Screening for cancer with "tumor markers" has become the standard for some wealthy people or those who take their health very seriously. But few people ask the question: does this screening really work?
Written by |Wang Chenguang.
For people who care about their health, "tumor marker" is already a familiar technical term. In the environment where most people talk about cancer discoloration, many physical examination institutions have taken the opportunity to launch "tumor physical examination" for healthy people, and "blood test for cancer" has become a gimmick for promotion. In recent years, with the advancement of genetic testing technology, gene sequencing and other methods have also been rapidly applied to cancer screening as one of the contents of the so-called high-end physical examination under the slogan of "precision medicine".
So, is it necessary for these popular and most medical examination institutions to provide early cancer screening based on blood biomarkers?
The answer is unequivocal: not necessarily. Not only is it unnecessary, but there is also potential harm. It is not clear to most of the public that these biomarker-based programs set up in the physical examination are not reasonable and do not allow the audience to benefit from the physical examination. Medical institutions take advantage of regulatory loopholes to abuse these testing items, which is illegal or even illegal.
There are two main types of tests used in cancer screening by medical institutions: those that detect changes in the levels of proteins in the blood that are thought to be related to cancer, and those that detect cancer-related genetic changes that have appeared in recent years in more advanced ways. These two types of tests are collectively referred to as tumor biomarkers.
Depending on the biomarker, the biomarker can be from tumor tissue, blood or other body fluids. This article will focus on the latter, focusing on blood sample-based biomarker testing in cancer screening programs. Unless otherwise specified, the following references to biomarkers refer to blood markers of proteins or genes, which are currently the most focused content of cancer screening.
Tumor markers: dual deficiencies in sensitivity and specificity.
Clinically, the application of tumor biomarkers is mainly reflected in the following aspects: auxiliary diagnosis, monitoring cancer development, judging the efficacy of the first means, and monitoring cancer.
Is the application of biomarkers as cancer screening in physical examinations missing here?Nothing was missed, as none of the biomarkers were approved for early cancer screening.
Since tumor markers can be used to assess tumor response to ** and prognosis, the investigators hope that they can also be used for early cancer screening (asymptomatic stage). A valuable screening tool should be sufficiently sensitive (to correctly identify people with the disease) and specific (to correctly distinguish between people who do not have the disease). If the test is highly sensitive, it will identify most patients with the disease. In other words, only a very small number of patients cannot be detected (low false negatives). If the test is highly specific, then only a small number of people who do not have cancer will test positive (low false positive).
Although tumor markers have some value in determining whether a cancer responds to ** or in assessing whether it is**, no single tumor marker has been found to date to be sensitive and specific enough to be used alone to screen for cancer.
For example, the prostate-specific antigen (PSA) test, measured through a blood sample, was once used to screen for prostate cancer in men. However, elevated PSA levels can be caused by benign prostate disease as well as prostatitis, and most men with elevated PSA levels do not have prostate cancer. In addition, the benefits of PSA screening do not outweigh the harms associated with a range of confirmatory tests and**. Because in most cases, these cancers do not affect the quality of life and survival of patients.
CA125 is another common tumor marker that is sometimes elevated in the blood of women with ovarian cancer and can also be elevated in women with benign conditions such as cysts, but it is not sensitive or specific enough to screen for ovarian cancer in women with ultrasound.
There are also many tumor markers such as CEA, AFP, CA153, CA724, etc., which have also been investigated for cancer screening. Unfortunately, no one has been found to be valuable for cancer screening in healthy people.
The clinical value of early screening of a variety of cancers for specific populations (different age groups, genders, ethnicities, lifestyle Xi s, family history and other cancer risks) and specific tumor types is clear, which is the consensus of the mainstream medical community and the concrete embodiment of evidence-based medicine in cancer screening. However, this is completely different from the above physical examination by measuring the level of biomarkers to determine whether cancer is present.
For healthy people, it is not necessary to do "cancer screening" by testing tumor markers, not only does it fail to achieve the intended purpose, but the interpretation of the test results will only lead to blind pessimism or blind optimism.
Why do you say that?Because whether it is the detection of protein in blood as a marker in the 90s of the last century, or the detection of genes as the core in the past 10 years, the problem is the same, that is, the clinical value of these tests for cancer screening has never been confirmed by rigorous clinical trials. Not only that, but multiple studies have come to opposite or unsupportive conclusions.
At present, some biomarkers in clinical application, such as PSA for prostate cancer, AFP for liver cancer, CA125 for ovarian cancer or CA19-9 for pancreatic cancer, are used with prerequisites, and can be used as companion diagnostic indicators, can be used to measure ** response, and can also be used to monitor**, but as a separate indicator for cancer screening in healthy people has no clinical significance, neither can be done early diagnosis as advertised, nor can it be talked about early treatment.
