When it comes to cancer, time is money: the earlier a tumor is detected, the more likely it is to be treated and have a more favorable prognosis. The problem is that the disease does not always show its face and is often already advanced by the time it appears in the form of symptoms or other malignant signs. Scientists have set out to find tools to advance diagnosis, and liquid biopsy, which detects biological traces of the tumor in blood or other fluids, is considered an early detection tool, even in seemingly healthy people. This type of blood test – for the patient it is like an extraction for a traditional analysis – is already used to monitor metastatic tumors or to refine the prognosis after some oncological surgeries, but a new study published in the journal The Lancet provides further evidence of this possible use of these techniques in the early detection of cancer in asymptomatic people. But experts warn that this tool still has a long way to go to serve as a population screener and that its effectiveness needs to be refined to avoid false positives and overdiagnosis.
The tumor usually releases signs of its presence into the body. Even if it appears invisible to the senses without showing symptoms or signs of malignancy, it may already be releasing tumor DNA, proteins or other molecules into the bloodstream that give away its existence. Through liquid blood biopsies, in which a sample of blood is taken and analyzed for these biological traces of the tumor, oncologists can gain invaluable information about the disease using a minimally invasive technique: from its mere presence, even if it responds to treatment or creates resistance. “Liquid biopsy has many applications,” says Ana Vivancos, head of the cancer genomics laboratory at the Vall d’Hebron Institute of Oncology (VHIO). “In the metastasis scenario, we use it to monitor mutations to see whether the patient is responding to therapy or progressing and how they will do so: the dynamics of tumor DNA in the blood informs you of what is happening in a clinic level in the patient. It’s also starting to be used in the surgical field: We know that if you operate on colon cancer and take a blood sample after a week or two and find tumor DNA, you haven’t cured that patient. and if you treat it with chemotherapy after surgery and then the tumor DNA disappears in the blood, you have cured it, but if it is still there, a relapse occurs,” explains the researcher. The third application – “the most difficult,” Vivancos suspects – is to use it to detect cancer in asymptomatic people.
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Research published in The Lancet by American scientists provides evidence of the potential of liquid biopsy in this third line of action: early detection in asymptomatic people. The researchers recruited more than 6,600 apparently healthy participants with and without risk factors for cancer and subjected them to one of these blood tests for early detection of the disease: Signs of cancer were detected in 92 cases, 38 of which were actually diagnosed with a tumor, but another 57 were false positives Results – meaning they didn’t actually have a disease. In total, during the year of follow-up during which the study lasted, 121 participants were diagnosed with cancer: in addition to the 35 who were detected with the liquid biopsy, another 86 who tested negative on this test (false negative) were ultimately diagnosed with cancer other techniques.
The test used in this study measures methylation patterns, which are like characteristic signatures in tumor DNA and not only reveal the presence of disease, but also indicate its origin. “The study discovered many cancers for which there are no screening tests, including some that are at an early stage. For example, cancers of the biliary tract, small intestine, and pancreas, as well as spindle cell neoplasm, were discovered in early stages that were susceptible to surgical resection. “It is unlikely that these fatal malignancies would have been identified through physical examinations or routine screening,” the authors agreed in the study. Almost half of the positive results detected by the test were tumors in the early stages of the disease, with stages I and II – IV being the most serious.
Despite the cases of false positives and false negatives reported in research, the scientists concluded that this study “demonstrates the clinical feasibility” of these tests, although of course they admit that further studies will be needed to “determine the safety and effectiveness.” “Benefit” and clinical effectiveness [de estas pruebas] as a cancer detection strategy.
In any case, the American researchers’ findings complement the previous scientific literature, which already pointed in this direction. For example, a study by scientists at Johns Hopkins University published in the journal Science in 2018 confirmed the potential of another test (CancerSeek) to detect eight types of tumors. In 2020, another study in the same journal showed that it is possible to use this test to find tumors in asymptomatic people: after the follow-up of 9,900 women, 26 women were found to have cancer, in some cases allowing treatments with curative potential.
There is much to do
“The Lancet study shows that they have a test that can detect cancer in a good proportion of cases, but the data tells us there is still a lot of work to do.” “You have 86 false negatives, people , that are not discovered,” says Vivancos, who was not involved in the investigation. In the same vein, Clara Montagut, head of the Digestive Oncology Department at the Hospital del Mar and researcher in the Molecular Cancer Therapy Group at the Research Institute of the Hospital del Mar, assures that the new study, in which she was also not involved, “is a important step in the right direction, but further research is still needed”: “The results are nothing special, but they are similar to breast or colon screenings.” With the advantage that adherence can increase here because many people do not take all the tests do mammograms, colonoscopies… but if it’s just a blood test, yes.”
Experts interviewed insist that the technique needs to be refined if it is to become a potential population screening tool in the long term. “It is progress, but not definitive,” says César Serrano, secretary of the board of the Spanish Society of Medical Oncology. The doctor, an oncologist from Vall d’Hebron, points out the technical and biological limitations of liquid biopsy, such as the fact that not all tumors release DNA into the blood. “There are tumors in which a lot of tumor DNA circulates in the blood, for example in the lungs, breasts and colon. Thyroid or sarcomas, on the other hand, release little. And in tumors of the same type, there are some that release DNA and some that don’t,” he argues.
In fact, one of the traditional obstacles to liquid blood biopsy is that tumor DNA is usually easier to detect when the disease is more advanced. In earlier stages it can be more complex, says Vivancos: “The patients who are missed are those who are in stages I and II because they have less DNA released into the blood.” The more metastatic they are, the more DNA is released, and regardless of stage, the more malignant, the greater the release. For example, although sarcomas release little and generally have a good prognosis, pancreatic cancer, which is very aggressive, releases little. “We still don’t understand exactly how tumors release DNA into the blood,” admits the researcher.
The scientists interviewed also emphasize the need to improve technology to avoid both false alarms and missed cases. “We have to be very sensitive so that cancer catches us; and that it has specificity, that is, it does not tell you that there is cancer where there is none,” Montagut summarizes. Detecting a false positive means exposing a truly healthy person to unnecessary medical tests and a lot of useless stress. Vivancos emphasizes: “We are not ready yet. Technology has advanced, but many patients miss it. The problem is not just the false positives, which are a problem because of the stress you create, but the false negatives.”
A promising technology
Experts point out that it is also necessary to assess the risk of overdiagnosis, that is, detecting lesions that may not develop into cancer or may disappear on their own. And Serrano also adds that in order to become a population screening, in addition to clinical validity – which identifies the biomarker in the blood – it is also necessary to demonstrate “the clinical benefit that has a positive impact on patients because it improves survival improved”.
The voices surveyed agreed that the possibilities of liquid biopsy are immense. Both in blood and other fluids – Vivancos has just taken part in research testing its possibilities in breast milk, and there are also studies in cerebrospinal fluid to detect brain tumors. The VHIO researcher is optimistic but “realistic,” she says: “I think it will reach screening.” [cribado] Population, but the technology needs to be improved.” It is currently used to monitor the disease in real time and is intended to guide treatment in the short term. “It’s very promising, but it’s still practically research,” Serrano clarifies.
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