Applications of Liquid Biopsy in Cancer and Beyond
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Liquid biopsies are becoming an increasingly important tool for the early detection, prognosis and monitoring of treatment outcomes in cancer, and hold the promise of transforming the management of other diseases in the future.
Liquid biopsies in cancer
Advances in liquid biopsy technologies are enabling the delivery of personalized medicine, especially for cancer diagnosis and management. Several of these tests for cancer have so far been approved by the US Food and Drug Administration (FDA) for use in patients – and they will undoubtedly continue to become an increasingly important tool for tumor profiling.
In 2004, the CellSearch® system was the first ever liquid biopsy test to receive approval for use in the clinical setting to predict outcomes for advanced breast cancer patients.1 It has also since been approved for monitoring patients with advanced colorectal2 or prostate3 cancer. The test detects the presence of circulating tumor cells (CTC) in a blood sample –patients with higher numbers of these rare cells are predicted to have poorer outcomes compared to those with fewer CTCs in their bloodstream.1
Companion diagnostics, which provide robust genotyping results, are an important part of personalized cancer treatment. The number of FDA-approved liquid biopsies based on the mutational profiling of circulating free DNA (cfDNA) from a blood sample is steadily increasing. In 2013, the cobas® EGFR mutation Test v2 liquid biopsy test for non-small cell lung cancer (NSCLC) was the first test of this type to receive approval.4 It detects mutations in the epidermal growth factor receptor (EGFR) gene – and is used for identifying patients with advanced NSCLC who are eligible for treatment with an approved EGFR inhibitor.5 Similarly, the therascreen® PIK3CA RGQ PCR Kit CDx test is a companion diagnostic for the PI3K inhibitor alpelisib, detecting specific mutations in the PIK3CA gene in breast cancer patients.6
The Guardant360® CDx and FoundationOne® Liquid CDx are two other cfDNA-based liquid biopsy assays approved as companion diagnostics for several targeted therapies, as well as for more comprehensive tumor profiling. 7,8 Such pan-cancer liquid biopsies that use next-generation sequencing to examine several cancer-related genes offer the potential to revolutionize cancer treatment – enabling doctors to identify cancer patients who may benefit from being prescribed targeted therapies off-label, or are eligible to participate in certain clinical trials.
One liquid biopsy test has received FDA approval for the early detection of cancer to date. Epi proColon® is a blood-based screening test that can help identify the presence of colorectal cancer by detecting the methylation of the SEPT9 gene in people aged 50 or older who are unwilling or unable to undergo a colonoscopy.9
Liquid biopsies in neurodegenerative diseases
Developing liquid biopsy tests to diagnose and monitor the progression of neurodegenerative diseases remains a huge challenge. For example, liquid biopsies offer the promise of improving the early detection of Alzheimer’s disease (AD) through a minimally-invasive screening test – and has been studied in cerebrospinal fluid and blood as well as ocular, oral and olfactory fluids.10 Many of these studies have looked to detect abnormal brain proteins linked with the disease, but advances in next-generation sequencing-based methods have led to increasing interest in cell-free RNAs and DNAs as potential biomarkers. The feasibility of using blood extracellular vesicles (EVs), such as exosomes, as a way to diagnose AD and other neurodegenerative diseases has also been investigated.11
What are the other clinical applications of liquid biopsy?
In the future, further advances in liquid biopsy technologies will ultimately lead to improvements in the management and outcomes for a plethora of different illnesses. Opportunities include:
- Improving the diagnosis of infectious diseases12
- Precision dosing for cardiovascular disease13
- Detection of biomarkers associated with certain psychiatric behaviors.14
- Cristofanilli M, Budd GT, Ellis MJ et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–791. doi: 10.1056/NEJMoa040766
- Negin BP, Cohen SJ. Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Options Oncol. 2010;11:1–13. doi: 10.1007/s11864-010-0115-3
- Resel Folkersma L, Olivier Gomez C, San Jose Manso L et al. Immunomagnetic quantification of circulating tumoral cells in patients with prostate cancer: clinical and pathological correlation. Arch Esp Urol. 2010;63:23–31. Link: https://pubmed.ncbi.nlm.nih.gov/20157216/
- Malapelle U, Sirera R, Jantus-Lewintre E et al. Profile of the Roche cobas® EGFR mutation test v2 for non-small cell lung cancer. Expert Rev Mol Diagn. 2017;17(3):209-215. doi: 10.1080/14737159.2017.1288568
- Torres S, González Á, Cunquero Tomas AJ, Calabuig Fariñas S et al. A profile on cobas® EGFR Mutation Test v2 as companion diagnostic for first-line treatment of patients with non-small cell lung cancer. Expert Rev Mol Diagn. 2020;20(6):575-582. doi: 10.1080/14737159.2020.1724094
- Narayan P, Prowell TM, Gao J et al. FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer. Clin Cancer Res. 2021;27(7):1842-1849. doi: 10.1158/1078-0432.CCR-20-3652
- Nakajima EC, Drezner N, Li X et al. FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC. Clin Cancer Res. 2022;28(8):1482-1486. doi: 10.1158/1078-0432.
- Milbury CA, Creeden J, Yip WK et al. Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors. PLoS One. 2022;17(3):e0264138. doi: 10.1371/journal.pone.0264138
- Shirley M. Epi proColon® for Colorectal Cancer Screening: A Profile of Its Use in the USA. Mol Diagn Ther. 2020;24(4):497-503. doi: 10.1007/s40291-020-00473-8
- Soelter TM, Whitlock JH, Williams AS, Hardigan AA, Lasseigne BN. Nucleic acid liquid biopsies in Alzheimer's disease: current state, challenges, and opportunities. Heliyon. 2022;8(4):e09239. doi: 10.1016/j.heliyon.2022.e09239
- Abdel-Haq H. The Potential of Liquid Biopsy of the Brain Using Blood Extracellular Vesicles: The First Step Toward Effective Neuroprotection Against Neurodegenerative Diseases. Mol Diagn Ther. 2020;24(6):703-713. doi: 10.1007/s40291-020-00493-4
- Han D, Li R, Shi J, Tan P, Zhang R, Li J. Liquid biopsy for infectious diseases: a focus on microbial cell-free DNA sequencing. Theranostics. 2020;10(12):5501-5513. doi: 10.7150/thno.45554
- Achour B, Gosselin P, Terrier J et al. Liquid Biopsy for Patient Characterization in Cardiovascular Disease: Verification against Markers of Cytochrome P450 and P-Glycoprotein Activities. Clin Pharmacol Ther. 2022;111(6):1268-1277. doi: 10.1002/cpt.2576
- Kouter K, Paska AV. Biomarkers for suicidal behavior: miRNAs and their potential for diagnostics through liquid biopsy - a systematic review. Epigenomics. 2020;12(24):2219-2235. doi: 10.2217/epi-2020-0196