Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling

Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling

The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of <20%. Beyond TNM (tumor–node–metastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we anal...

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Published in:Annals of oncology Vol. 32; no. 4; pp. 522 - 532
Main Authors: Ococks, E., Frankell, A.M., Masque Soler, N., Grehan, N., Northrop, A., Coles, H., Redmond, A.M., Devonshire, G., Weaver, J.M.J., Hughes, C., Lehovsky, K., Blasko, A., Nutzinger, B., Fitzgerald, R.C., Smyth, E.
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01-04-2021
Subjects:
Adenocarcinoma - drug therapy
Adenocarcinoma - genetics
Aged
Biomarkers, Tumor
CHIP
ctDNA
EAC
esophageal adenocarcinoma
Esophageal Neoplasms - genetics
Humans
Liquid Biopsy
Male
Neoplasm Recurrence, Local - genetics
Prospective Studies
CHIP
esophageal adenocarcinoma
EAC
ctDNA
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Summary:The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of <20%. Beyond TNM (tumor–node–metastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we analyze the prognostic potential of ctDNA dynamics in EAC, taking into account clonal hematopoiesis with indeterminate potential (CHIP). A total of 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium data set. A pan-cancer ctDNA panel comprising 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7082× (range 2196-28 524) and ctDNA results correlated with survival. Characteristics of the 97 patients identified were as follows: 83/97 (86%) male, median age 68 years (SD 9.5 years), 100% cT3/T4, 75% cN+. EAC-specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria 16/79 (20%) were ctDNA positive following resection; recurrence was observed in 12/16 (75%) of these. As much as 78/97 (80%) had CHIP analyses that enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded, 10/63 (16%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival for ctDNA-positive patients was 10.0 months versus 29.9 months for ctDNA-negative patients (hazard ratio 5.55, 95% confidence interval 2.42-12.71; P = 0.0003). Similar outcomes were observed for disease-free survival. We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, post-operative ctDNA could be used to risk stratify patients into high- and low-risk groups for intensification or de-escalation of adjuvant chemotherapy. •Exclusion of clonal haematopoiesis variants increased the positive predictive value and specificity of MRD detection by 15% and 6% respectively.
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ISSN:0923-7534
1569-8041
DOI:10.1016/j.annonc.2020.12.010