Genetics and Genomics

Longitudinal monitoring of circulating tumour DNA improves prognostication and relapse detection in gastroesophageal adenocarcinoma

Abstract

Background

Gastroesophageal adenocarcinoma (GOA) has poor clinical outcomes and lacks reliable blood markers. Here we present circulating tumour DNA (ctDNA) as an emerging biomarker.

Methods

Forty patients (17 palliative and 23 curative) were followed by serial plasma monitoring. Primary tumour DNA was analysed by targeted next-generation sequencing to identify somatic single-nucleotide variants (SNVs), and Nanostring nCounter® to detect copy number alterations (CNAs). Patient-specific SNVs and CNA amplifications (CNAamp) were analysed in plasma using digital droplet PCR and quantitative PCR, respectively.

Results

Thirty-five patients (13 palliative, 22 curative) had ≥1 SNVs and/or CNAamp detected in primary tumour DNA suitable for tracking in plasma. Eighteen of 35 patients (nine palliative, nine curative) had ≥1 ctDNA-positive plasma sample. Detection of postoperative ctDNA predicted short RFS (190 vs 934 days, HR = 3.7, p = 0.028) and subsequent relapse (PPV for relapse 0.83). High ctDNA levels (>60.5 copies/ml) at diagnosis of metastatic disease predicted poor OS (90 vs 372 days, HR = 11.7 p < 0.001).

Conclusion

Sensitive ctDNA detection allows disease monitoring and prediction of short OS in metastatic patients. Presence of ctDNA postoperatively predicts relapse and defines a ‘molecular relapse’ before overt clinical disease. This lead time defines a potential therapeutic window for additional anticancer therapy.

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Fig. 1: Consort diagram of patient workflow.
Fig. 2: Oncoprint of gene mutations and copy number changes in 37 GOA tumours.
Fig. 3: Treatment timeline for five palliative patients, showing ctDNA monitoring.
Fig. 4: Consort diagram of the distribution of patients within the curative patient cohort with ctDNA-positive/negative blood samples.
Fig. 5: Survival in patients receiving surgery with curative intent, in days from surgery.
Fig. 6: Overall survival in GOA patients with metastatic disease and a trackable SNV.

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Acknowledgements

We would like to acknowledge K. Kulbicki for help with sample management from the Leicester biobank, and L. Primrose, J. Riley and V. Parmar for assistance with sample processing.

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Affiliations

Authors

Contributions

Study Concepts: M.O., B.O., C.R., A.T. and J.S. Study Design: M.O., B.O., A.T. and J.S. Data acquisition: M.O., A.M., B.O., C.R. and A.T. Quality control of data and algorithms: All. Manuscript preparation: M.O., A.M., D.G., A.T. and J.S. Data analysis and interpretation: All. Statistical analysis: M.O., A.M., B.O., D.G., A.T. and J.S. Manuscript editing: M.O., A.M., D.G., A.T. and J.S. Manuscript Review: All.

Corresponding author

Correspondence to Mark R. Openshaw.

Ethics declarations

Ethics approval and consent to participate

Patients were recruited in accordance with the declaration of Helsinki and consented to sample storage and use at the University of Leicester Cancer Research Biobank, Research and development project number UHL11274. Ethical approval for the project was via the East Midlands Local Research Ethics Committee (REC: 13/EM/0196).

Consent for publication

Consent for publication is included within the ethics approval from the East Midlands Local Research Ethics Committee (REC: 13/EM/0196). All patients consented to the Leicester biobank study UHL11274 consented for use of their data in publication.

Data availability

Data are available in supplementary data files attached. Sequencing data readouts can be requested from the corresponding author.

Competing interests

The authors declare no competing interests.

Funding information

This study was funded by a ‘Hope Against Cancer’, Leicester UK grant [RM60G0494] and in conjunction with the UK Department of Health on an Experimental Cancer Medicine Centre grant [C10604/A25151]. A.A.M., K.P. and D.F.G. are funded by a Cancer Research UK via programme grant to J.A.S. [C63713/A25951]. A.A.M. was also funded by a National Institute for Health Research (NIHR) Academic Clinical Fellowship for this research project.

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Openshaw, M.R., Mohamed, A.A., Ottolini, B. et al. Longitudinal monitoring of circulating tumour DNA improves prognostication and relapse detection in gastroesophageal adenocarcinoma. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-1002-8

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