Modeling rectal cancer to advance neoadjuvant precision therapy.

Progress in rectal cancer therapy has been hindered by the lack of effective disease‐specific preclinical models that account for the unique molecular profile and biology of rectal cancer. Thus, we developed complementary patient‐derived xenograft (PDX) and subsequent in vitro tumor organoid (PDTO) platforms established from preneoadjuvant therapy rectal cancer specimens to advance personalized care for rectal cancer patients. Multiple endoscopic samples were obtained from 26 Stages 2 and 3 rectal cancer patients prior to receiving 5FU/RT and implanted subcutaneously into NSG mice to generate 15 subcutaneous PDXs. Second passaged xenografts demonstrated 100% correlation with the corresponding human cancer histology with maintained mutational profiles. Individual rectal cancer PDXs reproduced the 5FU/RT response observed in the corresponding human cancers. Similarly, rectal cancer PDTOs reproduced significant heterogeneity in cellular morphology and architecture. PDTO in vitro 5FU/RT treatment response replicated the clinical 5FU/RT neoadjuvant therapy pathologic response observed in the corresponding patient tumors (p < 0.05). The addition of cetuximab to the 5FU/RT regiment was significantly more sensitive in the rectal cancer PDX and PDTOs with wild‐type KRAS compared to mutated KRAS (p < 0.05). Considering the close relationship between the patient's cancer and the corresponding PDX/PDTO, rectal cancer patient‐derived research platforms represent powerful translational research resources as population‐based tools for biomarker discovery and experimental therapy testing. In addition, our findings suggest that cetuximab may enhance RT effectiveness by improved patient selection based on mutational profile in addition to KRAS or by developing a protocol using PDTOs to identify sensitive patients. What's new? Rectal cancer has largely been omitted in prior colorectal cancer (CRC) patient‐derived xenograft (PDX) and tumor organoid (PDTO) investigations, due to the vast majority of rectal cancers being radiated prior to surgery. Here, the authors established novel complementary PDX and subsequent PDTO platforms from pre‐neoadjuvant therapy rectal cancers. Furthermore, they demonstrated that cetuximab can selectively potentiate radiation based on KRAS mutational status and identified further mutations that may impact cetuximab sensitivity. Their results also indicated that rectal cancer PDTOs may serve as a clinical tool to identify 5FU/RT‐resistant cancer and assist clinicians with tailoring appropriate personalized therapy for the patient. [ABSTRACT FROM AUTHOR]