Circulating tumor DNA (ctDNA) has garnered attention in recent years as a potential noninvasive biomarker that could help determine prognosis and treatment responses in solid tumors. They could also provide a more complete picture of tumor genetics than the limited samples often available from a biopsy.
ctDNA studies have been conducted in a range of solid tumors, but esophageal cancer has received less attention than other cancers. It is currently diagnosed by endoscopy, but this method is not suitable for population-wide surveillance because of its cost and invasiveness.
Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type of esophageal cancer in China, and it is difficult to diagnose using normal radiological techniques because of the hollow nature of the esophagus.
In a virtual poster session at the annual meeting of the American Society for Radiation Oncology, Xin Wang, MD, discussed the results of a small study looking at ctDNA and ESCC. “We aimed to investigate if ctDNA could detect disease progression before radiological imaging and try identifying patients with inferior prognosis based on ctDNA positivity and dynamics,” said Dr. Wang, who is a researcher at the Chinese Academy of Medical Sciences, Beijing.
85% of enrolled patients were male, and the median age at diagnosis was 64 years. The gross tumor volume was larger in patients with ctDNA-positive tumors at baseline 40.1 cm3 versus 28.7 cm3 (P = .001) and 14% underwent esophagectomy following radiotherapy, compared with 58% of the ctDNA-negative group (P = .008). Other baseline factors were similar between the two groups.
The researchers used a 474-gene panel to analyze plasma samples. 106 of the genes are known to be associated with radiosensitivity. Prior to radiotherapy (T0), 28 of 40 patients (70%) had a positive ctDNA sample. At week 4 of radiotherapy (T1), 42% of 36 patients were ctDNA positive. One to 3 months after radiotherapy/chemoradiotherapy (T2), among 27 patients, 30% were ctDNA positive. 27 patients ultimately underwent esophagectomy, while 9 did not have surgery. Three to 6 months after radiotherapy/chemoradiotherapy (T3), among 23 patients, 22% were ctDNA positive. Of 14 patients alive after 1 year, 43% were ctDNA positive.
Over a median follow-up of 20.6 months, 17 patients were diagnosed with progression through radiological imaging. Of these, 13 patients (77%) were ctDNA positive before or after progression (Cohen’s kappa, 0.512; P < .01). The mean lead time was 5.5 months (95% confidence interval, 1.5-9.4 months).
The researchers also observed links between ctDNA and survival. “We observed a strong association between inferior progression-free survival [PFS] and ctDNA positivity at T1, T2, and T3 time points. Similar associations were detected in OS [overall survival] as well,” Dr. Wang said.
In a multivariate analysis, ctDNA positivity at T1 was associated worse PFS (hazard ratio, 3.35; 95% CI, 1.10-10.22), and there was a trend toward worse overall survival (HR, 2.48; 95% CI, 0.83-7.37). There were no statistically significant associations between ctDNA positivity and PFS or OS at T2.
Twenty-one patients experienced a decrease in ctDNA concentration between T0 and T1. Of these, eight patients achieved a clearance of ctDNA by T1, and they had a trend toward better PFS than patients who did not achieve clearance (HR, 0.31; P = .06).
“The relatively poor locoregional recurrence-free survival remains related to ctDNA positivity at T1. Interestingly, for ctDNA-negative patients who received surgery, none of them were diagnosed with radiological progression. To summarize, ctDNA is a promising biomarker for detecting disease progression. Positive ctDNA status indicates for PFS and OS, but patients achieving ctDNA clearance after radiation are likely to have a better PFS. There is also a potential association between ctDNA positivity at the fourth week during radiation therapy and higher risk of local recurrence, but further studies with a larger sample size are required,” Dr. Wang said.
Ann Raldow, MD, who served as a discussant following the poster presentation, pointed out that ctDNA has been found to be a useful prognostic and predictive tool in colon cancer. Of course, the ctDNA and esophageal cancer space is still in its infancy, and I would really encourage future studies to incorporate ctDNA as part of what they’re studying so that we can get more information about both the prognostic and predictive value of ctDNA in esophageal cancer,” said Dr. Raldow, who is an assistant professor of radiation oncology, University of California, Los Angeles.
Dr. Wang has no relevant financial disclosures. Dr. Raldow had received research funding from Intelligent Automation, Clarity, and Viewray.