Lung cancer remains one of the most common and deadly cancers worldwide, and finding better ways to detect, monitor, and treat it is a constant priority. Traditionally, molecular testing has relied on tissue biopsies – taking a sample of tumour tissue with a needle or during surgery – to understand a patient’s cancer. While invaluable, tissue biopsies are invasive, can’t always be repeated, and may not capture the full picture of a tumour as it changes over time.
Enter the liquid biopsy. Instead of looking directly at the tumour, liquid biopsies analyse for tiny fragments of cancer DNA or cells that shed into the blood. With just a blood test, clinicians can now gain insights into the genetic makeup of a patient’s cancer, track how it responds to treatment, and even detect resistance before it shows up on scans.
The Medical Services Advisory Committee (MSAC) is currently reviewing an application to make liquid biopsies for lung cancer eligible for Medicare funding. . Learn more about this application for Medicare-funding of liquid biopsy in NSCLC.
Read on to learn more about liquid biopsies and why they matter for people with lung cancer.
What is a Liquid Biopsy?
A liquid biopsy is a blood test that looks for tiny traces of cancer in the bloodstream. Unlike a traditional tissue biopsy, which requires a sample taken directly from the tumour, a liquid biopsy relies on the fact that cancers constantly shed material into the blood as they grow and change. By capturing and analysing this material, it is possible to learn about the tumour without needing to physically access it.
The main types of tumour-derived material detected include:
- Circulating tumour DNA (ctDNA):
Small fragments of DNA released by cancer cells when they die. By sequencing ctDNA, genetic mutations that drive the cancer or cause resistance to treatment can be identified and analysed.
- Circulating tumour cells (CTCs):
Whole cancer cells that have broken away from the tumour and entered the bloodstream. Studying CTCs can provide information about the biology of the cancer and its potential to spread.
- Circulating tumour RNA (ctRNA)
Similar to ctDNA, tumour cells also shed different types of RNA into the bloodstream, which can provide additional information into genetic mutations to be identified.
- Exosomes and other extracellular vesicles:
Tiny packets released by cancer cells that contain proteins, RNA, and DNA. These vesicles act like “messages in a bottle,” carrying signals that influence how the cancer interacts with the body.
Recent studies have shown that the combined use to ctDNA with ctRNA provides equal coverage of the various actionable lung cancer mutations that tissue biopsy can detect, including fusions that can be missed in some ctDNA assays. Furthermore, biomarkers are emerging including the detection of cancer-associated epigenetics through methylation analysis. These various biomarkers offer the opportunity for multi-omics technologies to enhance the precision of personalised treatment strategies.
Technologies for Detecting ctDNA
| Whole Genome Sequencing (WGS): | Targeted Next-Generation Sequencing (NGS) Panels | Tumour-Informed NGS (Personalised Panels) | Digital Droplet PCR (ddPCR) |
What it is | Sequencing of the entire genome to detect mutations, structural changes, and copy number alterations across all DNA. | Sequencing of a selected set of genes relevant to lung cancer (e.g. EGFR, ALK, KRAS, BRAF). | A customised sequencing approach where the patient’s tumour tissue is sequenced first, and then a ctDNA panel is designed to track those specific mutations in blood. | A highly sensitive PCR technique that partitions the blood sample into thousands of droplets to detect known mutations. |
Strengths | Provides the most comprehensive picture of tumour biology; can reveal unexpected or rare alterations. | Broad enough to capture multiple clinically relevant mutations; faster and cheaper than WGS; widely used in clinical practice. | Very sensitive for detecting minimal residual disease (MRD) and monitoring recurrence; tailored to each patient’s cancer. | Very accurate for detecting low levels of a specific mutation; relatively quick and cost-effective. |
Limitations | Expensive, complex to interpret, requires high ctDNA levels; currently used mostly in research settings rather than routine care. | Limited to the genes included in the panel, so novel or rare mutations outside the panel may be missed. | Requires a tumour sample upfront; not as fast or widely available; higher cost. | Restricted to searching for a handful of predefined mutations; doesn’t give a broad genomic profile. |
Uses of Liquid Biopsies in Lung Cancer
Liquid biopsies provide many opportunities to shape and influence lung cancer care. Critically, due to the non-invasive nature of liquid biopsies compared to tissue biopsies, these technologies open the door for multiple sampling throughout a patient’s cancer journey that hasn’t been possible in the past when purely reliant to tissue biopsies.
1. Initial Diagnosis & Molecular Profiling
- When tissue biopsy isn’t possible or yields insufficient material, ctDNA can provide the necessary genetic information.
- Identifies actionable mutations (e.g. EGFR, ALK, BRAF, KRAS) to guide targeted therapy.
- It is important to note, that the reimbursed access of targeted lung cancer treatments requires a histological confirmation of a lung cancer.
