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DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial.

Publication ,  Journal Article
Sundar, R; Ng, A; Zouridis, H; Padmanabhan, N; Sheng, T; Zhang, S; Lee, MH; Ooi, WF; Qamra, A; Inam, I; Hewitt, LC; So, JB-Y; Koh, V; Tan, P ...
Published in: Eur J Cancer
December 2019

BACKGROUND: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS). AIM: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort. METHODS: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy. RESULTS: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059) CONCLUSIONS: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC.

Duke Scholars

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Published In

Eur J Cancer

DOI

EISSN

1879-0852

Publication Date

December 2019

Volume

123

Start / End Page

48 / 57

Location

England

Related Subject Headings

  • Survival Rate
  • Randomized Controlled Trials as Topic
  • Proportional Hazards Models
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Neoplasm Grading
  • Neoadjuvant Therapy
  • Middle Aged
  • Male
 

Citation

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Sundar, R., Ng, A., Zouridis, H., Padmanabhan, N., Sheng, T., Zhang, S., … Tan, P. (2019). DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial. Eur J Cancer, 123, 48–57. https://doi.org/10.1016/j.ejca.2019.09.016
Sundar, Raghav, Alvin Ng, Hermioni Zouridis, Nisha Padmanabhan, Taotao Sheng, Shenli Zhang, Ming Hui Lee, et al. “DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial.Eur J Cancer 123 (December 2019): 48–57. https://doi.org/10.1016/j.ejca.2019.09.016.
Sundar R, Ng A, Zouridis H, Padmanabhan N, Sheng T, Zhang S, et al. DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial. Eur J Cancer. 2019 Dec;123:48–57.
Sundar, Raghav, et al. “DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial.Eur J Cancer, vol. 123, Dec. 2019, pp. 48–57. Pubmed, doi:10.1016/j.ejca.2019.09.016.
Sundar R, Ng A, Zouridis H, Padmanabhan N, Sheng T, Zhang S, Lee MH, Ooi WF, Qamra A, Inam I, Hewitt LC, So JB-Y, Koh V, Nankivell MG, Langley RE, Allum WH, Cunningham D, Rozen SG, Yong WP, Grabsch HI, Tan P. DNA epigenetic signature predictive of benefit from neoadjuvant chemotherapy in oesophageal adenocarcinoma: results from the MRC OE02 trial. Eur J Cancer. 2019 Dec;123:48–57.
Journal cover image

Published In

Eur J Cancer

DOI

EISSN

1879-0852

Publication Date

December 2019

Volume

123

Start / End Page

48 / 57

Location

England

Related Subject Headings

  • Survival Rate
  • Randomized Controlled Trials as Topic
  • Proportional Hazards Models
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Neoplasm Grading
  • Neoadjuvant Therapy
  • Middle Aged
  • Male