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Blood-based Biomarkers in Cancer

Updated: Mar 30, 2023

Summary in Thirty Seconds

  • Liquid biopsy for cancer is non-invasive and easily repeated, permitting molecular profiling for diagnosis, tracking of residual disease and recurrence risk, monitoring drug response/resistance, and monitoring disease evolution.

  • Different protocols have been developed, introducing variability in the accuracy of liquid biopsies, particularly in sensitivity.

  • Because liquid biopsies don’t rely on a specimen from one part of a tumor, better sampling of the tumor burden can be accomplished. Also, liquid biopsies typically have faster turn-around times than tissue biopsies.

  • Trending and awareness of liquid biopsies have risen steadily since the first liquid biopsy was FDA approved in 2016.

  • As research and development have advanced with liquid biopsies in the past year, study results have shown high concordance with tissue biopsies and notable improvements in specificity and sensitivity with ranges similar to that seen in tumor biopsies.

Liquid Biopsy

Targeted therapy depends on Next Generation Sequencing (NGS) to determine specific genetic biomarkers driving a person’s cancer.[1] The “gold standard” method to identify these molecular variants is through samples obtained from resected tumors.[2] However, over the past decade, liquid biopsies in oncology have emerged as a viable alternative.[3] The most commonly used liquid biopsies analyze circulating tumor cells (CTC—cells released from the primary tumor that circulate in the bloodstream[4]), circulating cell-free DNA (cfDNA—extracellular DNA originating from normal or cancerous cells identifiable in the serum[5]), and circulating tumor DNA (ctDNA—DNA fragments released by tumor cells into the blood, representing the cancer portion of cfDNA[6]). Such biopsies have great appeal because they are non-invasive and can be repeated easily.[7]


Liquid Biopsy Uses

Liquid biopsies permit molecular profiling across a range of malignancies for diagnosis. CTC, cfDNA, and ctDNA levels can be tracked over multiple samples to evaluate residual disease and recurrence risk,[8] to enable prediction and monitoring of drug response and/or resistance,[9] and to monitor the molecular evolution of the disease.[10] Additionally, liquid biopsies more comprehensively represent tumor/cancer molecular heterogeneity because the DNA originates from different areas of the same tumor and possible disease locations.[11] Blood-based biomarker analysis can also determine if genetic material in the blood represents metastatic potential.[12]


Challenges

One challenge with liquid biopsies is the wide range of assays using varying principles for the detection of circulating tumor cells and ctDNA.[13] Variability in sensitivity and specificity can be introduced when using different techniques or assays to detect markers in liquid biopsy.[14] To this end, while research has found strong specificity using ctDNA,[15] sensitivity levels have been less compelling because of variations in DNA shedding and tumor heterogeneity.[16] A 2021 meta-analysis of 17 studies found an overall specificity of 92% but a sensitivity of 76%, with cell-free DNA (cfDNA) showing the most promising results.[17] Notably, in early-stage cancer, the small size of tumors means that the level of tumor-related biomarkers shed into circulation is very low, making reliable and accurate detection a significant challenge.[18]


Advantages

DNA extracted after tissue biopsy samples and analyzes only a small section of the tumor; thus, ctDNA is now often used as an alternative to tissue biopsies because it provides information on all mutations across the tumor burden.[19] Using liquid biopsy for the identification of aggressive tumors at an earlier stage can enable more effective treatment,[20] thus improving the survival rates of many cancers. Additionally, the faster turn-around time of liquid biopsy versus tumor biopsy can result in quicker diagnosis leading to a timelier start of treatment resulting in better patient outcomes as well as financial savings in medication, home and clinical medical visits, and in-hospital care.[21],[22] And, because of non-invasiveness, liquid biopsies are far more amenable to repeated sampling for tracking the progression, molecular evolution, response, and resistance of cancer.


The following image provides an overview of liquid vs. tissue biopsy in cancer:[23]

Liquid Biopsy Trending and Awareness

An analysis of liquid biopsy trending and awareness over the past decade for oncologists, cancer researchers, and molecular pathologists reveals that trending rose notably in 2016, particularly for molecular pathologists. This rise coincided with the first FDA approval of a liquid biopsy using plasma specimens to detect EGFR mutations.[24],[25] Awareness levels have shown an accelerating awareness rise since 2016, most notably for molecular pathologists. The finding that molecular pathologists outpace the other two disciplines is expected, given the specific scope of a molecular pathologist’s diagnostic duties.


