Can you detect cancer by drawing blood? Is the popular tumor marker screening in physical examinations really useful?

Screening for cancer using "tumor markers" has become a standard for some wealthy people or those who pay special attention to their health. But few people ask a question: Is this screening really useful?

Written by | Wang Chenguang

For those who care about their health, "tumor marker" has become a familiar professional term. In an environment where most people are afraid of cancer, many medical examination institutions have taken the opportunity to launch "tumor examination packages" for healthy people, and "blood test for cancer" has become a promotional gimmick. In recent years, with the progress of gene detection technology, gene sequencing and other methods have also been rapidly applied to cancer screening under the slogan of "precision medicine" as one of the contents of so-called high-end physical examinations.

So, are these popular cancer early screenings based on blood biomarkers provided by most physical examination institutions necessary?

The answer is clear: it is not necessary. Not only is it unnecessary, but it also has the potential to cause harm. Most of the public is not aware that these biomarker-based items in physical examinations are unreasonable and cannot benefit the recipients. Medical institutions take advantage of regulatory loopholes and abuse these testing items, which is a violation of regulations or even illegal.

There are two major categories of tests used by medical institutions for cancer screening: one is to detect changes in the levels of proteins in the blood that are believed to be related to cancer, and the other is to detect changes in cancer-related genes that have emerged in more advanced ways in recent years. These two types of test substances are collectively called tumor biomarkers.

Depending on their source, biomarkers can be from tumor tissue, blood or other body fluids. This article will focus on the latter, which is the biomarker detection based on blood samples in cancer physical examination projects. Unless otherwise specified, the following biomarkers refer to blood indicators of proteins or genes, which are the most concentrated content of cancer screening.

Tumor markers: dual defects 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 treatment methods, and monitoring cancer recurrence.

Is the use of biomarkers as cancer screening during physical examinations missing here? No, because no biomarker has been approved for early cancer screening.

Because tumor markers can be used to assess a tumor's response to treatment and prognosis, researchers hope that they can also be used to screen for cancer in its early stages (when there are no symptoms). A useful screening test should have sufficiently high sensitivity (ability to correctly identify people who have the disease) and specificity (ability to correctly distinguish people who do not have the disease). If the test is highly sensitive, it will identify most patients who have the disease. In other words, only very few patients will not be detected (low false negatives). If the test is highly specific, only a small number of people who do not have cancer will test positive (low false positives).

Although tumor markers have some value in determining whether a cancer has responded to treatment or in assessing whether it has recurred, to date no tumor marker has been found to be sensitive and specific enough to be used alone to screen for cancer.

For example, the prostate-specific antigen (PSA) test, which is measured by a blood sample, was once used to screen men for prostate cancer. 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 offset the harms of a series of diagnostic tests and treatments. Because in most cases, these cancers do not affect the patient's quality of life and survival.

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 be used along with vaginal ultrasound to screen women for ovarian cancer.

There are also many tumor markers such as CEA, AFP, CA153, CA724, etc., which have also been investigated for cancer screening. Unfortunately, none of them has been found to be valuable for cancer screening in healthy people.

The clinical value of early screening for multiple cancers for specific populations (different age groups, genders, ethnicities, lifestyles, family histories, and other cancer risks) and specific tumor types is clear, which is the consensus of the mainstream medical community and the specific embodiment of evidence-based medicine in cancer screening. However, this is completely different from the above-mentioned physical examination to determine whether a person has cancer by testing the level of biomarkers.

For healthy people, it is unnecessary to do "cancer screening" by testing tumor markers. Not only will it fail to achieve the intended purpose, the interpretation of the test results will only lead to blind pessimism or blind optimism.

Why do I say this? Because whether it is the detection of blood protein markers in the 1990s or the detection of genes in the past 10 years, the problem is the same, that is, the clinical value of these detection methods for cancer screening has never been confirmed by rigorous clinical trials. In addition, many studies have reached opposite or unsupportive conclusions.

Some biomarkers currently in clinical use, such as PSA for prostate cancer, AFP for liver cancer, CA125 for ovarian cancer, or CA19-9 for pancreatic cancer, have prerequisites for their use. They can be used as companion diagnostic indicators to measure treatment response or to monitor recurrence, but as separate indicators for cancer screening in healthy people, they have no clinical significance and cannot achieve early diagnosis as advertised, let alone early treatment.

