Predicting platinum chemotherapy sensitivity in advanced oesophageal cancer using a DNA Damage Immune Response (DDIR) assay


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Mark Baxter1,Shaun Walsh2,Russell Petty1
1University of Dundee,2NHS Tayside

Abstract

Background

In advanced oesophageal adenocarcinoma (OAC) median overall survival is less than 12 months. Platinum-based chemotherapy (PBC) is the first-line treatment and is associated with significant toxicity.  In the adjuvant setting, positivity of a 44-gene RNA-seq DNA-Damage-Immune-Response (DDIR) assay predicts sensitivity to PBC. Biologically this assay indicates constitutive activation of the cGAS/STING pathway. We aimed to investigate the role of the DDIR assay in predicting response in advanced OAC in our population. Identification of a biomarker for chemotherapy sensitivity may enable dose de-escalation in appropriate patients with a corresponding reduction in toxicity.

Method

Exceptional responders to PBC were defined as having progression free survival ≥18 months from starting treatment. Chemotherapy records identified 9 eligible patients retrospectively. They were matched to poor responders, defined as progression during PBC treatment. We enriched our cohort to maximise the chance of detecting a biological signal. Pre-chemotherapy FFPE biopsy tissue was obtained from Tayside Biorepository. Each sample was tested externally for the Almac DDIR assay and locally with immunohistochemistry for CD4, CD8 and PD-L1. PCR for CXCL10 and CCL5 was performed as a marker of cGAS/STING pathway activation. Local ethical approval was obtained. Funding was provided by Tenovus Scotland.

Results

16 FFPE samples were tested. 1 sample contained insufficient tumour tissue and 2 did not meet quality control. DDIR scores were available for 8 exceptional responders and 5 poor responders. Exceptional responders had a significantly higher median DDIR expression score (0.625 v 0.25, p=0.045). There was no significant difference in tumour CD4, CD8 or PD-L1 between the groups. Results on the cGAS/STING pathway are pending.

Conclusion

This pilot study in advanced OAC suggests that DDIR positivity is associated with predicting response to PBC, which could enable dose de-escalation in the palliative setting. This is ongoing research using patient samples from the GO2 trial.