Esophageal Cancer-Derived Organoids to Predict Patients' Treatment Response

Abstract

The absolute 10-year overall survival of esophageal adenocarcinoma (EAC) has significantly increased from 26% to 36% due to neoadjuvant chemoradiotherapy (nCRT) with consecutive radical resection. However, 20-25% of EAC patients don't respond to nCRT and need alternative treatment, and 20-30% have a complete pathological response and may not need resection. Therefore, there is an urgent need for better models to accurately predict response of EAC to nCRT. Accumulating evidence indicates that patient-derived organoids (PDOs) may predict treatment responses, but the ability of PDOs to predict responses to chemoradiation in EAC patients remains unknown. Hence, we generated patient derived EAC cancer organoids (ec-PDOs) to examine their response to nCRT. The biopsies from treatment-naïve EAC patients after informed consent were used to establish ec-PDOs. Next, we investigated the response of ec-PDOs to the components of standard-of-care neoadjuvant treatment, including irradiation, carboplatin, and paclitaxel. Finally, the potential of ec-PDOs to reflect patients' response to nCRT before esophageal resection was evaluated. Mechanically and enzymatically dispersed patient derived EAC biopsies were cultured as ec-PDOs for up to 10 passages, indicating the self-renewal and expansion potential. These ec-PDOs expressed the EAC marker MUC5AC, indicating the EAC origin. Differences in growth kinetics and response to irradiation, carboplatin, and paclitaxel were observed between patients specific ec-PDOs. However, similar dose-response curves were seen within ec-PDOs from the same patient after different passages. This indicates that ec-PDOs exhibit interpatient response heterogeneity but have good reproducible responses within the same patient. Moreover, after combined treatment with irradiation (IR), carboplatin (Car), and paclitaxel (Pac) to mimic nCRT in EAC patients, the stem cell survival of ec-PDOs from patients with complete response (CR) and partial response (PR) are lower than that from those with progressive disease (PD). The preliminary findings in this study suggest a great potential of ec-PDOs to predict patient-specific responses to neoadjuvant treatment in EAC patients.