Abstract
BackgroundGastroesophageal adenocarcinoma (GOA) has poor clinical outcomes and lacks reliable blood markers. Here we present circulating tumour DNA (ctDNA) as an emerging biomarker.MethodsForty 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.ResultsThirty-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).ConclusionSensitive 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.
Highlights
Gastroesophageal adenocarcinoma (GOA) has poor clinical outcomes and lacks reliable blood markers
Analysis may detect variants not present in single GOA tumour biopsies,[17] that are present when multiple tumour biopsies are analysed.[18]. This demonstrates the inherent ability of circulating tumour DNA (ctDNA) to reflect underlying tumour heterogeneity, which has been reported in several cancers,[19] and indicates ctDNA may become an important tool in disease monitoring
Sequencing results were orthogonally validated by ddPCR (Supplementary Fig. 8a), showing excellent variant allele frequency (VAF) concordance in tumour DNA (R2 = 0.978, p < 0.001)
Summary
Gastroesophageal adenocarcinoma (GOA) has poor clinical outcomes and lacks reliable blood markers. 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). RESULTS: Thirty-five patients (13 palliative, 22 curative) had ≥1 SNVs and/or CNAamp detected in primary tumour DNA suitable for tracking in plasma. Genetic analysis of GOA has revealed significant genetic heterogeneity, including high levels of somatic alterations comprising single-nucleotide variants (SNVs), short INDELS, translocations and copy number alterations (CNAs).[4,20,21] Previous studies have demonstrated detection of a subset of these variants in plasma cfDNA, using next-generation sequencing (NGS), droplet digital (dd)PCR and quantitative (q)PCR.[18,22,23,24,25]
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