Functional assay to guide precision radiotherapy by assessing individual patient radiosensitivity

Abstract

Approximately half of all patientswith cancer receive radiation therThe development of a radiation-induced sarcoma (RIS) is a rare but apy (RT) during the course of their treatment, oftenwith curative intent [1]. Radiation therapy is a highly effective modality for treating cancers, but despite advances in treatment planning and delivery, some patients will experience acute toxicity or long-term side effects after RT. Radiation treatments are designed to deliver the prescribed dose of radiation to the tumor while minimizing the risk of a clinically significant toxicity to surrounding normal tissue. The radiation oncologist identifies the optimal RT plan for each patient by comparing dose volume histograms (DVH) for different plans to determine how much radiation dose will be delivered to different volumes of the tumor target and each adjacent normal organ. Utilizing the DVH, the risk of radiation toxicity to a given tissue type can be estimated based on population-level data [2], and for many clinical scenarios a 5% risk for toxicity is applied as a threshold. However, individual patient responses are heterogeneous. Therefore, biomarkers are needed to determine radiosensitivity before treatment and individualize risk assessment. Biomarkers to predict which patients will develop complications after radiation therapy could be used to customize treatment planning by allowing clinicians to prescribe higher doses of radiation which could lead to better tumor control for patients at low risk for developing complications. Moreover, a biomarker that identifies radiosensitivity of a specific patient prior to therapy could guide the selection of a lower radiation dose or even an alternate therapeutic approach omitting RT tominimize radiation dose to normal tissue in high-risk patients. Potential biomarkers of radiation-associated toxicities include genomic sequencing of germline DNA [3], measurement of serum factors [4], and cellular and functional assays following radiation exposure. Previously, levels of radiation-induced CD8 T-lymphocyte apoptosis (RILA) in peripheral blood exposed to radiation ex vivo were shown to predict the risk of fibrosis, a late complication of radiation therapy [5]. In irradiated peripheral blood samples from patients with breast cancer, lower levels of RILA were associated with increased risk for developing breast fibrosis after radiation treatment.