Liquid biopsies, the Grail?

Synthesis Dr. C.Bour, September 15, 2022

Main article

Article by Brenna Miller

The Damocles syndrome


Early cancer detection is and remains a Grail for which we have absolute faith in technology. Despite all the failures of screening (melanoma, thyroid, prostate, breast) to overcome cancer and its, unfortunately, most serious forms[1], we nevertheless remain convinced that if we detected all cancerous cells, we could "beat" the disease.
Studies show that the small gains in mortality in cancerology are not due to detection but almost essential to progress in treating advanced forms. Breast cancer is an example.

The media is often the spokesperson for "spectacular discoveries," and we have already reported on the problem of the media coverage of scientific innovations, such as screening and blood tests (liquid biopsies) for early detection of cancer, which was the subject of a study published in JAMA in 2021.

With the multiplication of screenings, most of them failing to decrease overall mortality and reduce the most advanced forms of cancers, our societies have ended up with two kinds of diseases.
On the one hand, diseases that are experienced by the patient, with specific symptoms and identified by the clinician, and on the other hand, conditions that are not experienced but detected by screening and defined as diseases. In the latter case, it is complicated to determine what a patient is. A person in whom the pathologist has found a cancerous cell under his microscope?  A person with a cancerous cell cluster in an organ that will never affect it? A person with a polyp that might have become cancerous one day?

The paradox is that with mass screening and no particular selection, more and more people are declared "sick" without being so, and above all, "cured" before ever being clinically ill. Thanks to the biomedical miracle, they are even treated and then cured of a disease they would never have known. If this is not progress... The problem is that, on the one hand, the treatments themselves can make people sick. On the other hand, the knowledge of their "cancer" exposes people to a suicide rate five times higher, with a maximum observed just after the diagnosis's announcement, whether it is a detected lesion or a "real" clinical cancer. The announcement multiplies by 12 the risk of death by cardiovascular accident.

We (re)-talk about liquid biopsies

An article in La Croix (French newspaper) announces, as did other media recently (Futura Science, Tops Santé, etc.), a blood test consisting of detecting tumor DNA circulating in the blood and thus making it possible to detect 50 types of cancers.

But, as explained above, early detection of cancers does not mean an automatic cure and does not protect against false positives or unnecessary detections.

This is the concern expressed by Gilbert Welsch and Barnett Kramer in an article published in the journal STAT.
Welsch, a general internist and senior researcher at the Center for Surgery and Public Health at Brigham and Women's Hospital in Boston, details this notion in the article dedicated to liquid biopsies, with a critical analysis that you can find here in STAT+
Barnett Kramer is an oncologist, member of the Lisa Schwartz Foundation for Truth in Medicine, and former director of the Division of Cancer Prevention at the National Cancer Institute.

What are liquid biopsies?

A liquid biopsy allows the detection of circulating tumor cells dislodged from a primary tumor or even from metastases and carried in the vascular system, as well as the circulating DNA of these circulating tumor cells. The hope is to be able to detect cancer before its expression.

It was back in 2015 in the United States when members of Congress introduced a bill requiring US Medicare to cover a costly cancer screening test offered to the entire population, but for which so far, there is no scientific evidence that the procedure saves lives.
The American Cancer Society, an American nonprofit organization founded in 1913 to fight cancer and firmly in favor of screening, approved the project, arguing that this expensive and unproven test would solve health disparities.

The two American authors then asked two fundamental questions:
Do liquid biopsies work as advertised?
If liquid biopsies are effective, are they effective enough to be worthwhile?
Finally, a third question emerges: What about the reduction in disparities that the American Cancer Society claims?

Do liquid biopsies work as advertised?

It is claimed, say the authors, like a mantra, regularly repeated in a loop by opinion leaders and media who do not care about the controversy, that 90% of cancers detected very early are cured. This is not, nevertheless, proof that screening saves lives...

What does the notion of 5-year survival mean?

