Liquid Biopsy For Cancer - Circulating Tumor DNA
The same tube of blood can answer three questions. Which drug fits an advanced cancer, whether cancer is left after surgery, and whether a healthy person has one. Only the first two have trial evidence behind them. This guide explains each test, what a positive or negative result means, the false alarms, and how results are handled from abroad.
About This Department
A tube of blood can now say which drug a lung cancer will respond to, and whether cancer is still present after surgery. Whether a healthy person has cancer, it cannot yet say.
Tumors shed fragments of their DNA into the bloodstream. Liquid biopsy finds them. In newly diagnosed metastatic lung cancer, a blood test found the mutations that guide treatment at least as frequently as tissue testing, in 9 days against 15. After bowel cancer surgery, letting a blood test decide halved chemotherapy use. Recurrence did not rise. Each of those uses is a different test answering a different question, and choosing the wrong one produces results nobody can act on. Send us your diagnosis and treatment history, and a medical oncologist will tell you which test fits your question and what its answer would change.
Plasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors.International Association for the Study of Lung Cancer consensus statement, 2021
What circulating tumor DNA is
Every cell that dies releases short pieces of its DNA into the blood, where they survive for a few hours before the liver and kidneys clear them. Most of this cell-free DNA comes from blood cells. In a patient with cancer, a share comes from the tumor, and that share, circulating tumor DNA, carries the tumor's mutations.
The share is tiny. In a small tumor the ratio falls to one fragment in ten thousand, and the tests therefore rely on deep sequencing that reads the same stretch of DNA thousands of times. A large or widespread cancer sheds more, so a blood test finds it more easily. A small, slow or brain-confined cancer may shed too little to find at all.
A validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as standard-of-care tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping.NILE study, 282 patients with metastatic lung cancer, Clinical Cancer Research, 2019
Which questions can a liquid biopsy answer?
A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival.DYNAMIC trial, New England Journal of Medicine, 2022
Question one, which drug for an advanced cancer
In advanced lung cancer, treatment depends on the tumor's mutations, EGFR, ALK, ROS1, BRAF, KRAS, MET, RET and others, and tissue from the first biopsy is frequently too scant or too slow to test for all of them. The NILE study took blood from 282 patients with newly diagnosed metastatic lung cancer at the same time as their standard tissue testing. The blood found a guideline-recommended mutation in 77 patients and the tissue in 60, the results matched for the targets with approved drugs in more than 98 percent, every positive blood result was confirmed, and blood results arrived in a median of 9 days against 15.
Combined, the two found 89 patients with a treatable mutation, half again as many as tissue alone. Plasma first is now acceptable. A positive blood result is enough to start a targeted drug, and a negative one sends the patient back for tissue, since the tumor may simply not have shed enough DNA to find. The same logic applies at progression, when blood can show the resistance mutation that decides the next drug, and in breast, prostate, bowel and other cancers with targeted treatments.
Postsurgical ctDNA positivity at 4 weeks after surgery was the most significant prognostic factor associated with recurrence risk in patients with stage II or III colorectal cancer.GALAXY, 1,039 patients, Nature Medicine, 2023
Question two, is any cancer left after surgery?
Three-year recurrence-free survival was 86.4 percent among ctDNA-positive patients who received adjuvant chemotherapy and 92.5 percent among ctDNA-negative patients who did not.DYNAMIC trial, stage II colon cancer, New England Journal of Medicine, 2022
This table scrolls sideways on a narrow screen. Swipe or drag to see every column.
| Test | Answers | Strength of evidence | A negative result means |
|---|---|---|---|
| Genotyping panel in advanced cancer | Which targeted drug fits, and why a drug stopped working | Strong in lung cancer, endorsed by consensus. Growing in breast, prostate and bowel cancer | Nothing on its own. Tissue testing follows |
| Tumor-informed residual disease test | Whether cancer remains after surgery, and whether it has returned | One randomized trial in stage II colon cancer and large observational studies. Trials in other cancers are running | A lower risk, with no guarantee. Standard follow-up continues |
| Multi-cancer screening test | Whether a healthy person may have an undiagnosed cancer | Feasibility studies only. No proof yet that it saves lives | Very little. Standard screening continues |
- The pathology report, and for a residual disease test, confirmation that the tumor tissue block is available for sequencing.
- Any genetic results already obtained from tissue or blood, with the name of the laboratory and panel.
- The stage, the date of surgery and any chemotherapy given or planned.
- The question you want answered, in your own words, which decides the test more than anything else.
Can a blood test screen healthy people for cancer?
Screening is the use most advertised.
Tests that look for the methylation pattern of cancer DNA in the blood of people with no symptoms are sold directly to the public in some countries, and their promise is real.
