Differential Response to Radiation Fractionation in Head and Neck Cancer Patient-Derived Xenografts

Abstract

Despite optimal management with conventionally fractionated radiotherapy, head and neck cancer (HNC) mortality is driven by locoregional failure. With the increasing development of hypofractionated regimens in other malignancies, we sought to investigate the sensitivity of patient HNC to radiation fractionation using murine patient-derived xenografts (PDXs). We developed PDXs from three HNC patients who underwent primary surgical resection and enrolled on our IRB-approved (PRO00040992) prospective HNC tumor bank by implanting freshly resected tumors subcutaneously in the flank of NSG-SGM3 mice. PDXs from each patient were randomized to receive no radiation, 2 Gy x 5 fractions delivered daily (conventional arm) or 10 Gy in a single fraction (hypofractionation arm). Tumor volume was measured until 15 days post-RT, when mice were sacrificed. Bulk RNA sequencing analysis was performed on PDX tumors after intervention. Three PDX tumors from three unique patients (P006, P010 and P016) were successfully developed and irradiated per protocol. Unique responses to radiation were seen with each tumor: P010 showed equal sensitivity to both the conventional and hypofractionated regimens; P006 showed intermediate sensitivity to the conventional regimen with high sensitivity to hypofractionation, and P016 was resistant to conventional fractionation but showed sensitivity to hypofractionation. Concurrent with the patient-specific PDX response to fractionation, principal component analysis demonstrated that each patient PDX had a unique signature of differentially expressed genes in response to the conventional and hypofractionated regimens. HNC PDXs show differential tumor and genomic response to radiation fractionation regimens. A precision approach to radiation fractionation for HNC may improve tumor control outcomes in HNCs.