The "90% survival at five years" for cancers is true, but only for cancers with a very good prognosis and those that should never have been discovered and would never have made anyone sick. For cancer that would never have killed its host, it is quite normal that the host is alive after 5 years. It is also true that cancers with a good prognosis have a better survival rate than those with a poor prognosis and metastatic disease. Still, the real question is: is screening capable of discovering these latter cancers in due time, the ones we should be catching because they kill? And this is where the problem lies (see ref 1)...

First, say Welsch and Kramer", early detection of some cancers may not be possible. Despite four decades of mammography screening, for example, the incidence of metastatic breast cancer remains virtually unchanged. Very aggressive cancers have often spread by the time they become detectable." Indeed, aggressive, metastatic cancers do not arise from smaller or lower-grade cancers; they are lesions that are aggressive from the start and have such a molecular component that they have already metastasized in the body; even when they can be detected, they are large at the time of diagnosis because they are very fast. Lanning's study explains the mechanics of cancer very well.

"Second, although earlier detection of some potentially aggressive cancers is possible, early treatment may not change the time of death. Survival statistics hide this possibility."
This is called lead time, which is explained in detail here.
Detection advances the "birth date" of cancer and thus benefits survival statistics but has no impact on people's longevity. It is an optical illusion.

And third, survival statistics are inflated by overdiagnosis, i.e., the unnecessary detection of lesions that would never have killed.
According to Prof. Welsch, "High survival statistics may indicate a problem. For example, the 90% 5-year survival for early-stage cancers includes many cancers detected by blood tests, such as prostate cancer and PSA testing, or by imaging, such as breast cancer and mammography, that were not intended to progress to late-stage cancer or cause death. Overdiagnosis - common in breast, prostate, thyroid, and melanoma skin cancers - significantly inflates survival rates. Higher survival due to overdiagnosis is not a benefit, but harm, with more people, diagnosed and treated for "cancers" that were never going to cause problems."

If liquid biopsies are effective, are they effective enough to make them worthwhile?

We quote below what the two scientists write:

"Even if medical intervention is effective, it is essential to evaluate its side effects. Aspirin, for example, is effective in preventing heart attacks and strokes but not enough in the general population to justify the associated harms, such as brain and intestinal bleeding.
Liquid biopsies will have unintended disadvantages: more tests, more treatments, and the psychological and physical problems that come with them. Some people will be told they have a "cancer signal" - triggering fear and more tests - only to learn later that it was a false alarm. Others will be overdiagnosed and treated for cancers that otherwise would never have worried them. Some will be affected by the treatment; some may even die.
Still, others will have significant cancers discovered earlier than they would have without the liquid biopsy but will not live longer. They will be subjected to the toxicity of cancer therapies earlier, at a time when they would otherwise have no symptoms. These side effects exist in all cancer screening programs. But multicancer liquid biopsy screening has one of its own: While it may be evident that a person has cancer, it is not always clear where that cancer is. Imagine being told you have cancer, but no one knows what type it is.
No one knows how common these side effects are because these tests have not been rigorously studied. But a bad test is as bad as a wrong drug. That's another reason why a randomized trial is needed - not just to determine if liquid biopsies provide benefits but also to determine how often they cause harm.
One thing we know about liquid biopsy screening is that it will be costly."

One test, the Galleri test, for example, costs $949. If it's recommended every year for people 50 and older, Welsch calculates, with 100 million Americans in that age range, that would be about $100 billion a year, he says.
Moreover, additional examinations and other tests will be required to search for and confirm cancer that the liquid biopsy suggests, and the number of medical consultations will be multiplied.

Because if there are wandering tumor cells, cancer must still be found.

Reduction of disparities?

Here again, the two researchers are very doubtful...

"Those who want to address the significant drivers of health disparities should be less concerned with the Medicare population and more concerned with people under age 65, especially where the disparities really start: among young adults and children. And they should be less concerned with medical interventions such as cancer screening and more concerned with the real determinants of health, such as diet, housing, and income security.
Increased mammograms and colonoscopies have not solved the health effects of poverty, and liquid biopsies won't solve them."

