Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma

Abstract

<p></p><p>Simple Summary Esophageal cancer is an aggressive disease with dismal survival. Circulating tumor cells (CTCs) may provide useful information for the unmet needs of early predictive and prognostic biomarkers for therapeutic responses and disease progression. Our novel longitudinal CTC findings demonstrated the potential clinical utilities of real-time CTC monitoring for locally advanced esophageal squamous cell carcinoma (ESCC) patients along with curative resection treatment at multiple timepoints for prediction of treatment efficacies, prognostication, and real-time tracking of minimal residual disease for earlier detection of relapse. The presence of pre-surgery CTC clusters is independently associated with relapse. The unfavorable CTC status at any pre-treatment time and 1-/3-month post-surgery are independent prognosticators of disease progression and survival. For patients receiving chemoradiation therapy (CTRT), unfavorable CTC status at pre-/post-CTRT may serve as potential predictive biomarkers for monitoring treatment efficacy and guiding treatment decisions. Longitudinal CTC monitoring may be taken repetitively as non-invasive liquid biopsies to provide supplementary information with clinical imaging. We aim to reveal the clinical significance and potential usefulness of dynamic monitoring of CTCs to track therapeutic responses and improve survival for advanced ESCC patients. Peripheral blood (PB) (n = 389) and azygos vein blood (AVB) (n = 13) samplings were recruited prospectively from 88 ESCC patients undergoing curative surgery from 2017 to 2022. Longitudinal CTC enumeration was performed with epithelial (EpCAM/pan-cytokeratins/MUC1) and mesenchymal (vimentin) markers at 12 serial timepoints at any of the pre-treatment, all of the post-treatments/pre-surgery, post-surgery follow-ups for 3-year, and relapse. Longitudinal real-time CTC analysis in PB and AVB suggests more CTCs are released early at pre-surgery and 3-month post-surgery into the circulation from the CTRT group compared to the up-front surgery group. High CTC levels at pre-treatments, 1-/3-month post-surgery, unfavorable changes of CTC levels between all post-treatment/pre-surgery and 1-month or 3-month post-surgery (Hazard Ratio (HR) = 6.662, p < 0.001), were independent prognosticators for curative treatment. The unfavorable pre-surgery CTC status was independent prognostic and predictive for neoadjuvant treatment efficacy (HR = 3.652, p = 0.035). The aggressive CTC clusters were more frequently observed in AVB compared to PB. Its role as an independent prognosticator with relapse was first reported in ESCC (HR = 2.539, p = 0.068). CTC clusters and longitudinal CTC monitoring provide useful prognostic information and potential predictive biomarkers to help guide clinicians in improving disease management.<br></p>