Drugs targeting the epidermal growth factor receptor (EGFR), such as panitumumab and cetuximab, are standard of care for metastatic colorectal cancer (mCRC) patients with RAS/BRAF-wildtype tumors. Nevertheless, a fraction of these patients does not respond to them. There is a clinical need for an effective biomarker to further select patients for EGFR inhibition. A promising predictive biomarker is in vitro response testing using patient-derived organoids (PDOs).
Drug screens were performed by exposing 19 PDOs from 18 patients (1 patient with 2 PDOs) to a concentration range of panitumumab for 5 days. Drug sensitivity was measured by cell viability. Growth rate (GR) inhibition metrics were used for drug response curve fitting (area under the curve [GRAUC], GRmax) to quantify PDO sensitivity. We compared in vitro sensitivity for all PDOs based on RAS/BRAF mutational status and sidedness. PDO sensitivity (n=6) was also compared to patient response (n=5), which was evaluated using % change in the sum of the size of target lesions on CT scans.
PDOs derived from left-sided RAS/BRAF-wildtype tumors were more sensitive to panitumumab than rectum and right-sided RAS/BRAF-wildtype tumors and RAS/BRAF-mutant tumors (p < 0.05, Kruskal-Wallis test), concurrent with patient response in clinical trials. We observed varying PDO sensitivities to panitumumab for left-sided RAS/BRAF-wildtype tumors. For 6 PDOs receiving panitumumab, decrease in the size of target lesions was associated with PDO response in most patients (GRAUC, GRmax). PDOs from patients previously exposed to chemotherapy did not show increased resistance to panitumumab.
We confirmed panitumumab sensitivity for PDOs from left-sided RAS/BRAF-wildtype tumors. PDOs from RAS/BRAF-wildtype rectum tumors were less sensitive to panitumumab compared to other left-sided tumors. Even within PDOs from left-sided RAS/BRAF-wildtype tumors, sensitivity to panitumumab varied. These results imply that PDOs may further aid in guiding EGFR inhibition compared to molecular pathology and sidedness only. We demonstrate that PDO response is associated with patient response to panitumumab, suggesting that PDOs can serve as a predictive biomarker for EGFR targeting treatment.
ABR NL61668.041.17.
University Medical Center Utrecht (UMCU).
Foundation Hubrecht Organoid Technology.
All authors have declared no conflicts of interest.