Volume 33, Issue 3, July 2023, Pages 262-278Author links open overlay panel, , , , ,

Recent breakthroughs in circulating tumor DNA (ctDNA) technologies present a compelling opportunity to combine this emerging liquid biopsy approach with the field of radiogenomics, the study of how tumor genomics correlate with radiotherapy response and radiotoxicity. Canonically, ctDNA levels reflect metastatic tumor burden, although newer ultrasensitive technologies can be used after curative-intent radiotherapy of localized disease to assess ctDNA for minimal residual disease (MRD) detection or for post-treatment surveillance. Furthermore, several studies have demonstrated the potential utility of ctDNA analysis across various cancer types managed with radiotherapy or chemoradiotherapy, including sarcoma and cancers of the head and neck, lung, colon, rectum, bladder, and prostate . Additionally, because peripheral blood mononuclear cells are routinely collected alongside ctDNA to filter out mutations associated with clonal hematopoiesis, these cells are also available for single nucleotide polymorphism analysis and could potentially be used to detect patients at high risk for radiotoxicity. Lastly, future ctDNA assays will be utilized to better assess locoregional MRD in order to more precisely guide adjuvant radiotherapy after surgery in cases of localized disease, and guide ablative radiotherapy in cases of oligometastatic disease.

Section snippetsPersonalizing Radiotherapy

Radiation oncology is rapidly evolving and continues to incorporate emerging technologies into the clinical setting. Over the past two decades, numerous innovations have advanced radiation dosimetry and image guidance, which have enabled radiation therapy (RT) plans that both increase dose delivery to the clinical target volume and limit off-target radiation exposure to organs at risk.1 Updated image-guided radiotherapy modalities providing CT or MRI resolution have improved safety margins,

Cell-Free DNA and Precision Radiogenomics

Radiogenomics is an emerging field within radiation oncology that seeks to better understand how tumor genomic features correlate with responses to RT.11, 12, 13 Several genomic, epigenomic, and transcriptomic studies have demonstrated the potential to predict tumor radiosensitivity,10 radioresistance,14,15 and treatment-associated toxicities, based on molecular biomarkers identified in tumor and healthy tissue.11,12 However, tumor biopsy sequencing typically lacks temporal resolution,

Head and Neck Cancer

HNC, a heterogeneous group of malignancies of the mucosal squamous cells lining the upper aerodigestive tract, collectively comprise the seventh most common cancer type globally.53,54 In HNCs, disease localization determines management. For tumors originating in the oral cavity, sinuses, and salivary glands, the primary treatment is surgery with or without neck dissection.55,56 Thyroid cancer is also managed with surgery followed by radioactive iodine (RAI) and occasionally additional external

Lung Cancer

For patients with lung cancer, RT is an essential component of modern treatment paradigms, particularly in cases of nonoperable early-stage or unresectable locoregionally advanced disease. However, a significant subset of patients will experience recurrence after curative-intent treatment,94 providing an opportunity to identify these patients earlier and offer personalized and precise adjuvant therapy while their disease burden is lowest. We demonstrated the prognostic utility of ctDNA MRD

Gastrointestinal Cancers

As the second most prevalent cancer in women and third most prevalent in men, colorectal cancer is one of the most common solid tumor malignancies in the world. Most cases arise in the sigmoid colon or rectum, and patients typically present at stage II or higher.102 While stage II-III colon cancer is treated with surgery which can be followed by adjuvant chemotherapy, stage II-III rectal cancer is typically treated with preoperative RT or CRT followed by surgery.103 Indeed, in a cohort of 230

Genitourinary Cancers

Bladder cancer is the fourth most commonly diagnosed malignancy in men,114 and clinical management of localized disease is largely dependent on the extent to which the tumor penetrates the bladder wall. Approximately 25% of cases are muscle-invasive bladder cancer (MIBC) at the time of presentation, meaning cancer tissue extends into the underlying detrusor muscle. The remaining 75% of patients have non-MIBC (NMIBC) tumors that are retained within the mucosa and submucosa of the bladder.115

Sarcomas

Sarcomas represent a broad class of mesenchymal malignanciesi and consist of 100 different histologic subtypes.143 Despite RT playing an important therapeutic role in stage II-III disease,143,144 most sarcoma liquid biopsy studies tracked ctDNA in patients managed with surgery or chemotherapy.145 As a group, sarcomas tend to harbor low mutational burdens with relatively few recurrently mutated genes, and instead are characterized predominantly by gene fusions and genomic copy-number changes.146,

Emerging Applications

Modern genomic assays hold great promise to further personalize RT. Outside of the disease-specific examples above, we specifically highlight the potential for liquid biopsies to guide individual tumor radiosensitivity prediction, patient radiotoxicity prediction, adjuvant RT or other treatment decisions (in patients with detected MRD), and risk-stratification in oligometastatic disease.

Conclusions and Future Directions

The potential applications of ctDNA to personalized radiogenomics are wide-ranging, from early use pre-RT that may alter therapy plans (or postpone RT altogether), to toxicity and treatment response prediction, to post-RT MRD detection. As the technologies underlying ctDNA continue to evolve, now is a critical time to establish research protocols and sample banking to address these pressing questions in radiation oncology. Importantly, cfDNA can be noninvasively and serially sampled from plasma

Acknowledgments

Figure design: Figures were created using BioRender.com.

View full text

© 2023 Elsevier Inc. All rights reserved.