Next, we will take the blood CA19-9 test of pancreatic cancer patients as an example to further explain the scope of application of this type of biomarker and why it cannot be used to screen asymptomatic and undiagnosed pancreatic cancer populations. The following content 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 blood. By detecting changes in the protein content of CA19-9 in the blood, the development of pancreatic cancer in the patient can be inferred.

A healthy person's blood may contain a small amount of CA19-9, but this indicator often rises a lot in pancreatic cancer patients. Although the CA19-9 content in the blood of different patients may vary greatly, for the same patient, the CA19-9 content in the blood is positively correlated with the number of tumor cells in the patient's body (tumor size).

Therefore, testing the level of this marker can help understand how cancer changes over time, and can also be used to examine whether a treatment is effective and monitor whether cancer recurs. After cancer is diagnosed, relevant tumor biomarker tests are performed to determine the levels before treatment. These are necessary tests, which are equivalent to setting a "baseline" for future tests. During the treatment process, the identified markers may be tested frequently to observe the treatment effect. Regular follow-up after the end of treatment will also continue to test to provide a basis for judging whether there is recurrence and metastasis.

CA19-9 levels can also be used as an auxiliary indicator to judge whether surgery is necessary. Extremely high CA19-9 levels are often associated with distant organ metastasis of the tumor, which means that the conditions for surgery are not met. CA19-9 levels (changes) are also important for judging the patient's prognosis. For example, a decrease or normalization of CA19-9 levels after surgery is associated with a longer survival period. On the contrary, if CA19-9 levels remain high after surgery, it is more likely that there are residual cancer cells in the body. These patients are more likely to relapse and have a relatively short survival period.

CA19-9 levels can also be used to monitor the tumor's response to surgery and subsequent treatments, whether it is chemotherapy, radiotherapy, or other targeted or biological therapies. A decrease in CA19-9 levels is related to the effectiveness of the treatment plan. If CA19-9 levels do not decrease significantly or even increase after a treatment is completed, it indicates that the plan is ineffective and needs to be adjusted in time.

In addition to the limitations of the detection technology and methods themselves (false positives and false negatives, etc.), the diagnostic sensitivity and specificity of CA19-9 levels for patients with symptomatic pancreatic cancer are only about 80%, respectively. Even for patients diagnosed with stage I pancreatic cancer, the positive rate is only about 40%. This means that CA19-9 negativity cannot be used as an indicator to exclude the possibility of pancreatic cancer, because the cancer cells of some patients do not produce CA19-9, and the content in the serum is no different from that of healthy people. This has shown that its screening value for healthy people is extremely low (the sensitivity is too low).

On the other hand, for every 100 asymptomatic healthy people with a positive CA19-9 test result, less than one is diagnosed with cancer. The academic expression of this situation is that the positive prediction value (PPV) of the test method is less than 1%. This is because high levels of CA19-9 may be a sign of pancreatic cancer, but it may also be a sign of other types of cancer or certain non-cancer diseases. For example, pancreatitis, gallstones, bile duct disease, liver disease, cystic fibrosis, etc. may show elevated CA19-9 serum levels.

In addition to pancreatic cancer, patients with bile duct cancer, colorectal cancer, gastric cancer, ovarian cancer, and bladder cancer may also have elevated levels of CA19-9 in their blood, but the percentage of patients with elevated levels is lower. Therefore, this test cannot be used for screening of these types of cancers either.

Despite this, early cancer screening by testing protein biomarkers in the blood has almost become a standard physical examination in China. There have been institutions in the United States that provide similar services, such as Theranos, which was once very popular in the United States. However, 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 its president and CEO, were both sentenced to heavy penalties for fraud in the testing service and were imprisoned this year.

Currently in the United States, almost no medical institution uses the above biomarkers to provide cancer screening services for healthy people. Some places may still retain PSA testing for men over 50 years old, and family doctors usually tell them that it is of little value.

Nucleic acid screening: another kind of fortune telling

Over 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 the blood has become another hot topic. The status of cancer-specific DNA or RNA as a biomarker is likely to replace the protein factors as tumor markers in the 1990s, especially in the application of early cancer screening. Many companies and research institutions have carried out a lot of work in this field and rushed to the market before their clinical value was verified, starting cancer screening services for healthy people. GRAIL, founded in 2016 in San Francisco, California, is a leader in this field.

