Personalized multimodal treatment for resectable esophageal cancer by detecting minimal residual disease (MRD) using circulating tumor DNA (ctDNA):

Esophageal cancer is the 7th leading cause of death from cancer in the world and accounts for half a million deaths each year. Squamous cell carcinoma rates remain stable, although adenocarcinoma rates are rising in the western world. For patients with cT1-2N0 disease primary surgery is chosen followed by observation. Neoadjuvant chemoradiotherapy followed by surgery (multimodal treatment) remains the current standard of care in all patients with >cT3 or node positive esophageal cancer. However the risk of recurrence after complete treatment in patients without complete pathological response remains 70-75% with most patients needing palliative chemotherapy or immunotherapy. Recently adjuvant treatment by immunotherapy for one year additional post multimodal treatment showed an increase in disease free survival in patients without a complete pathological response post-surgery. The use of multimodal treatment has improved the prognosis of resectable esophageal cancer, however biomarkers are lacking for the individual patient, resulting in under and overtreatment. In UZ Leuven for example, 36% of patients undergoing primary surgery for presumed local disease, turn out to be understaged at pathological examination. Recurrence rates in this population are as high as 45%. These patients should therefore have been treated with induction chemo radiation and adjuvant immunotherapy when applicable. On the other hand, half of patients with locally advanced esophageal cancer and residual pathological disease are cured by chemoradiation and surgery. Identifying patients correctly, could limit adjuvant immunotherapy with its associated toxicity and costs. In patients that do need adjuvant treatment, the current duration of one year is arbitrarily chosen and probably too long. With this project, we want to measure the value of minimal residual disease (MRD) testing using circulating tumour DNA (ctDNA) during the multimodal treatment of esophageal cancer. First of all, we hypothesize that the degree to which ctDNA is detectable at diagnosis can improve the clinical staging and help to refine the multidisciplinary treatment decision. Second, we aim to determine the potency of a postoperative test to identify patients who are cured after surgery and do not need additional interventions. Finally, we aim to observe ctDNA dynamics/clearance at serial time points during adjuvant immunotherapy to optimize treatment duration in the future.