Recent Findings

A 2023 comparison of 170 patients with NSCLC who received both ctDNA and tissue biopsies for Next Generation Sequencing found faster turn-around times (27 days faster) for liquid biopsies. Additionally, almost three-quarters of physicians used liquid biopsies for diagnostic results because of their relative rapidity, and liquid biopsies were 95%-100% concordant with tissue biopsy results. Furthermore, liquid biopsies identified actionable biomarkers in 77% of patients compared with 55% in tissue biopsies, and there was no significant difference seen in time-to-treatment or overall survival/progression-free survival between liquid vs. tissue biopsy findings.[26] Recent research shows that liquid biopsy is able to detect minimal residual disease in early-stage lung cancer, leading to the potential application of this technique in the adjuvant setting, in early detection of recurrence, and in cancer screening.[27]


Research in the past year on other cancer types has also found encouraging diagnostic results. A 2022 study comparing patients with pancreatic adenocarcinoma versus those with benign pancreatic disease using cfDNA methylation level found 100% sensitivity and 95% specificity using liquid biopsy.[28] Research on the detection of breast cancer using liquid biopsy in 544 patients versus 427 healthy controls found specificity at 99% and a sensitivity of 80%.[29a] In the past year, the FDA has approved liquid biopsies using cfDNA to identify specific mutations in breast cancer (2023) and NSCLC (2022).[29b] A study evaluating the diagnostic accuracy of circulating cell-free mRNA from plasma samples obtained from 107 patients with metastatic colorectal cancer patients compared with healthy controls found a specificity of 93% and sensitivity of 82%.[30]


Bottom Line

The development and use of blood-based biomarkers for molecular profiling and disease monitoring in cancer represents a huge step in the advancement of oncology. There are a variety of uses for liquid biopsies across types and stages of cancer. Clear progress is being made in improving the diagnostic accuracy of liquid biopsies, with strong accuracy seen in a variety of cancer types. Nevertheless, additional research is needed on the accuracy, reliability, and clinical utility of this assay.[31]


Early, rapid, and accurate diagnosis is vital for optimal clinical outcomes.[32] Clack et al., conclude their 2023 review of personalized nanomedicine by stating, “non-invasive analysis of circulating biomarkers via liquid biopsy offers hope for a better method of early detection. Such a method has massive lifesaving potential.”[33]

[1] Curr Oncol. 2019, April;26(2):e241-e254 [2] Molecular Cancer. 2022; 21:79 [3] Cancer Discov. 2021; 11(4):858–873 [4] Int J Mol Sci. 2022; 23(14):7588 [5] ibid [6] Front. Oncol. 2021; 11:763790 [7] ibid [8] Curr. Prob. In Cancer. 2018; 42(6):593-600 [9] Molecular Cancer. 2022; 21:79 [10] Methods in Enzymology. 2019; 629:1-15 [11] BMC Medicine. 2017; 15:75 [12] Cancer Metastasis Rev (2023); 42:1 [13] Cancer Discov. 2021; 11(4):858–873 [14] Int J Mol Sci. 2022; 23(14):7588 [15] Nat Rev Clin Oncol. 2021; 18(1):56–62 [16] JCO Precis Oncol. 2019; 3:1–14 [17] Exp. Rev. Mol. Diag. 2021; 21(4):417-424 [18] Science. 2022; 375(6586):9040 [19] Small 2023; 2205856 [20] Cancers. 2021; 13(14):3600 [21] Curr. Oncol. 2021; 28(2):1216–48 [22] J of Transl. Med. 2023; 21:118 [23] Lung Cancer: Targ. & Ther. 2023; 14:11-25 [24] cobas EGFR Mutation Test v2 | FDA [25] Ann Transl Med. 2017 Feb; 5(3): 46 [26] Clin. Lung Cancer. 2023; 24(2):120-129 [27] Lung Cancer: Targ & Ther. 2023; 14:11-25 [28] Clinical Epigenetics. 2022; 14:28 [29a] Clinical Chem. 2022; 68(2):344–353

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