Urine-derived bladder cancer organoids (urinoids) as a tool for cancer longitudinal response monitoring and therapy adaptation

BACKGROUND: Bladder cancer is one of the most common cancer types worldwide. Generally, research relies on invasive sampling strategies. METHODS: Here, we generate bladder cancer organoids directly from urine (urinoids). In this project, we establish 12 urinoid lines from 22 patients with non-muscle and muscle-invasive bladder tumours, with an efficiency of 55%. RESULTS: The histopathological features of the urinoids accurately resemble those of the original bladder tumours. Genetically, there is a high concordance of single nucleotide polymorphisms (92.56%) and insertions & deletions (91.54%) between urinoids and original tumours from patient 4. Furthermore, these urinoids show sensitivity to bladder cancer drugs, similar to their tissue-derived organoid counterparts. Genetic analysis of longitudinally generated tumoroids and urinoids from one patient receiving systemic immunotherapy, identify alterations that may guide the choice for second-line therapy. Successful treatment adaptation was subsequently demonstrated in the urinoid setting. CONCLUSION: Therefore, urinoids can advance precision medicine in bladder cancer as a non-invasive platform for tumour pathogenesis, longitudinal drug-response monitoring, and therapy adaptation

Combined KRAS and TP53 mutation status is not predictive in CAPOX-treated metastatic colorectal cancer

The response of colorectal tumours to chemotherapy is highly variable. Preclinical work has shown that the Kirsten ras (KRAS) oncogene sensitizes colorectal tumour cells to oxaliplatin and capecitabine in a wild-type tumour suppressor p53 (TP53)-dependent manner. Therefore, whether or not the combined mutation status of KRAS and TP53 could predict response to chemotherapy in metastatic colorectal cancer was tested. A subgroup of patients from the CAIRO2 study (randomized phase III study on capecitabine, oxaliplatin, bevacizumab with or without cetuximab in first-line advanced colorectal cancer) that received capecitabine plus oxaliplatin (CAPOX) treatment in combination with bevacizumab was selected. The tumours were analyzed for KRAS and TP53 mutations by PCR/sequencing. The relationship between tumour response and genotype was analyzed. The following KRAS/TP53 genotypes were identified: KRASmut/TP53mut n=21, KRASmut/TP53wt n=20, KRASwt/TP53mut n=25, KRASwt/TP53wt n=15. No genotype was associated with a significantly better or worse progression-free or overall survival. The combined mutation status of KRAS and TP53 does not predict response to CAPOX in patients with metastasized colorectal cance

Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy

DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the KRAS and BRAF oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms—for instance signals derived from the microenvironment—must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status