Also in 2016, Illumina, a leader in the gene sequencer manufacturing industry in California, USA, joined forces with Bill Gates and Amazon founder Jeff Bezos to invest $100 million in the field of blood tumor detection. In 2021, it acquired GRAIL to develop detection based on tumor-specific nucleic acid substances in the blood, with a focus on cancer screening for healthy people.

At this point, this type of detection of nucleic acid substances in the blood has deviated from the concept of general tumor biomarkers and has become the main force of another technical term "liquid biopsy".

"Liquid biopsy" was introduced into the field of cancer diagnosis as a new concept in 2010 to detect circulating tumor cells (CTCs) in the blood of cancer patients. This concept has now been extended to factors derived from circulating tumor cells, including circulating DNA (ctDNA), mRNA, circulating microRNA (cfmiRNA), long non-coding RNA, small RNA, vesicles (EVs) shed by cancer cells, etc. Of course, in a broad sense, it also includes the protein biomarkers mentioned above. The main sample source of liquid biopsy is blood, but it also includes cerebrospinal fluid, urine, sputum, ascites, and theoretically any other body fluid that can be collected.

Liquid biopsy is theoretically feasible. As early as the 1940s, people had realized that nucleic acids existed in the blood, even before we knew the structure of DNA. In the 1970s, this understanding was further improved and a connection was established with tumors. It took another 20 years to discover that these DNAs carry specific mutations. This is very important because it provides direct evidence that some nucleic acid substances in the blood come from cancer tissues, and also provides a theoretical basis for detecting cancer-specific nucleic acid fragments (mutations) in the blood. Inspired by progress in cancer research, Professor Dennis Lo of the Chinese University of Hong Kong has made progress in the field of minimally invasive prenatal diagnosis. Combined with the development of DNA sequencing technology, minimally invasive prenatal diagnosis has been successfully applied to clinical practice in recent years.

DNA sequencing technology has been developed rapidly over the past two decades, and it is not a big problem in terms of technical implementation. However, the problem of using liquid biopsy for cancer screening is the same as that of protein markers, which can be seen from the discovery process of these markers. That is, to find out the components in the blood of confirmed cancer patients that are different from those of healthy people, and in turn use these components to screen healthy people for cancer.

To understand this problem, we can make an analogy and start with the once popular "blood type and personality".

There are only a limited number of blood types, but the characteristics that can be used to describe each person are almost infinite, such as your personality, taste, physical characteristics, hobbies, birth time, etc. The combination of these characteristics is astronomical, and this combination determines that a person is different from others. But when analyzing these characteristics, different groups of people can always find some common characteristics. After limited observation, some people find that people with a certain blood type have some "common characteristics" of that type, and then spread it as truth and use it as a tool to infer personality characteristics.

Of course, the relationship between blood type and personality has no scientific basis at all, and the example may not be very appropriate, but its operation process and the technology of realizing blood detection of tumors are comparable to a certain extent. Many studies of this kind start by comparing the DNA differences between tumor patients and healthy people. After complex statistical calculations, a group of gene mutations are obtained that are unique to tumor patients (common characteristics), and then these changes are used to infer whether healthy people have tumors.

In order to further understand whether the detection technology based on characteristic gene fragments of cancer in the blood can be used for early cancer screening, we need to first understand the hot topic in this field - multi-cancer early detection (MCED).

The developers of MCED technology claim that the test has the potential to detect multiple cancers from a single blood sample. The blood sample is tested for certain signatures (DNA or protein fragments) found in cancer cells. If these signatures are found, it means that the person may have cancer. As if this was not enough to attract people's attention, the developers claim that the test results may also show where (organ) the cancer is located.

Different MCED detection methods are being developed, and the product Galleri developed by GRAIL mentioned above has been used for cancer screening. Let's take this as an example to see how this product works.

Galleri was advertised as being able to detect more than 50 types of cancer, and this news occupied the headlines of many media two years ago. The media often found some patients to tell their personal experiences to prove how this technology can save lives. However, these media rarely paid attention to the technical details of the screening product and the problems that exist in their reports.

Data from the early development stages (based on confirmed cancer patients) showed that Galleri's detection rate for stage I cancer was less than 40%, stage II was 69%, stage III was 83%, and stage IV was 92%.

