101P - Prediction of radiation responses in patients with locally advanced rectal cancer with a patient-derived organoid-based radiosensitivity model

Background

Identifying locally advanced rectal cancer patients responsive to chemoradiotherapy before surgery remains a challenge. Patient-derived organoid (PDOs) biobanks may potentially predict therapeutic response to chemotherapy and radiation. We conducted a prospective clinical trial with treatment-naive rectal cancer patients and matched patient-derived tumor organoids to determine whether a correlation exists between experimental results obtained after irradiation in patients and organoids.

Methods

Between May 2019 and June 2021, 55 patients who were diagnosed with pathologically confirmed mid-to-lower rectal cancer were prospectively enrolled. High-risk patients with locally advanced rectal cancer (LARC) indicating neoadjuvant chemoradiotherapy (NCRT) according to ESMO guidelines. Pre-NCRT rectal cancer tissue samples were obtained. Tumor organoids were isolated and cultured. The mutational status of tissues and organoids was analyzed. Long course NCRT with total dose of 50.4-55.8Gy in 28 to 31 fractions was performed. Infusional 5-FU or oral capecitabine or XELOX was administered. Radical surgeries performed at 8-12 weeks after completing radiation. Pathologic response after NCRT was evaluated using the tumor regression grade (TRG) system. To validate the response of PDTOs to irradiation in vitro, we performed a radiation dose-dependent (0, 2, 4,6 and 8Gy) survival analysis of 37 PDOs.

Results

PDOs radiation dose-viability curves showed substantial inter-patient heterogeneity in radiosensitivity. PDOs from post-NCRT tissues displayed higher radioresistance than those from treatment-naïve specimens. We observed strong correlation between each group and clinical outcome post NCRT. 6 of 7 patients (85.7%) whose PDOs assigned to PDOs-radioresistant group showed poor response (TRS score = 2) after NRCT, while 4 of 7 patients (57.1%) whose PDOs assigned to PDOs-radiosensitive group displayed good response (TRS = 1) and 2 of 7 patients (28.5 %) showed complete response (TRS = 0).

Conclusions

Our data provide promising evidence for correlations between in vitro organoid responses and clinical responses to NCRT in locally advanced rectal cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Faculty of Medicine, Chulalongkorn University.

Funding

C2F Funding, Chulalongkorn University.

Disclosure

All authors have declared no conflicts of interest.