Circulating tumour DNA (ctDNA) variants can be detected in patients with oesophageal adenocarcinoma (OAC) and may have prognostic significance in a complex disease with typically poor survival.

A Queensland study performed whole-genome and exome sequencing on pre- and post-treatment plasma samples and tissue biopsies obtained perioperatively in 57 patients with locally advanced, resectable OAC.

The study, published in ESMO Open Cancer Horizons, found ctDNA variants in 38% of patients and a total of 90 ctDNA variants (range 0–7 per sample) in pre- and post-therapy plasma samples.

TP53 was the most frequently mutated gene in patients with detectable variants (45%).

The study said the detection of one or two ctDNA variants was significantly associated with disease-specific survival (DSS).

It found ctDNA-positive patients had significantly worse DSS (median 58.8 months) and a trend towards worse PFS (median 23 months) when compared with ctDNA-negative patients (median DSS and median PFS not reached).

The study also found that ‘shedders’, where ctDNA variants in plasma were verified by the primary tumour genomic profile, had worse DSS and worse PFS than ‘non-shedders’ (primary tumour variants not detected in plasma) and patients with no variant detected in their primary tumour.

The study, led by Dr Vanessa Bonazzi from the University of Queensland Diamantina Institute, said it had demonstrated the utility of ctDNA as a clinical marker in OAC which is characterised by intratumour heterogeneity (ITH).

“We showed that when only one tumour biopsy was sequenced, only [a] few variants were identified in both ctDNA and the tumour, most likely due to ITH. When we sequenced multiple biopsies from each patient, there was greater concordance between the tumour and ctDNA genomic profiles,” it said.

“This suggests that tumours may not shed ctDNA homogenously across the tumour mass, and raises the question of whether only certain sub-clones shed ctDNA.”

The researchers concluded ctDNA may represent a viable liquid biopsy for shedders specifically, as it captures the heterogeneity associated with OAC.

“Indeed, these patients have the worst outcomes and it is of particular importance to improve prognostication and treatment options for this group.”

“In clinical trials, ctDNA-positive patients may be the ideal candidates for post-operative immunotherapy. In CheckMate 577, 42 patients with MRD benefited from immunotherapy; perhaps patients that are ctDNA shedders should also be considered for therapy.”

Dr Bonazzi, who coordinates the Cancer Evolution Biobank, told the limbic that the findings supported a personalised medicine approach to OAC in the future.

“Heterogeneity is a big factor in OAC because it adds another layer of complication when trying to treat patients. You manage to treat some of the population of tumour cells …but others might escape the treatment and create potential recurrence and metastasis down the track.”

She said the research was probably 5–10 years ahead of what was feasible in the clinic.

“As researchers we are planning on the treatment that will come in future. We try to develop tools and methods that will help to develop treatment down the track.”

“If for example, I say there is a TP53 mutation and you can follow that in different blood samples in the patient, down the track you could use a TP53 inhibitor and … hopefully be able to target a specific population of cells.”