Moving the Needle Forward in Genomically-Guided Precision Radiation Treatment

Abstract

Radiation treatment (RT) is a mainstay treatment for many types of cancer. Recommendations for RT and the radiation plan are individualized to each patient, taking into consideration the patient's tumor pathology, staging, anatomy, and other clinical characteristics. Information on germline mutations and somatic tumor mutations is at present rarely used to guide specific clinical decisions in RT. Many genes, such as ATM, and BRCA1/2, have been identified in the laboratory to confer radiation sensitivity. However, our understanding of the clinical significance of mutations in these genes remains limited and, as individual mutations in such genes can be rare, their impact on tumor response and toxicity remains unclear. Current guidelines, including those from the National Comprehensive Cancer Network (NCCN), provide limited guidance on how genetic results should be integrated into RT recommendations. With an increasing understanding of the molecular underpinning of radiation response, genomically-guided RT can inform decisions surrounding RT dose, volume, concurrent therapies, and even omission to further improve oncologic outcomes and reduce risks of toxicities. Here, we review existing evidence from laboratory, pre-clinical, and clinical studies with regard to how genetic alterations may affect radiosensitivity. We also summarize recent data from clinical trials and explore potential future directions to utilize genetic data to support clinical decision-making in developing a pathway toward personalized RT.

Keywords: DNA; cancer; genes; germline; mutations; oncology; radiation sensitivity; radiation treatment; radiogenomics.

Figure 1

In response to DNA damage response from radiation, a cascade of events along the “gatekeep” and “caretaker” pathways are activated that ultimately leads to cell cycle arrest or DNA repair.

Figure 2

Cell cycle checkpoint “gatekeeper” genes and DNA repair “caretaker” genes are important regulators in ensuring the integrity of the genome prior to cell division. Mutations of these genes can lead to their loss of function and dysfunction of the regulatory mechanism, as well as potential uncontrolled cell growth “carcinogenesis”. These genes also have important roles in conferring “radio-sensitivity” due to impaired surveillance and/or repair of radiation-induced DNA damage.

Figure 3

The Paradigm of Genomically-Guided Radiation Treatment.