Routine use lies some way off.
The only published prospective study in ordinary adults over 50 shows how far they are from routine use. PATHFINDER tested 6,621 people. A cancer signal appeared in 92, 1.4 percent. Of those, 35 had cancer and 57 did not, and the people without cancer spent a median of 162 days in scans and tests before being told so.
Cancers were found, including types with no screening test at all.
Whether finding them earlier saves lives is being tested in large randomized trials, and until those report, a multi-cancer blood test is an addition to standard screening, never a replacement for a colonoscopy, a mammogram or a cervical smear.
This study supports the feasibility of MCED screening for cancer and underscores the need for further research investigating the test's clinical utility.PATHFINDER, 6,621 adults, The Lancet, 2023
What are the limits, and how is testing arranged from abroad?
False negatives and false positives
A negative result can mean no cancer, or a cancer that sheds too little DNA. Brain tumors, small early cancers, and cancers in the kidney or thyroid shed the least. A negative genotyping result is therefore never the final answer, and a negative residual disease test lowers the risk without removing it.
Blood cells can also produce a positive result. With age, blood-forming cells acquire mutations of their own, and some panels mistake them for cancer. Good laboratories sequence the white cells alongside the plasma for that reason. Screening positives need imaging and biopsy. Most in PATHFINDER were not cancer.
Utilizing cfDNA, in addition to tissue, increased detection by 48 percent, from 60 to 89 patients.NILE study, Clinical Cancer Research, 2019
Days in Istanbul, and results at home
A blood draw takes minutes. A genotyping panel returns in one to two weeks, and a first residual disease test in three to five, since the tumor must be sequenced first, and later ones in one to two weeks. None of this requires a stay in Istanbul, and a blood draw places no limit on flying. Patients who come for a consultation, surgery or treatment have the test drawn during that visit, and the results arrive by e-mail and WhatsApp, followed by a video review with the oncologist. Repeat samples for residual disease monitoring are drawn at home in most countries and shipped under the laboratory's own arrangements.
What decides the cost
Type of test decides it. Genotyping panels of several dozen genes cost less than tumor-informed residual disease tests, which charge for the tumor sequencing and then for each blood sample. Multi-cancer screening tests have their own price. Most of these tests are run by specialized laboratories in Europe or the United States, with the sample shipped under temperature control, so the shipping, the turnaround and any repeat draw when a sample arrives unusable belong in the quote as surely as the test itself, and a laboratory that cannot say how it handles a failed sample has told you something about how it handles the rest. Ask which laboratory runs the test, how many genes it covers, whether white cells are sequenced to rule out false positives, and what a repeat sample costs. No Istanbul hospital publishes a package for it. Your own figure follows the free review of your file.
Language, companions and follow-up at home
One coordinator from the international patients team is assigned from your first message and stays with you until the result has been explained. The team works in English, Arabic, French, Russian, Serbian, Romanian and Spanish and arranges interpreting in other languages on request. When a visit is needed, an invitation letter naming the hospital and the treating oncologist is sent ten days before travel, and the international patients office arranges the transfer and a hotel for you and a companion. Halal, vegetarian and diabetic meals are available, a prayer room is on site, and a request for a female doctor is passed to the department and met wherever the rota allows. Back home, the coordinator stays reachable on the same WhatsApp number, and every report goes to your own oncologist with a written interpretation.
In the ctDNA-guided group, 15 percent received adjuvant chemotherapy, against 28 percent under standard management, with two-year recurrence-free survival of 93.5 and 92.4 percent.DYNAMIC trial, 455 patients, New England Journal of Medicine, 2022
Liquid biopsy FAQ
What is a liquid biopsy?
Can a liquid biopsy replace a tissue biopsy?
How accurate is ctDNA testing after surgery?
Should a healthy person have a multi-cancer blood test?
How long do results take?
Can my family come with me?
References
- Tie J, Cohen JD, Lahouel K, et al. Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer. New England Journal of Medicine. 2022;386(24):2261-2272.
- Kotani D, Oki E, Nakamura Y, et al. Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nature Medicine. 2023;29(1):127-134.
- Leighl NB, Page RD, Raymond VM, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clinical Cancer Research. 2019;25(15):4691-4700.
- Rolfo C, Mack P, Scagliotti GV, et al. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer. Journal of Thoracic Oncology. 2021;16(10):1647-1662.
- Schrag D, Beer TM, McDonnell CH, et al. Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Lancet. 2023;402(10409):1251-1260.
Editor's note
Written by the Biruni Hospital medical editorial team. Reviewed by Prof. Dr. Özcan YILDIZ, Medical Oncology.
Medically reviewed by
Prof. Dr. Özcan YILDIZ
Medical Oncology
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