Circulating tumor DNA (ctDNA) has changed the game in diagnostic oncology. Classic tumor markers (PSA, CA 125, ACE) remain useful for therapeutic monitoring, but their sensitivity in primary screening is too low to justify routine use. The most significant advances are focused on liquid biopsy, with direct implications for patient management.
Circulating tumor DNA and liquid biopsy: what the sample really measures
Liquid biopsy relies on the detection of DNA fragments released by tumor cells into the blood. These fragments, called ctDNA (circulating tumor DNA), carry the specific mutations of the tumor. Analyzing them allows for the identification of genomic alterations without resorting to invasive tissue biopsy.
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There are clearly two distinct uses. The first concerns the monitoring of an already diagnosed cancer: ctDNA is then used to assess treatment response or to detect molecular relapse before any clinical manifestation. The second, more ambitious, aims at screening asymptomatic individuals through so-called MCED tests (Multi Cancer Early Detection).
To understand how to detect cancer with a blood test, it is important to distinguish these two contexts: one is already integrated into clinical practice, while the other remains confined to trials.
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MCED tests and multi-cancer screening: promises and technical limitations
MCED tests analyze the methylation profiles of ctDNA to identify signatures associated with around fifty types of cancers. Some are also capable of indicating the likely tissue of origin of the tumor. Professor Fabrice André from the European Society for Medical Oncology (ESMO) believes these tests could become commonplace within five to ten years.
Caution is still advised. These tests should currently only be used within the framework of clinical trials. Several technical reasons explain this restriction:
- Sensitivity remains insufficient for certain tumor locations, particularly early-stage cancers that release little ctDNA into the bloodstream
- The rate of false positives poses a major issue: a positive result triggers a cascade of additional examinations (imaging, biopsies) in patients who do not have cancer
- Some cancers do not release a detectable amount of tumor DNA into the blood, leading to potentially misleading false negatives
- Any positive result requires confirmation through imaging or traditional histopathological examination, as the blood test alone is never sufficient to make a diagnosis
For cancers that are difficult to detect at an early stage, such as pancreatic cancer, these tests still represent a valuable avenue. Existing screening protocols (mammography for breast cancer, occult blood testing for colorectal cancer) will not be replaced but may potentially be complemented.
Predicting treatment response: the PARADIGM study on prostate cancer
ctDNA allows for predicting treatment efficacy within six to twelve weeks, well before control scans or PSA levels. This is demonstrated by the UK PARADIGM study, conducted in fourteen hospitals with patients suffering from metastatic prostate cancer.
The principle is straightforward: ctDNA is measured before and during first-line treatment. When ctDNA becomes undetectable during treatment, the two-year survival rate reaches 85%. In patients where ctDNA remains detectable, this rate drops by about half.
This approach alters the timing of therapeutic decision-making. Instead of waiting several months and a scan to observe progression, the oncologist has an early molecular signal that guides the decision to continue or change the treatment line. The median follow-up of the study exceeds three years, which strengthens the robustness of the results.
ESR1 mutations and metastatic breast cancer: adapting treatment through blood tests
In hormone-dependent metastatic breast cancer, the search for mutations in the ESR1 gene through liquid biopsy illustrates an already operational use. These mutations confer resistance to aromatase inhibitor treatments, and their detection in the blood allows for earlier adaptation of the therapeutic strategy.
The value of this approach lies in its repeatability. A tissue biopsy is burdensome, sometimes risky, and only reflects a geographical point of the tumor. Blood sampling, on the other hand, captures tumor heterogeneity: mutations present in different metastatic locations are found in the circulating ctDNA.
This application goes beyond simple screening. The blood test becomes a real-time therapeutic management tool, not just a means of making an initial diagnosis.
Classic tumor markers in blood tests: what they detect and what they miss
Serum tumor markers (PSA, CA 19-9, CA 125, ACE, AFP) remain present in daily practice. Their measurement is integrated into a blood test guided by clinical indications or post-treatment monitoring.
- PSA is used in monitoring prostate cancer, but its specificity in primary screening remains debated due to numerous false positives related to benign conditions
- CA 125 is involved in monitoring ovarian cancers, rarely as a first-line diagnostic
- ACE is primarily used for monitoring colorectal cancers under treatment, not for screening
These markers are not standalone screening tests. An isolated elevation of a tumor marker without clinical context does not have reliable diagnostic value. It is their kinetics (changes over time) that provides exploitable information, particularly for detecting recurrence.
The complete blood count (CBC) sometimes reveals abnormalities suggestive of malignant hematopathies (leukemias, lymphomas), but again, no blood test result alone can diagnose cancer. Histopathological examination remains the gold standard.
The convergence of classic markers, liquid biopsy, and imaging outlines an increasingly stratified diagnostic pathway. Blood sampling has never been as influential in oncological decisions, provided that the limitations of each tool are respected and that molecular signals are not confused with confirmed diagnoses.