted, CRC tumours with competent repair signalling that may respond to immune checkpoint blockade.

No abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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 (<i>n</i> = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (<i>n</i> = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.</p>Results:<p>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.</p>Conclusions:<p>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.</p></div>

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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 (<i>n</i> = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (<i>n</i> = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.</p>Results:<p>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.</p>Conclusions:<p>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.</p></div>

<p>Supplementary Results</p>

<p>supplementary methods</p>

<p>Figures S1-S9, Tables S1, S2</p>