Liquid Biopsies in Cancer

BIOMARKER ctDNA CTCs Exosomes ISOLATION DNA isolation kits Physical and biological approaches based on microfluidics, filtration and magnetics Physical and biological approaches based on microfluidics, filtration and magnetics ANALYSIS • PCR and NGSbased methods • PCR and NGSbased methods • Proteomics • Histology • PCR and NGS-based methods • Proteomics Techniques used for isolation and analysis2 depend on the type of biomarker the liquid biopsy is targeting. A liquid biopsy involves the sampling and analysis of bodily fluids, such as blood, urine, or saliva, to look for signs of cancer or other diseases. Liquid biopsies can detect a range of biomarker1 types shed by tumors, including: In this infographic, we outline the fundamentals of liquid biopsies and explore their use in cancer diagnosis and monitoring. Circulating tumor DNA (ctDNA) Circulating tumor cells (CTCs) Exosomes What is a liquid biopsy? What can liquid biopsies tell us? Liquid biopsies can be used to provide clinicians with a variety of information3, including: How do liquid biopsies compare to traditional surgical biopsies? Liquid biopsies offer several advantages4 over surgical tumor tissue biopsies, which are considered the current “gold standard” for cancer diagnosis and treatment: Interest in the use of liquid biopsies to revolutionize cancer care is growing, with hopes that they could be developed as reliable and practical screening and monitoring tools for a range of cancers. If and where cancer is present Genomic alterations driving cancer Suitability of a potential treatment If the cancer has spread Effectiveness of an existing treatment Minimal residual disease detection Brain cancer5 Quantification of ctDNA was used to monitor tumor response in children with diffuse midline gliomas, demonstrating the potential liquid biopsies could have in longitudinal surveillance. Breast cancer6 Evidence from the plasmaMATCH trial demonstrated that liquid biopsies analyzing ctDNA can help to reliably match women with advanced breast cancer to effective targeted treatments. Lung cancer7 Liquid biopsies can detect several sensitizing and resistance mutations including EFGR, ROS1, ALK, BRAF and KRAS, informing clinicians of the most appropriate treatment selections for patients with non-small-cell lung carcinoma. Pancreatic cancer8 Study demonstrated the value of liquid biopsy combining CTC and exosome detection for earlier diagnosis of resectable pancreatic ductal adenocarcinomas. CancerSEEK9 Developed by researchers at Johns Hopkins Kimmel Cancer Center, this single blood test can screen for eight common cancer types by evaluating the levels of a combination of protein and ctDNA biomarkers. Prostate cancer10 A team from The Institute of Cancer Research demonstrated the potential of analyzing CTCs to help identify emerging drug resistance in men with advanced prostate cancer. Skin cancer11 Liquid biopsies detecting ctDNA were shown to help predict survival and the chances of cancer returning for malignant melanoma patients. Specificity Detecting highly specific biomarkers is necessary to prevent misdiagnosis. Liquid biopsies must accurately distinguish cancer biomarkers from healthy or other disease markers. Sensitivity Many of the biomarkers liquid biopsies look for are present at incredibly low concentrations, especially at pre-symptomatic stages of cancer. Technologies are needed that can improve the detection of these “needles in haystacks”. Pre-analytical sample handling Efforts are needed to standardize and improve pre-analytical tools and procedures to reduce the chances of errors and associated suboptimal treatment decisions. 1. Zhang W, Xia W, Lv Z, Xin Y, Ni C, Yang L. Liquid biopsy for cancer: circulating tumor cells, circulating free dna or exosomes? CPB. 2017;41(2):755- 768. doi:10.1159/000458736 2. Mathai R, Vidya R, Reddy B, et al. Potential utility of liquid biopsy as a diagnostic and prognostic tool for the assessment of solid tumors: implications in the precision oncology. JCM. 2019;8(3):373. doi:10.3390/jcm8030373 3. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472-484. doi:10.1038/nrclinonc.2013.110 4. Qi Z, Xu H, Zhang S et al. The Significance of Liquid Biopsy in Pancreatic Cancer. J Cancer. 2018;9(18):3417-3426. doi:10.7150/jca.24591 5. Panditharatna E, Kilburn LB, Aboian MS, et al. Clinically relevant and minimally invasive tumor surveillance of pediatric diffuse midline gliomas using patient-derived liquid biopsy. Clin Cancer Res. 2018;24(23):5850-5859. doi:10.1158/1078-0432.CCR-18-1345 6. Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. The Lancet Oncology. 2020;21(10):1296-1308. doi:10.1016/s1470-2045(20)30444-7 7. Saarenheimo J, Eigeliene N, Andersen H, Tiirola M, Jekunen A. The value of liquid biopsies for guiding therapy decisions in non-small cell lung cancer. Front Oncol. 2019;9:129. doi:10.3389/fonc.2019.00129 8. Buscail E, Alix-Panabières C, Quincy P, et al. High clinical value of liquid biopsy to detect circulating tumor cells and tumor exosomes in pancreatic ductal adenocarcinoma patients eligible for up-front surgery. Cancers. 2019;11(11):1656. doi:10.3390/cancers11111656 9. Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926-930. doi:10.1126/science.aar3247 10. Lambros MB, Seed G, Sumanasuriya S, et al. Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis. Clinical Cancer Research. 2018;24(22). doi:10.1158/1078-0432.CCR-18-0862 11. Lee RJ, Gremel G, Marshall A, et al. Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma. Annals of Oncology. 2018;29(2):490-496. doi:10.1093/annonc/mdx717 12. Rossi G, Ignatiadis M. Promises and pitfalls of using liquid biopsy for precision medicine. Cancer Res. 2019;79(11):2798-2804. doi:10.1158/0008-5472.CAN-18-3402 13. Neumann MHD, Bender S, Krahn T, Schlange T. ctDNA and CTCs in Liquid Biopsy – Current Status and Where We Need to Progress. Computational and Structural Biotechnology Journal. 2018;16:190-195. doi:10.1016/j.csbj.2018.05.002 Liquid biopsies are likely to become the preferred choice for dynamic monitoring of cancer patients and more widely used in predicting immunotherapy responses and tailoring treatments. The long-term goal is their widespread use in early diagnosis and screening, detecting cancers sooner, when the success of interventions is higher. It is unlikely that they will completely replace surgical biopsies, but rather be used as a complementary tool. Challenges However, before the full clinical utility of liquid biopsies12 can be reached, there are still a few hurdles13 to overcome, including: The future of liquid biopsy References Less invasive Lower risk Overcome challenges of sampling difficult-to-obtain tissue Reflect tumor heterogeneity Real-time detection Faster time to results Facilitate repeated sampling and longitudinal analysis