Another validation study showed that Galleri's overall positive rate for diagnosing cancer was 52%, with detection rates of 77% and 90% for stage III and IV (advanced) cancer patients, respectively. However, Galleri's detection rate for early-stage cancer was very low, at 17% and 40% for stage I and II, respectively.

Recently, the results of a clinical trial based on screening of non-(confirmed) cancer populations in the UK were released. This is a multicenter, prospective observational study. The subjects included in the clinical trial included patients with non-specific symptoms or symptoms related to gynecological cancer, lung cancer or digestive tract cancer, and confirmed cancer patients were excluded. The researchers performed Galleri tests on DNA isolated from the blood of the participants and then compared the test results with standard clinical diagnostic results.

A total of 5,461 participants received evaluable test results and clinical diagnosis results and were included in the final cohort for analysis. The test results of 323 cases suggested cancer, of which 244 were ultimately diagnosed with cancer, with a positive predictive value of 75.5%. The conclusions of this prospective study are basically consistent with the data from the aforementioned research and development process, both showing that the sensitivity of the test method increases with the increase in cancer stage. The detection rate of stage I cancer in this study was 24.2%.

However, such a product, which has an overall detection rate of less than 1/4 for stage I confirmed patients, was touted by developers and the media as an innovative and revolutionary breakthrough and was used in early cancer screening.

This is just a problem with the detection technology, or the technical limitations of using nucleic acid biomarkers in the blood for cancer screening, which also determines the limited clinical value of blood screening. On the one hand, there are low (or even non-existent) clinical benefits, and on the other hand, there are clear health risks (further diagnosis and overtreatment), which determines that blood screening for tumors has no practical value.

But that’s not the whole problem.

Screening alone is not enough

We need to fully understand the problems with this type of detection method and figure out the purpose of cancer screening and early diagnosis. Then we can consider a series of questions, such as whether the current technical means can achieve this and what can be done after it is achieved.

Is the purpose of screening and early diagnosis just to know whether a person has cancer? Obviously not. The main purpose is to intervene in advance after the tumor is discovered, reduce the risk of death from cancer and prolong the patient's life. Therefore, theoretical and technical feasibility is not enough to support the clinical use of blood tests for tumors. The key question is whether there is a clinical demand and whether it can help the clinical treatment and 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 the study of cancer prevention methods, when developing and testing interventions for screening and early detection, it often takes years to decades to verify. The most important criterion is whether a new screening method reduces the number of people who are eventually diagnosed with advanced cancer or die from cancer. Many biomarkers that show promise in early studies are often abandoned in further testing because there is no clear clinical benefit.

Once again, tumor screening and early detection alone are far from enough. It is crucial to ensure that there are methods to further diagnose individuals who screen positive and to have effective clinical intervention methods after diagnosis. Otherwise, no matter how sensitive, specific, or cheap a method is, it is not enough to serve as supporting evidence for clinical use.

Even if these detection methods are 100% accurate, without false positives and negatives (in fact, such methods do not exist), and the sensitivity exceeds that of other detection methods, can they solve the problem? Imagine if the test results tell you that there are cancer cells in your body, but other methods cannot detect them. In addition to the psychological pressure of having cancer, what value is there? This is the reality of MCED of companies such as GRAIL, and it is also the contradiction of these projects. There is no need for patients with advanced symptoms to first undergo this test result to indicate cancer, and then go for the corresponding cancer confirmatory examination. For early patients who usually do not show cancer-related symptoms, a 20% positive detection rate means that 80% of cancer patients may lose the opportunity to be diagnosed.

Those who test positive but cannot be diagnosed with cancer by conventional means will become the landlord living on the first floor in Su Wenmao's stand-up crosstalk "Throwing Boots", who cannot sleep at night waiting for the second boot of the tenant upstairs to drop.

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 "hundred billion dollar" market for tumor screening in healthy people. This is a feast for capital speculation, but it may be a threat to people's health.

The author of this article is a PhD in biology. He has served as a researcher at the Sidney Kimmel Cancer Center of 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/director of the Radiation Damage Protection and Drug Research Laboratory, and a professor/doctoral supervisor at Peking Union Medical College. He is currently engaged in the research and development of anti-tumor drugs.

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.

[2] https://www.fireengineering.com/industry-news/fdic-intl-2023-postscript-onetest-cancer-helps-spot-early-detection-in-firefighters/#gref

[3] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01700-2/fulltext

[4] https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00277-2/fulltext#%20

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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