DNA repair proteins XPF and MUS81 are predictive biomarkers for oxaliplatin-fluorouracil chemotherapy in patients with oesophageal cancer


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Thomas MacGregor1,2, Richard Gillies2, Natasha Sahgal3, Rebecca Carter1, Runjan Chetty4, Lai-Mun Wang4, Nicholas Maynard2, Peter McHugh5, Mark Middleton1, Ricky Sharma1
1Department of Oncology, Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK, 2Department of Upper GI Surgery, Churchill Hospital, OUH NHS Trust, Oxford, UK, 3Wellcome Trust Centre for Human Genetics, Oxford, UK, 4Oxford NIHR Biomedical Research Centre/Department of Cellular Pathology OUH NHS Trust, Oxford, UK, 5Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

Background

Pre-clinical data suggest that oxaliplatin-induced DNA interstrand cross-links (ICLs) are a principal mechanism of tumour cell kill. We tested the hypothesis that expression of ICL repair proteins predicts clinical response to treatment with oxaliplatin-based chemotherapy.

Method

Samples were obtained from 38 patients with oesophageal adenocarcinoma who received neoadjuvant oxaliplatin-fluorouracil chemotherapy in a clinical trial and a historic cohort of 48 patients treated with surgery alone. Expression of 276 genes encoding DNA damage repair proteins was measured in tumour samples obtained before and after chemotherapy. Immunohistochemistry was performed to measure levels of two key ICL repair proteins, XPF and MUS81. Results were tested for association with histopathological regression and 1-year disease-free survival; disease-free survival and overall survival; and alterations in gene and protein expression following treatment. The prognostic significance of XPF and MUS81 expression were explored in the surgery-alone cohort.

Results

Pre-treatment expression levels of 26 DNA damage repair genes were associated with 1-year DFS (P<0.05), including two ICL genes, ERCC1 and EME1. These encode proteins that function as obligate heterodimers; protein levels of their binding partners, XPF and MUS81 respectively, predicted clinical outcomes. Low XPF correlated with pathological response (OR 3.846, P=0.041). Low MUS81 correlated with improved 1-year DFS (OR 5.000, P=0.037) and OS (median not reached v 15.5 months, P=0.013) in the trial patients. Tumour expression of 16 DNA repair genes significantly increased (P<0.05) following chemotherapy, including ERCC1 and MUS81. XPF protein levels also increased following chemotherapy (P=0.004). In the prognostic cohort, neither XPF nor MUS81 levels were associated with OS.

Conclusion

Low pre-treatment levels of XPF and MUS81 are not prognostic, but are predictive of response to oxaliplatin-fluorouracil chemotherapy. They have the potential to be developed as biomarkers for predicting response to platinum chemotherapy.