Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling.

BACKGROUND: The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate <20%. Beyond TNM staging, no reliable risk stratification tools exist and no large-scale studies have profiled 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).

PATIENTS AND METHODS: 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK OCCAMS consortium dataset. A pan-cancer ctDNA panel comprising of 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7,082x (range: 2,196-28,524) and ctDNA results correlated with survival.

RESULTS: Characteristics of the 97 patients identified were: 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 post-resection; recurrence was observed in 12/16 (75%) of these. 78/97 (80%) had CHIP analyses which enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded 10/63 (17%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival ctDNA positive patients was 10.0m vs 29.9m ctDNA negative (HR 5.55, (95% CI 2.42- 12.71, P= 0.0003). Similar outcomes were observed for disease-free survival.

CONCLUSION: We demonstrate in a large, national, prospectively-collected dataset 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.