Next, the blood CA19-9 test in pancreatic cancer patients is used as an example to further explain the scope of application of this type of biomarker and why it cannot be used for screening in asymptomatic and undiagnosed pancreatic cancer populations. The following also applies to other tumor markers in the blood.
CA19-9 (cancer antigen 19-9) is a tumor biomarker that is produced by pancreatic cancer cells and released into the bloodstream. By detecting changes in the protein content of CA19-9 in the blood, it is possible to predict the development of pancreatic cancer in the patient.
Healthy people may have small amounts of CA19-9 in their blood, a marker that often rises a lot in people with pancreatic cancer. Although the amount of CA19-9 in the blood may vary greatly from patient to patient, the amount of CA19-9 in the blood is positively correlated with the number of tumor cells (tumor size) in the patient for the same patient.
Therefore, the detection of the level of this marker can help understand how the cancer changes over time, and can also be used to see if a disease is effective and whether the cancer is monitored. After the cancer is diagnosed, relevant tumor biomarker tests are carried out to determine the level before **, these are necessary tests, which are equivalent to setting a "baseline" for future tests. During the process, the identified markers may be frequently tested to observe the effect. Regular follow-up after the end of the ** will also continue to be tested to provide a basis for judging whether there is ** and metastasis.
CA19-9 levels can also be used as an auxiliary indicator to judge whether surgery is necessary, and ultra-high CA19-9 levels are often associated with metastasis of distant organs of the tumor, which means that surgical conditions are not available. CA19-9 levels (changes) are also important for the prognosis of patients, such as postoperative CA19-9 levels are reduced or normalized, which is associated with longer survival. Conversely, if CA19-9 levels remain high after surgery, it is more likely that there are still residual cancer cells in the body, and these patients are more likely to have ** and have a relatively short survival.
CA19-9 levels can also be used to monitor tumor response to surgery and follow-up**, whether chemotherapy, radiotherapy, or other targeted or biological**. The decline of CA19-9 level is related to the effectiveness of the ** program, if the CA19-9 level does not decrease or even increase significantly after the completion of a **, it indicates that the program is ineffective and needs to be adjusted in time.
In addition to the limitations of the detection technology and method itself (false positives and false negatives, etc.), the sensitivity and specificity of CA19-9 levels for the diagnosis of symptomatic pancreatic cancer patients are only about 80%, respectively. Even in patients diagnosed with stage I pancreatic cancer, the positive rate is only about 40%. This means that CA19-9 negative is not an indicator to rule out pancreatic cancer, because some patients' cancer cells do not produce CA19-9, and the serum content is no different from that of healthy people. This has shown that it has very low screening value (too low sensitivity) for healthy people.
On the other hand, for every 100 asymptomatic healthy people who test positive for CA19-9, less than one is diagnosed with cancer. The academic expression of this situation is that the ** value (PPV) of the detection method is less than 1%. This is because high levels of CA19-9 can be a sign of pancreatic cancer, but they can also be a sign of other types of cancer or certain non-cancerous diseases. For example, pancreatitis, gallstones, bile duct disease, liver disease, cystic fibrosis, etc., may all present with elevated serum levels of Ca19-9.
In addition to pancreatic cancer, patients with bile duct, colorectal, stomach, ovarian, and bladder cancers may also have elevated levels of Ca19-9 in their blood, although the proportion of patients with elevated levels is lower. Therefore, this test cannot be used to screen for these cancer types.
Despite this, early cancer screening by detecting protein biomarkers in the blood has become almost the standard in China. There have been organizations in the United States that have provided similar services, such as Theranos, which was once in the ascendant in the United States. But in the United States, such companies are likely to be prosecuted by law. Elizabeth Holmes (founder of Theranos) and her ex-boyfriend, Ramesh Balwani, who later joined the company and became president and CEO, have both been heavily sentenced for fraud in testing services and are serving prison sentences this year.
Currently, there is hardly any medical facility in the United States that uses these biomarkers to provide cancer screening services to healthy people. PSA testing for men over the age of 50 may also be available in some places, and your GP will usually tell you that it is of little value.
Nucleic acid screening: another kind of fortune telling.
In the past two decades, with the development of gene sequencing technology and the establishment of high-throughput analysis methods, the presence of tumor-related gene fragments in blood has become another hot topic. The status of cancer-specific DNA or RNA as a biomarker has a tendency to replace protein factors as tumor markers in the 90s of the last century, especially in the application of early cancer screening. Many companies and research institutes have done a lot of work in this area and rushed to market before the clinical value is validated, starting cancer screening services for healthy people. Founded in 2016 in the San Francisco, California area, GRAIL is a leader in this field.