2. Treatment Selection
- Helps clinicians decide which targeted therapy, immunotherapy, or combination is most appropriate.
- Example: detecting EGFR mutations to prescribe osimertinib.
3. Monitoring Treatment Response
- Tracks how well a therapy is working in real time by measuring ctDNA levels.
- A drop in ctDNA after starting treatment can indicate tumour shrinkage before imaging shows it.
4. Detection of Resistance Mutations
- Identifies genetic changes that cause therapies to stop working.
- Example: detecting the EGFR T790M resistance mutation, which can then be targeted with specific next-line drugs.
5. Minimal Residual Disease (MRD) and Recurrence Monitoring
- Highly sensitive tumour-informed ctDNA assays can detect microscopic disease left after surgery or treatment.
- Allows earlier detection of relapse than imaging.
TOGA trials involving ctDNA
TOGA members lead and are involved in several clinical trials and studies involving ctDNA as a central component of the study, including:
ASPiRATION-2L: Which seeks to use ctDNA to inform treatment when patients with non-small cell lung cancer (NSCLC) progress or relapse after targeted treatment.
DYNAMALK: investigating the potential of comprehensive genomic profiling using ctDNA to shape the treatment of ALK+ NSCLC.
OCEANiC: Focusing on resected stage IIA to IIIA EGFR mutant NSCLC and using ctDNA to determine treatment strategies.
FAST: The use of ctDNA to rapidly identify genetic mutations in patients with suspected metastatic lung cancer who are unable to undergo a biopsy in New Zealand.
Advantages, Disadvantages, and Common Misconceptions of Liquid Biopsy
Advantages
- Minimally invasive: A simple blood draw is far less invasive than a tissue biopsy, reducing risks and discomfort.
- Repeatable over time: Because it’s easier to collect, liquid biopsies can be done at multiple timepoints to monitor treatment response and disease progression.
- Broader tumour picture: Tumours can be genetically diverse. A tissue biopsy samples one site, but ctDNA may reflect alterations from multiple tumour sites, giving a more comprehensive snapshot.
- Faster turnaround: Results can sometimes be delivered quicker than a tissue biopsy, especially when urgent treatment decisions are needed.
Disadvantages
- Sensitivity issues: In some patients, especially those with early-stage or low-burden disease, ctDNA may be too low to detect. A “negative” liquid biopsy does not always mean no mutation is present.
- Limited by technology: Some assays only test for known mutations, while broader panels may miss rare or unexpected changes.
- Cost and access: Advanced NGS-based liquid biopsy tests can be expensive and may not be widely available in all healthcare systems.
- Not always a substitute: Tissue biopsies remain essential for confirming histology and tumour subtype, which ctDNA alone cannot provide.
Common Misconceptions
- “A liquid biopsy can replace tissue biopsy in all cases.”
Not true — liquid biopsy is complementary. It can help when tissue is unavailable, but histology and some biomarkers still require tissue, particularly those that measure protein levels, such as PD-L1 and MET.
- “If ctDNA isn’t detected, the cancer isn’t there.”
False — a negative result may simply reflect low ctDNA levels. Clinical judgment and imaging are still crucial.
- “All liquid biopsies test for everything.”
In reality, different technologies (ddPCR, targeted NGS, WGS, tumour-informed assays) have different scopes and sensitivities. Not all tests are equally comprehensive.
- “They are standard everywhere.”
While increasingly common, liquid biopsies are not yet routine in all cancer centres, and their role continues to evolve.
Current Access & Barriers
- Low usage: Only a small proportion of lung cancer patients currently have access to ctDNA testing. According to TOGA survey data, about 12% of patients in Australia & NZ have access to ctDNA testing.
- Funding gaps: Very few tests are publicly funded. The same survey showed only ~ 8% of ctDNA tests are funded by government/public system. Most are paid out-of-pocket (~62%) or via clinical trials (~58%).
- Geographic disparities: Patients in remote or regional areas have more difficulty accessing testing due to logistical issues.
- Knowledge and confidence: Clinician knowledge of ctDNA is variable, with many reporting limited understanding or concerns about assay reliability.
How and where is ctDNA accessible for managing lung cancer?
In Australia at the time of writing, the MSAC is currently reviewing an application (closing Oct 10) to reimburse ctDNA testing for a subset of lung cancer patients through Medicare. If approved, it will be more accessible to patients who haven’t had the means to privately fund this testing.
In the meantime, there are several ongoing clinical studies incorporating the use of ctDNA and liquid biopsies in various ways, but otherwise liquid biopsy testing must be privately funded.
Listen to The Role of Liquid Biopsy in Modern Oncology
To hear the full discussion with A/Prof Malinda Itchins, Dr. Annie Wong, and A/Prof Stephen Kao, listen to the episode here:
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