Liquid Biopsies for Molecular Biology-Based Radiotherapy

Abstract

Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance.

Keywords: biomarkers; circulating tumor DNA; liquid biopsies; precision oncology; radiation biology; treatment resistance; tumor evolution.

Figure 1

Tracking radiotherapy response using circulating tumor DNA (ctDNA) analysis. Two patients with cancer undergo definitive radiotherapy, with one patient ultimately progressing (pink) and the other patient being cured (teal). Standard radiographic imaging during radiotherapy and follow up is inconclusive due to radiographic similarities between viable tumor and other benign processes such as inflammation. In contrast, ctDNA changes during radiotherapy may identify early and mid-treatment ctDNA changes associated with response to treatment. After completing radiotherapy, ctDNA minimal residual disease can identify patients who are at risk of relapse. Escalating or de-escalating treatment based on ctDNA levels may improve the probability of cure while minimizing the risk of toxicity.

Figure 2

Interrogating tumor heterogeneity, clonal evolution, and resistance to radiotherapy using liquid biopsies. Tumors consist of multiple subclones with distinct genetic alterations. Tumor biopsies sample a single region of one tumor deposit. As a result, resistant subclones may be missed due to sampling error. In contrast, liquid biopsies may characterize the full extent of intratumoral heterogeneity by sampling circulating tumor DNA released from all of the tumor deposits within a patient. Liquid biopsies can also be repeated at multiple time points, enabling the longitudinal tracking of clonal evolution during radiotherapy and the identification of emergent and expanding tumor subclones that mediate radiation resistance.