Patient-Derived Organoids (PDO) As the Potential Model to Predict Treatment Outcome of Rectal Cancer Patients Underwent Neo-Adjuvant Chemoradiotherapy

Abstract

Recent researches showed patient-derived organoids (PDO) could recapitulate main features of the primary tumors, and could be used as in vitro clinical model to predictive outcome in clinical setting. Here, we have launched the observational investigation to prove whether the PDO radiosensitivity could predict the clinical outcome in locally advanced rectal cancer (LARC) patients (pts) underwent neo-adjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). Primary tumor tissues of LARC pts for PDO culture were collected by rectal biopsy before any treatment. Rectal cancer cells were isolated and cultured following established protocols for PDO culture and expansion. PDOs were exposed to 8Gy X-rays at 246 cGy/min, 5-fluorouracil (10μM) and CPT-11 (10μM), respectively, and PDO images were captured every 3 days in the following 24 days. PDO radiosensitivity and drugs sensitivity was determined by ROC area changes. Tumor response to neoadjuvant therapy was evaluated according to the pathological tumor regression grading (TRG). Finally, PDO radiosensitivity and drug sensitivity data compared with clinical patients outcome. We established 34 rectal adenocarcinoma organoids from 40 pts with 85% success rate. RCO data showed 23, 25 and 17 pts’ organoids were resistant, while 11, 9 and 13 pts’ organoids were sensitive to irradiation, 5-fluorouracil and CPT-11 treatment, respectively. All of the 34 pts received surgery (total mesorectal excision) and got the pathologic TRG data, or achieved clinical complete response (cCR). Clinical data showed 19 pts achieved good response (TRG=0 or 1, or cCR), and other 15 pts had poor response (TRG= 2 or 3). Through comparative analysis, RCO radiosensitivity and drug sensitivity (5-fluorouracil and CPT-11) were concordant with clinical outcome in 76.5% (26/34), 70.6% (24/34) and 70 % (21/30) pts, respectively. In consideration of combined treatment in clinic, chemoradiation responses in patients are highly matched to RCO responses, with 86.70 % sensitivity, 94.70% specificity, 92.90 % positive predict value, 90.0 % negative predict value and 91.20 % accuracy. The patient-derived organoids’ radiosensitivity correlates to clinical outcome and indicated that organoid model may be used to predict TRG and prognosis in LARC patients receiving nCRT. PDO may be potentially used as a biomarker to for treatment stratification and worth study further.