Why Liquid Biopsy May Be Replacing The Tissue Biopsy

Introduction to Liquid Biopsies

Tissue biopsies or cell samples can be obtained from almost any part of the body. Samples can be taken depending on where the abnormal tissue is. Limitations of tissue biopsy includes:

  • In most of the advanced stage patients, the tissue usually becomes insufficient for genomic analysis after the preliminary histological diagnosis.
  • Studies report that up to 30% of patients at a community-based academic center did not undergo guideline-recommended molecular testing even when there was an institutional reflecting testing policy.
  • Inter and intra-tumoral heterogeneity may limit tissue based genotyping especially when mechanisms for resistance to tyrosine kinase inhibitors need to be evaluated.
  • Rebiopsy may be required to obtain tissue for additional molecular profiling.
  • In patients with multiple metastases, selection of a single biopsy site may not be a representative profile of the predominant resistance mechanism.
  • Some patients with recurrence and poor performance statuses are not fit enough to have multiple biopsies obtained.

Simply put, for most patients, a tissue biopsy can be costly, painful, and potentially risky.

Regardless of the challenges in obtaining adequate tissue for biopsy purposes, minimally invasive technologies have managed to:

  • Capture genomic contents of tumor in fluids
  • Combine sensitive genotyping assays

Hence, the potential role of “liquid biopsy” is now being evaluated as an alternative for tissue biopsy.

Background on Liquid Biopsies

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Cell-free circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are plasma sources of tumor DNA that are investigated for non-invasive detection and monitoring of tumors. Although the Food and Drug Administration (FDA) has approved that liquid biopsy can be used to measure intact CTCs to give a prognosis of overall survival, the potential predictive value of ctDNA potentially allows us to understand specifically the molecular changes happening in the tumor in real time. Liquid biopsy is a minimally invasive technology that captures circulating biomarkers such as:

  • CTCs
  • Cell-free RNA
  • Micro-RNA (miRNA)
  • Circulating cell-free DNA (cfDNA)
  • ctDNA

How Liquid Biopsies Work

Instead of taking tissue from the tumor itself, liquid biopsies:

  • Enable CTCs or ctDNA in the blood to be captured. Although rare, detected CTCs can be used for DNA-based analysis, RNA, and protein-based profiling.
  • Is one of the first non-invasive ways to repeatedly sample a cancer so its genes can be profiled allowing drugs to specifically target mutations
  • Also helps to tell quickly if the treatment is working and enables the adjustment of treatment as the cancer evolves

Multiple studies have also reported the potential of circulating miRNAs to diagnose and screen non-small cell lung cancer (NSCLC) and to predict the prognosis and response to treatment. Due to the different set of markers and thresholds of positivity used, the circulating miRNAs do not appear to have an immediate clinical effect.]

Other Potential Uses of Liquid Biopsies

  • cfDNA may contribute to clinical decision making as the genotyping of cfDNA has been studies as an alternative to tumor tissue genotyping.
  • ctDNA with its 166 base pair of double strand DNA fragments leads to release of nuclear DNA in the circulation due to apoptosis and necrosis. Since these fragments have a short half-life in circulation due to the rapid hepatic and renal clearance, ctDNA reflects a real time genomic signature of the tumor.
  • A recent meta-analysis of 20 studies have also reported that the evaluation of EGFR mutation status in plasma has an overall sensitivity of 67.4% and specificity of 93.5% of genotyping using cfDNA compared to tissue genotyping. More recent studies have reported 96-100% specificities.

Can Liquid Biopsy Replace Tissue Biopsy?

Liquid biopsy has screening and complementary roles in clinical management and may replace tissue biopsy to some extent in the future. However, it is unlikely that it will completely replace tissue biopsy anytime soon as:

  • The diagnosis and subtyping of certain cancers needs to be established based on histology.
  • Plasma genotyping assays are more sensitive in patients with widespread metastases.
  • The possibility of detecting a mutation in cfDNA in early stage patients is significantly lower.
  • Circulating miRNAs may become useful in the future for the initial diagnosis and histologic subtyping.

However, liquid biopsy will not be able to replace tissue biopsy until:

  • Technologies advance to capture miRNA, CTCs, and cfDNA
  • Genotyping assays become more sensitive
  • We improve our understanding of histology regarding specific molecular alterations


Liquid biopsies are becoming increasingly popular as it can provide a non-invasive, ongoing picture of the cancer while offering valuable insight on how best to fight it. It is also able to offer clues regarding the staging and spread of the cancer, monitoring the effects of treatment, and forewarn regarding possible recurrences while offering clues to why the treatment is resistant. Serial ctDNA investigations are increasingly performed during treatment to provide a dynamic picture of the molecular disease changes. This suggests that it can be used to monitor the resistance and identify heterogenous subclonal populations of tumor cells that develop during treatment. It is the hope that liquid biopsies could be used to guide cancer treatment and screening that are not yet visible through imaging in the future instead of having to rely on extensive imaging and invasive tissue biopsies.