TL;DR
Liquid biopsies detect cancer signals in blood, most often through circulating tumor DNA (ctDNA). These assays can identify minimal/molecular residual disease (MRD) after curative-intent treatment and profile tumor genetics in advanced disease.
After surgery or chemoradiation: Serial ctDNA is one of the strongest predictors of recurrence. A positive test often precedes imaging by months; a negative test lowers short-term risk but does not rule out relapse.
In metastatic disease: Plasma next-generation sequencing (NGS) reveals targetable mutations and resistance mechanisms when tissue biopsy is non possible, unsafe, inadequate, or delayed.
Adjuvant decisions: Randomized evidence supports ctDNA-guided de-escalation of chemotherapy in stage II colon cancer. In stage III, ctDNA is prognostic but intensifying therapy based on ctDNA positivity has not yet shown benefit.
Surveillance and monitoring: Serial ctDNA can detect recurrence earlier than scans, and falling levels during therapy predict better outcomes, particularly in immunotherapy trials.
Technology advances: Tissue-free assays incorporating methylation scores, fragmentomics, and copy-number changes improve detection without tumor tissue and underpin multi-cancer early detection (MCED) tests.
Limits: False positives from clonal hematopoiesis, low-shedding tumors, and sanctuary sites (like brain-only disease) can reduce accuracy. Assay sensitivity and thresholds differ by platform.
Access: Medicare now covers MRD testing in several solid tumors, commercial coverage is expanding, and regulators are considering ctDNA clearance as a trial endpoint. Out-of-pocket costs typically range from $0 to $500.
First, plain language definitions
ctDNA (circulating tumor DNA): Small DNA fragments shed into the blood by tumor cells. Modern assays can detect a few mutant fragments among thousands of normal ones.
CTCs (circulating tumor cells): Intact cancer cells that have detached from a primary or metastatic tumor and entered the bloodstream. They are rarer than ctDNA but can reveal tumor biology, metastatic potential, and resistance mechanisms. Though technically challenging to isolate, they allow functional assays and single‑cell analysis.
MRD (minimal or molecular residual disease): Residual cancer cells or their molecular traces after curative‑intent therapy, invisible to imaging. MRD detection via ctDNA is highly sensitive for predicting recurrence risk and guiding adjuvant decisions.
Tumor‑informed vs tissue‑free
Tumor‑informed tests are built from an individual’s tumor. They sequence tumor tissue and design a custom panel to track selected mutations. These have high sensitivity and strong filters against false positives from clonal hematopoiesis (CHIP).
Tissue‑free tests require no tumor tissue. They detect cancer signals from methylation patterns, genomic variants, and fragmentomics. They start faster and are practical when tissue is limited.
Methylation score or signature: A summary of DNA methylation patterns that distinguish tumor DNA from normal DNA. These patterns boost sensitivity in tissue‑free MRD and form the basis of multi‑cancer early detection (MCED) screening tests.
Image credit: Husain H, Velculescu VE. Cancer DNA in the Circulation: The Liquid Biopsy. JAMA. 2017;318(13):1272–1274. doi:10.1001/jama.2017.12131
Where liquid biopsy is used today
1) Guiding therapy in metastatic disease
Why: Provides a safe, minimally invasive alternative when biopsy is unsafe or inadequate, and detects resistance mutations that emerge during therapy.
Examples: EGFR, ALK, ROS1 in lung cancer; ESR1 and PIK3CA in metastatic breast cancer; KRAS G12C resistance in colorectal cancer.
Integrative oncology use: Offers a rapid snapshot of tumor genetics. With ctDNA’s short half-life (~2 hours), results may reflect treatment response sooner than imaging, aligning systemic therapies with supportive care and reducing unnecessary biopsies.
2) Adjuvant decisions after surgery
Why: Clarifies relapse risk and informs chemotherapy intensity.
Examples: Stage II colon cancer (DYNAMIC showing safe de-escalation), Stage III colon cancer (DYNAMIC-III showing prognostic but not predictive value), CIRCULATE-Japan (GALAXY showing higher relapse risk when ctDNA is positive).
Integrative oncology use: Helps avoid overtreatment while supporting recovery with nutrition, lifestyle, and mind-body approaches.
3) Surveillance for people who are NED (no evidence of disease)
Why: Detects recurrence earlier than imaging, sometimes reducing scan frequency.