Also in 2016, Illumina, a leader in the gene sequencer production industry in California, USA, joined forces with Bill Gates and Amazon founder Jeff Bezos to invest $100 million to enter the field of blood detection tumors, and in 2021, Grail was taken over to develop a test based on tumor-specific nucleic acid substances in the blood, with a focus on cancer screening for healthy people.
At this time, this kind of detection of nucleic acid substances in the blood has moved away from the concept of general tumor biomarkers and has become the main force of another proper term, "liquid biopsy".
"Liquid biopsy" was introduced into the field of cancer diagnostics in 2010 as a new concept for the detection of circulating tumor cells (CTCs) in the blood of cancer patients. This concept has now been extended to derived factors from circulating tumor cells, including circulating DNA (ctDNA), mRNA, circulating microRNAs (CFmirNAs), long non-coding RNAs, small RNAs, vesicles (EVs) shed by cancer cells, and more. Of course, in a broad sense, it also includes the protein biomarkers mentioned above. The primary sample of a liquid biopsy** is blood, but also cerebrospinal fluid, urine, sputum, ascites, and theoretically any other body fluid that can be collected.
Liquid biopsy is theoretically possible. As early as the 40s of the 20th century, people have recognized the existence of nucleic acids in blood, even before we know the structure of DNA. In the 70s, this understanding was further improved, and a correlation was established with tumors. It took almost 20 years for the DNA to be discovered to carry specific mutations. This is important because it provides direct evidence that some nucleic acid substances in the blood come from cancer tissues, and also provides a rationale for detecting cancer-specific nucleic acid fragments (mutations) in the blood. Inspired by the progress in the field of cancer research, Professor Dennis Lo of the University of Chinese of Hong Kong has made progress in the field of minimally invasive prenatal diagnosis, which has been successfully applied to clinical practice in recent years in combination with the development of DNA sequencing technology.
DNA sequencing technology has developed significantly over the past two decades, and it is not a big problem in terms of technical implementation at present. However, liquid biopsy screening for cancer has the same problems as protein markers, as can be seen from the discovery of these markers. That is, to find out the components in the blood of patients who have been diagnosed with cancer that are different from those of healthy people, and then use these components to screen healthy people for cancer.
To understand this problem, we can make an analogy, and we might as well start with the popular "blood type and personality".
There are only a few blood types, and the characteristics of each person that can be described are almost infinite, such as your personality, tastes, physical characteristics, hobbies, birth moment, etc., and the combination of these characteristics is even more astronomical, and this combination determines that a person is different from others. But when analyzing these traits, different groups of people can always find some common traits, and some people, after making limited observations, find that people with a certain blood type have some "common traits" of that type, which are then disseminated as truth and used as a tool for inferring personality traits.
Of course, the relationship between blood type and personality is completely unscientific, and the examples may not be very appropriate, but the operation process and the technology to achieve blood detection for tumors are somewhat comparable. Many of these studies begin by comparing DNA differences between cancer patients and healthy people, and then perform complex statistical calculations to arrive at a set of genetic mutations that are unique to cancer patients (common features), and then use these changes to infer whether tumors develop in healthy people.
In order to further understand whether the detection technology based on cancer-specific gene fragments in blood can be used for early cancer screening, it is necessary to first recognize the hot spot in this field - multi-cancer early detection (MCED).
The developers of the MCED technology claim that the test has the potential to detect multiple cancers from a single blood sample. Detection of certain characteristic substances (DNA or protein fragments) in cancer cells in blood samples. If these characteristics are found, it means that the person may have cancer. That's not enough to attract attention, and the developers claim that the test results may also show where the cancer occurred (organ).
Different MCED assays are being developed, and the aforementioned Grail company has developed Galleri, a product that has been used for cancer screening. Let's take this as an example to see how this product is.
Galleri was advertised as being able to detect more than 50 types of cancer, and the news had dominated a lot of the headlines two years ago. **Patients are often found to have their personal experiences to illustrate how this technology can save lives. However, these ** rarely pay attention to the technical details and existing problems of the screening product in the report.
Data from the early stages of development (based on studies in patients with diagnosed cancer) showed that Galleri had less than 40% of stage I cancers, 69% for stage II, 83% for stage III, and 92% for stage IV.
In another validation study, Galleri had an overall positive rate of 52% for diagnosed cancer, 77% for patients with stage III and IV (advanced) cancer, and 90% for patients. However, Galleri's detection rate for early-stage cancer is low, at 17% for stage I and 40% for stage II.