In another article published in the Boston Globe, Welsch cites the example of the Galleri test, which has avoided the FDA approval process (the U.S. Food and Drug Administration, which verifies and approves the marketing of drugs) through a waiver. Galleri is sold directly to consumers for $949 per person.
"The company that sells Galleri," says Welsch, "recommends that people take the test once a year. Let's do the math. Given that there are about 60 million Medicare beneficiaries, that would be about $60 billion a year. That would represent a 7% increase in total Medicare spending ¬- to be passed on to taxpayers and/or Medicare beneficiaries in the form of higher premiums.
All this for one test. And no one knows if that test helps people live longer or better."

What should be done?

For G.Welsch, there is only one way to test liquid biopsies on their effectiveness in detecting cancers early: to conduct a randomized trial in which participants are divided into two groups. One group is screened regularly; the other is not. The participants are then followed for about ten years, counting the number of deaths in each group. Randomized controlled trials are the "gold standard" of scientific studies and are a proven method. England's National Health Service (NHS) is currently recruiting 140,000 people for such a trial. The most relevant outcome to measure would be the number of deaths in each group.

The US National Cancer Institute is planning a randomized trial of liquid biopsy screening. Ironically, says G. Welsch in the Boston Globe, the adoption of Medicare coverage for these tests would hamper this trial "because of a dynamic we've already seen. In the 1990s, many doctors and patients believed that a transplant of one's bone marrow was an effective treatment for metastatic breast cancer. The press focused on young women who were dying of aggressive cancer without access to this "life-saving" procedure ...... The presumption of benefit was so strong that researchers had difficulty finding volunteers to participate in studies to determine whether the procedure worked. Everyone already assumed it did. But it didn't.
.... "randomized trials finally showed that bone marrow transplants didn't help women live longer. And they certainly didn't live better. Tens of thousands of women underwent an arduous procedure, often complicated by anemia, infection, and diarrhea. And some died as a result."

So don't put the cart before the horse; it's urgent...wait, the researcher implores Congress at the end of the article to let the American National Cancer Institute and the US Preventive Services Task Force do their work. (USPSTF: group mandated to review the evidence and make recommendations on prevention devices).

Article by Brenna Miller, Lown Institute

Finally, you can find here the summary of the facts, written by Brenna Miller, a health communication specialist at the Lown Institute. She holds a master's degree in public health from Tufts University School of Medicine.

The Lown Institute is "a nonpartisan think tank that advocates bold ideas for a fair and caring health care system."

The author refers to Theranos, an American health technology company that supposedly developed the first liquid biopsy tests without independent evaluations or scientific publications and whose executives were finally indicted in 2018 for massive fraud.

The Damocles Syndrome
Blood Tests That Detect Cancers Create Risks for Those Who Use Them

The New York Times, By Gina Kolata on June 10, 2022


The article features testimonials highlighting the benefits of these tests for patients, but also the risks they pose, especially if, as is currently the case, companies don't wait for a green light from legislators, shortcut approvals and sell the tests directly to consumers.

"Jim Ford considers himself a lucky man: An experimental blood test found his pancreatic cancer when it was at an early stage. It is among the deadliest of all common cancers and is too often found too late. After scans, a biopsy and surgery, then chemotherapy and radiation, Mr. Ford, 77, who lives in Sacramento, has no detectable cancer.
“As my doctor said, I hit the lottery,” he said."