Examples: Colorectal cancer (serial ctDNA), HPV-positive oropharyngeal cancer (ctHPV DNA).
Integrative oncology use: Enables closer monitoring and proactive survivorship care. If ctDNA is detected but imaging is negative, some patients may clear ctDNA with interventions such as supplements, off-label drugs, or IV therapies. Typical schedule: every 3 months in year 1, every 6 months in year 2, then annually through year 5.
4) Immunotherapy and on-treatment monitoring
Why: Decline or clearance of ctDNA correlates with better outcomes, serving as an early biomarker of response.
Examples: ctDNA kinetics during systemic therapy across multiple tumor types, especially in immunotherapy.
Integrative oncology use: Provides early feedback during treatment, guiding adjustments if ctDNA or methylation scores are not falling as expected.
5) Methylation, fragmentomics, and “scores”
Why: Boost detection without tumor tissue and provide complementary data on early detection and treatment response.
Examples: Tissue-free MRD assays (e.g., Guardant Reveal) and MCED screening tests (e.g., Galleri).
Note: MCED is for screening, not MRD, and requires careful counseling due to uncertain mortality impact and false-positive risks.
Practical workflows
After curative surgery or chemoradiation
Platform choice: Tumor-informed if tissue and time are available; tissue-free if not.
Timing: First draw at week 4, then every 3 months for 2 years, every 6–12 months through year 5.
Interpreting results:
Negative: Lowers short-term risk but not a guarantee; continue surveillance.
Positive: Suggests microscopic disease. Confirm with repeat testing, stage with imaging, and discuss clinical trials or tailored therapies.
Metastatic disease
Use plasma NGS when biopsy is unsafe, inadequate, or delayed. Re-profile at progression to detect resistance or new targets.
HPV-positive oropharynx
Add serial ctHPV DNA to surveillance. Two positives should trigger imaging and multidisciplinary review.
Key commercial players
ctDNA, MRD, plasma NGS: Natera (Signatera), Guardant (Guardant360, Reveal), Foundation Medicine (FoundationOne Liquid), Tempus, BillionToOne, NeoGenomics, Lucence, PGDx, Freenome.
MCED: GRAIL (Galleri), Freenome.
ctHPV DNA: Roche (cobas HPV), QIAGEN (digene HPV), Naveris, OncoHealth.
Costs and coverage
Medicare now covers MRD testing in several solid tumors, and commercial coverage is expected to expand in 2025. Most liquid biopsies are billed to insurance, with out-of-pocket costs typically ranging from $0 to $500 depending on deductibles and co-pays. Some companies also provide treatment-response testing at no cost to patients.
Strengths and limits
Strengths
Early relapse detection: ctDNA often becomes positive months before changes appear on imaging, giving a critical window for intervention.
Dynamic disease profiling: Plasma-based sequencing can uncover emerging resistance mutations and evolving tumor biology in real time.
Minimally invasive monitoring: Serial blood draws are safer and more tolerable than repeat tissue biopsies, supporting long-term disease tracking.
Expanding access: Increasing reimbursement from Medicare and commercial insurers makes these tests more feasible in routine care.
Limitations
False positives from CHIP: Clonal hematopoiesis of indeterminate potential (CHIP), an age-related process, can generate mutations mistaken for tumor-derived DNA. Tests with paired white blood cell sequencing help minimize this risk.
Low-shedding tumors and sanctuary sites: Certain cancers (e.g., mucinous subtypes, indolent disease, or central nervous system–restricted tumors) release little or no ctDNA into circulation. Imaging or site-specific sampling (e.g., CSF for brain involvement) may still be required.
Assay variability: Sensitivity, detection thresholds, and reporting differ among platforms. Clinical interpretation must be tailored to the specific assay used, in consultation with the laboratory or ordering provider.
Context required: A negative test does not rule out disease, and results should always be integrated with imaging, pathology, and clinical findings.
What’s next
Better endpoints: Trials are testing ctDNA clearance as a surrogate for long-term outcomes. If validated, this could accelerate drug development.
ctDNA-guided immunotherapy: Bladder cancer may be first to adopt ctDNA-guided adjuvant strategies, pending IMvigor011. Similar studies are underway in other cancers.
Multi-omic plasma: Combining mutations, methylation, fragmentomics, and copy-number analysis promises further gains, especially for tissue-free MRD.
For more information or to schedule a one-on-one consultation, visit drkseniamalarkey.com