Recently, the results of a clinical trial of screening based on non-(confirmed) cancer populations in the UK were published. This is a multicenter, prospective observational study. Included in the clinical trials included patients with non-specific symptoms or who may have symptoms associated with **cancer, lung cancer, or gastrointestinal cancer, while patients with confirmed cancer were excluded. DNA isolated from the participants' blood was tested for Galleri and the results were then compared to standard clinical diagnoses.
A total of 5461 participants received evaluable test results and clinical diagnoses and were enrolled in the final cohort for analysis. The test results of 323 cases were suggestive of cancer, of which 244 were eventually diagnosed with cancer with a positive ** value of 755%。The conclusions of this prospective study, which are generally consistent with the data from the previous development process, show that the sensitivity of the test increases with increasing cancer stage, and the detection rate of stage I cancer in this study is 242%。
However, such a product with an overall detection rate of less than 1 4 for stage I patients has been touted as an innovative and revolutionary breakthrough by developers and **, and has been used in early cancer screening.
This is only the problem of detection technology, or the technical limitations of using nucleic acid biomarkers in blood for cancer screening, which also determines the limited clinical value of blood screening. On the one hand, there is a low (or even non-existent) clinical benefit, and on the other hand, there are clear health risks (further diagnosis and over**), which determine that blood screening for tumors has no practical value.
But that's not all.
Screening alone is not enough.
It is necessary to fully understand what problems exist in this type of testing method, and to understand what the purpose of cancer screening and early diagnosis is, and then a series of questions such as whether the current technical means can be realized and what can be done after it is realized.
Is the purpose of screening and early diagnosis just to know if a person has cancer?Apparently not. The main purpose is to intervene early after the detection of the tumor, reduce the risk of dying from cancer and prolong the life of the patient. Therefore, the theoretical and technical feasibility is not enough to support the clinical use of blood to detect tumors, and the key question is whether there is a clinical need and whether it can help the clinical prognosis of tumors so that patients can benefit from it.
To truly realize the clinical application of a technology and demonstrate that it can save lives, prospective studies of all cancer types in large populations are needed. As with cancer prevention, it often takes years to decades to test interventions for screening and early detection, and the most important criterion is whether a new screening method reduces the number of people who end up with advanced cancer or die from cancer. Many biomarkers that have shown promise in early studies are often discarded in further testing because there is no clear clinical benefit.
Again, tumor screening and early detection alone are not enough, and it is important to ensure that there are methods to further confirm the diagnosis of individuals who are screened positive and that effective clinical interventions are available once they are diagnosed. Otherwise, no matter how sensitive, specific, or inexpensive a method is, it is not enough to support clinical use.
Even if these detection methods are 100% accurate, there is no false yin and yang (in fact, such means do not exist), and the sensitivity exceeds that of other detection methods, can the problem be solved?Think about it, if the test results tell you that there are cancer cells in your body, but other means can't detect them, what is the value except for the psychological pressure of cancer?And this is the reality of MCED for companies like Grail, and the paradox of these projects. In patients with advanced symptoms, it is not necessary to go through this test to indicate cancer before going for a cancer-definitive test. For early-stage patients who usually do not show cancer-related symptoms, a 20% positive detection rate means that 80% of cancer patients may lose the chance of diagnosis.
And those who test positive but can't be diagnosed with cancer by conventional means will become the landlord who lives on the first floor in Su Wenmao's stand-up comedy "Throwing Boots", and can't sleep at night waiting for the second boot of the tenant upstairs to land.
Encouraged by the clinical application of non-invasive prenatal molecular diagnosis and the pursuit of capital, more and more companies will set their sights on the "100 billion US dollars" market for cancer screening in healthy people, which is a feast of capital speculation, but it may be a health problem for the people.
The author of this article is a Ph.D. in biology, a former researcher at the Sidney Kimmel Cancer Center at Thomas Jefferson University, an associate professor in the Department of Cancer Biology, a researcher at the Institute of Radiation Medicine, Chinese Academy of Medical Sciences, the director of the Radiation Injury Protection and Drug Research Office, and a professor and doctoral supervisor at Peking Union Medical College.
References and links.
1] ballehaninna uk, chamberlain rs. the clinical utility of serum ca 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. j gastrointest oncol. 2012 jun;3(2):105-19.
This article is supported by the Science Popularization China Star Program Project, produced by the Science Popularization Department of the China Association for Science and Technology, supervised by the China Science and Technology Press, Beijing Zhongke Galaxy Culture Media***