Abstract
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 2196-28524) 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.
Highlights
Introduction of liquid biopsy sampling has the potential to change the management of cancer, as circulating tumor DNA has well-defined prognostic and predictive value across tumor types
This study describes the prognostic value of circulating tumor DNA (ctDNA) in a large prospectively collected cohort of patients with operable esophageal adenocarcinoma (EAC)
We demonstrate that the finding of ctDNA following resection for curative intent is strongly associated with an increased risk of cancer recurrence and shorter survival
Summary
Introduction of liquid biopsy sampling has the potential to change the management of cancer, as circulating tumor DNA (ctDNA) has well-defined prognostic and predictive value across tumor types. CtDNA in plasma following surgical resection has been strongly associated with a high risk of tumor recurrence and ctDNA is used for adjuvant chemotherapy risk stratification in ongoing trials.[1,2] In non-small-cell lung cancer, the presence of specific mutations or fusions in plasma can be used to select patients for targeted therapy and to detect the emergence of resistant clones suitable for subsequent lines of treatment.[3]. 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 1⁄4 0.0003). Conclusions: We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
