Liquid biopsy testing for cancer detection in dogs
by Jenny Alonge
Approximately 6 million dogs are diagnosed with cancer every year. The Veterinary Cancer Society estimates that one in four dogs will develop cancer at some point in their life, and almost 50% of dogs older than 10 will develop the condition. Cancer is the leading cause of death in dogs, likely because most cases aren’t detected until the cancer is advanced and prognosis is poor. Research in this area has led to some promising findings, including liquid biopsy testing to help detect genomic alterations in cell-free DNA fragments in blood as a non-invasive means to facilitate earlier cancer detection, characterization, and management to improve patient outcomes.
Liquid biopsy versus current diagnostic methods
Liquid biopsy is a broad term that describes sampling and analyzing biological fluids, such as blood, urine, and other secretions, that can be obtained with minimal or no invasion. Current cancer detection methods have significant drawbacks, including:
- Fine needle aspiration (FNA) cytology — FNA is a minimally invasive, low-risk method to make a preliminary or definitive cancer diagnosis. However, an FNA can be inconclusive or result in a misdiagnosis for various reasons, including low cellularity, artifact, tissue necrosis, and lack of tissue architecture. In addition, not all tumors can be easily accessed to obtain an FNA, and the procedure is contraindicated when the tumor is highly vascular or the body wall is at risk for seeding.
- Traditional biopsy — Traditional biopsies are invasive and entail risks such as infection, internal bleeding, intestinal perforation, fracture after bone biopsy, and non-diagnostic results.
Circulating biomarkers detected by liquid biopsy
Liquid biopsy is used to detect cancer-related biomarkers, including:
- Protein markers — Protein markers are frequently used in human cancer screening to detect colon, prostate, and ovary cancers. Veterinary medicine researchers are using similar ELISA testing methods to measure histone protein concentrations to detect cancer. However, these assays produce a high number of false-positive and false-negative results, because the same proteins that circulate in healthy animals can be increased not only because of cancer, but also inflammation, sepsis, and trauma. Protein markers are most commonly used to monitor cancer in cases with an abnormal value at diagnosis.
- Circulating tumor cells (CTCs) — CTCs are intact tumor cells from the original solid tumor. However, multiple human studies have demonstrated that 20% to more than 50% of patients have no detectable CTCs in the typical sample. Similar results were observed in metastatic canine cancer.
- Circulating nucleic acids — Circulating nucleic acids, and cell-free DNA (cfDNA) in particular, are the most promising circulating biomarkers for non-invasive cancer detection and characterization. As cells experience programmed cell death and necrosis, the cell and nuclei membranes deteriorate, and the contents, including cfDNA, are released into the circulation. While healthy cells and tumor cells contain DNA that becomes cfDNA in circulation, only tumor cells harbor somatic genomic alterations in cancer-related genes. Detecting these genomic alterations in a patient’s cfDNA indicates tumor cells are somewhere in their body.
Next generation sequencing
Current leading liquid biopsy assays use advanced next-generation sequencing (NGS)-based techniques to evaluate across-genome abnormalities and characteristics that have been identified as cancer-related. Most of these techniques don’t identify a particular cancer type, but indicate that some form of cancer is present.
Effectiveness of next-generation sequencing-based liquid biopsy testing for cancer detection in dogs
Veterinary researchers recently performed a retrospective observational study to determine the effectiveness of NGS-based liquid biopsy testing for detecting cancer in dogs in a clinical setting. They reviewed data from 1,500 consecutive clinical samples submitted from liquid biopsy testing that was obtained from medical records, direct communication with the referring clinic, and patient outcome surveys. Results demonstrated that real-world use of NGS-based liquid biopsy testing can deliver test sensitivity and specificity and clinical performance at levels that meet or exceed the test’s clinical validation study.
Liquid biopsy applications
Liquid biopsy is unlikely to completely replace traditional tissue biopsy to diagnose and manage cancer in dogs, but the non-invasive technique has many useful applications, including:
- Screening — Certain dog breeds, including Labrador retrievers, Great Danes, boxers, and rottweilers, are at increased cancer risk, and a dog’s risk also increases with age. Screening high-risk dog populations, such as predisposed breeds and senior dogs, can help identify cancer in the early stages when the condition is more easily managed.
- Diagnosis — When clinical signs are present, a liquid biopsy can determine cancer presence. A result that indicates cancer can help guide decisions about additional diagnostics and treatment strategies.
- Minimal residual disease (MRD) detection — MRD is occult malignant disease that exists after surgery but is undetectable by conventional methods. However, ctDNA can often detect MRD and can be used to guide decisions about adjuvant therapies, such as chemotherapy and radiation.
- Treatment response monitoring — Treatment response is typically monitored by clinical observation, radiography, and ultrasound, but these techniques can be misleading. Tumors can hyperprogress (i.e., grow faster than expected while under treatment) and psuedoprogress (i.e., increase initially in size or appearance followed by regression). Cell-free DNA monitoring may offer more sensitive monitoring of a dog’s treatment response.
- Recurrence monitoring — Cancer recurrence is always a possibility, and routine cfDNA testing after remission can help detect as early as possible that cancer has returned.
Promising advances, such as NGS-based liquid biopsy testing for canine cancer detection and characterization, allow veterinarians to make more informed decisions about cancer treatment strategies, which improves patient outcomes and client satisfaction.
Allison O'Kell, Kathryn Lytle et al. "Clinical experience with next-generation sequencing–based liquid biopsy testing for cancer detection in dogs: a review of 1,500 consecutive clinical cases." Journal of the American Veterinary Medical Association. 17 March 2023. https://doi.org/10.2460/javma.22.11.0526
Jason Chibuk et al. "Horizons in Veterinary Precision Oncology: Fundamentals of Cancer Genomics and Applications of Liquid Biopsy for the Detection, Characterization, and Management of Cancer in Dogs." Front. Vet. Sci., 23 March 2021 Sec. Comparative and Clinical Medicine. Volume 8 - 2021 | https://doi.org/10.3389/fvets.2021.664718
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