Discussion
tumor, colorectal cancer
METASTATIC COLORECTAL CANCER, COLORECTAL CANCER, TUMOR, METASTASIS, METASTASES
Several early-phase clinical trials have shown specific anti-cancer effects from more drugs than recommended by clinical guidelines (such as ESMO and NCCN), but the average effect is too low to be generally approved. Also, third-line drugs recommended in international guidelines have no substantial clinical benefit, and it is not known which patients will benefit from re-challenge with a previously given treatment. A standard for identifying the patients who may benefit from these drugs is lacking. Functional precision medicine based on patient-derived tumor organoids for drug sensitivity screening is a new platform with a robust preclinical rationale, but prospective and interventional evidence is scarce. To our knowledge, this is the largest prospective clinical study using TDOs and drug sensitivity screening for the treatment of metastatic colorectal cancer after standard treatments.We demonstrated that precision oncology using a functional approach with organoids derived from the individual patient’s metastasis and in vitro sensitivity testing was feasible. The primary endpoint was met, as half of the patients (17 of 34) were without progression at two months compared to the predefined limit of at least 14 of 45. A limitation of the study was the non-randomized comparison with the control arm derived from two historic last-line phase III trials. Another limitation was the rate of success in generating TDOs. To improve the rate, others have suggested organizing biopsy sessions and introducing new methods [In several observational trials, patient-derived tumor organoids underwent drug screening with a subsequent correlation between observed sensitivity and clinical effect. Wang et al. [Ooft et al. [The clinical applicability of our functional approach could be argued against based on the challenges in the culture of biopsies from heavily pre-treated metastases and patients at risk of clinical deterioration. Ninety patients entered our trial, successful biopsies were obtained in 82, and only 34 received individualized treatment (37.8%). However, the much more widely used genomic approach results in a lower rate of treated patients. In a large trial with 6000 patients, molecular profiling was successful in 93% while 18% were offered treatment [In the daily clinic, several treatment decisions to be made with colorectal cancer patients might benefit from establishing TDOs and ex-vivo sensitivity data. Even though the effect of different standard chemotherapies is comparable, selecting the most effective first-line treatment may impact the overall outcome and increase the resection rate in potentially resectable cases. In the adjuvant setting, treatment is based on risk factors such as lymph node positivity. Tumor-derived organoids is an encouraging model for refining the selection of the best treatment for a specific patient.In conclusion, this is the largest prospective, interventional clinical trial of last-line systemic therapy in colorectal cancer based on tumor-derived organoids. We showed improved clinical outcomes compared to that expected from the best supportive care alone. Although our study has limitations, including a one-arm design and a historical control, the findings herein reported provide valuable insights into the potential clinical utility of TDOs in guiding last-line systemic therapy in colorectal cancer.