1565P - ERCC1 gene polymorphism influences overall survival in early oesophageal cancer: Results from the phase III MRC OEO2 randomised controlled trial

Background

Germline polymorphisms may have an association with survival and response to chemotherapy. We examined the gene polymorphism data from the landmark OEO2 trial which compared chemotherapy plus surgery vs surgery alone in early oesophageal cancer. We reviewed common DNA repair genes polymorphisms and selected a subset that has been validated as predictors of survival or chemotherapy toxicity across different tumor types.

Methods

DNA formalin-fixed paraffin embedded normal tissue was available for 515/802 OEO2 patients and successfully extracted in 90% (464/515) of samples. Gene polymorphisms were investigated for GSTP1, TS 3’UTR, TS 5’UTR, OPRT, DYPD, ERCC1, ERCC2, XRCC1 using Sequenom or multiplex PCR and gel electrophoresis. We investigated these polymorphisms and their relationship with clinicopathological variables including overall survival (OS) and progression free survival (PFS).

Results

All patients with the ERCC1_rs116115 CT genotype had superior OS and PFS when compared to those with a non CT genotype, OS HR 0.790 95% CI 0.642-0.972 (p=0.026), PFS HR 0.80 95% CI 0.656-0.979 (p=0.03). When stratified into chemotherapy + surgery (C+S) vs surgery alone (S), OS for those in the C+S arm was statistically significantly better in the CT genotype (OS 1.975 vs 1.547 years p=0.047) (HR 0.744 95% CI 0.55-0.998 p=0.048). In the S arm there was no significant difference in OS in the CT vs non CT genotype (1.339 vs 1.258 years p=0.275) (HR=0.849 95%CI 0.633-1.140 p=0.276). Test of interaction between treatment groups and ERCC1 polymorphisms was not significant for OS (p=0.58) and PFS (p=0.17). In patients who received preoperative chemotherapy, those with ERCC1 CT genotype were more likely to have any response to chemotherapy (Mandard TRG 1-4) than patients with non CT genotypes (CT vs non CT, 63% vs. 37%, p=0.031).

Conclusions

Patients with ERCC1 CT genotype had superior OS and PFS when compared to those with non CT genotype. Patients with ERCC1 CT genotype receiving preoperative chemotherapy had a better response compared to those with non CT genotype. ERCC1 polymorphisms have prognostic implications and may serve as biomarkers for preoperative chemotherapy response.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

MRC medical research council.

Funding

CRUK.

Disclosure

D. Cunningham: Financial Interests, Institutional, Research Grant: Clovis, Eli Lilly, 4SC, Bayer, Celgene, NIHR EME, Roche; Non-Financial Interests, Institutional, Product Samples, Provision of investigational product for study: Leap; Non-Financial Interests, Institutional, Advisory Role: Ovibio. P. Tan: Financial Interests, Personal, Advisory Board, I am on the Venture Corp Council of Experts: Venture Corp; Financial Interests, Personal, Advisory Board, Advisory Board member for Riyadh Biotech City: Riyadh Biotech City; Financial Interests, Institutional, Full or part-time Employment, I am a Professor at Duke-NUS Medical School Singapore: Duke-NUS Medical School; Financial Interests, Institutional, Full or part-time Employment, I serve as the Executive Director of the Genome Institute of Singapore: Agency for Science, Technology and Research; Financial Interests, Institutional, Full or part-time Employment, I serve as the Executive Director of Precision Health Research Singapore under the Ministry of Health.: Precision Health Research Singapore; Financial Interests, Personal, Stocks/Shares, I own shares in Tempus Healthcare: Tempus Healthcare; Financial Interests, Personal, Stocks/Shares, Auristone is a start-up from the Agency of Science, Technology and Research focused on cancer epigenetics: Auristone Pte Ltd. R. Sundar: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Eli Lilly, BMS, Roche, Taiho, AstraZeneca, DKSH, Ipsen; Financial Interests, Personal and Institutional, Local PI: MSD, Taiho, BMS, Novartis; Financial Interests, Personal, Stocks/Shares: Teladoc; Financial Interests, Institutional, Advisory Board: Paxman Coolers; Non-Financial Interests, Advisory Role: Paxman Coolers; Non-Financial Interests, Principal Investigator: MSD, Natera. All other authors have declared no conflicts of interest.