The Damocles syndrome

But there are other testimonials and less enthusiastic comments on the tests:

“When Susan Iorio Bell, 73, a nurse who lives in Forty Fort, Pa., saw an ad on Facebook recruiting women her age for a study of a cancer blood test, she immediately signed up. It fit with her advocacy for preventive medicine and her belief in clinical trials.
The study was of a test, now owned by Exact Sciences, that involved women who are patients with Geisinger, a large health care network. The test looks for proteins and DNA shed by tumors. Ms. Bell’s result was troubling: Alpha-fetoprotein turned up in her blood, which can signal liver or ovarian cancer. She was worried — her father had had colon cancer and her mother had breast cancer. Ms. Bell had seen what happened when patients get a dire prognosis. “All of a sudden, your life can be changed overnight,” she said. But a PET scan and abdominal M.R.I. failed to find a tumor. Is the test result a false positive, or does she have a tumor too small to be seen? For now, it is impossible to know. All Ms. Bell can do is have regular cancer screenings and monitoring of her liver function. “I just go day by day,” she said. “I am a faith-based person and believe God has a plan for me. Good or bad, it’s his will.”
Some cancer experts say Ms. Bell’s experience exemplifies a concern with the blood tests. The situation may involve only a small percentage of people because most who are tested will be told their test did not find cancer.
Among those whose tests detect cancer, scans or biopsies can often locate it. But Dr. Susan Domchek, a breast cancer researcher at the University of Pennsylvania, warned that when large numbers of people get tested, false positives become “a real problem,” adding, “we need to know what to do with those results and what they mean.”

Dr. Daniel Hayes, a breast cancer researcher at the University of Michigan, refers to the situation as a Damocles syndrome: “You’ve got this thing hanging over your head, but you don’t know what to do about it.”

Donald Berry, a statistician at MD Anderson Cancer Center in Houston, shares his experience and doubts. When GRAIL was first formed, its leaders invited him, to be on its scientific advisory board.
“They said they needed a skeptic,” Dr. Berry said. “I told them I was a skeptic and I was quite negative. I told them there was this real hurdle — they will have to run very large clinical trials and the endpoint must be survival. They have to show that detecting cancer early is more than just detecting cancer early. It has to mean something.”
A few years later, the company restructured its scientific advisory board to include many new experts, and Dr. Berry is no longer a member. He is not sure why.
“Being generous, I’d say they no longer needed my expertise,” Dr. Berry said. “Being realistic, they got tired of hearing my complaints that finding cancer early was not enough.”

Reasons for reluctance

Difficult questions from Donald Berry concern overdiagnosis: "finding small tumors that would never have been noticed and may not have caused any harm. Some cancers simply fail to grow or are destroyed by the body’s immune system.
But without knowing if the cancer is dangerous, it will be treated as though it is, subjecting people to therapies that are often difficult or debilitating and may be unnecessary. Dr. Kramer said this also happens with standard screening tests, which can result in the removal of thyroid glands, breasts or prostates for small tumors that are actually harmless."

Another issue is the efficiency of detection for these tests, especially in the most aggressive cancers, according to Dr. Kramer, an oncologist, member of the Lisa Schwartz Foundation for Truth in Medicine, and former director of the Division of Cancer Prevention at the U.S. National Cancer Institute.
“We will dip more and more deeply into the iceberg of disease,” Dr. Kramer said, finding “lesions that look like a cancer to the pathologist but may not have the same natural history at all.” It may not even be possible to find the most aggressive cancers early enough for a cure, Dr. Kramer added. The tumors that shed the most DNA and proteins into the blood are the largest tumors.”

The article concludes with the opinion of the aforementioned statistician Dr. Berry:
“Dr. Berry, though, is not assuaged and fears that the public’s faith in early detection which, he says, “is like a religion,” will rule the day, even without good evidence.“Everybody loves early detection, but it comes with harms,” Dr. Berry said. “The harms, we know,” he added. “The benefits are very uncertain.”

“But a definitive study to determine whether the tests prevent cancer deaths would have to involve more than a million healthy adults randomly assigned to have an annual blood test for cancer or not” explains the article. “Results would take a decade or longer”.

Will the public, the media, the companies marketing the tests have the patience to wait?


[1] Non reduction of metastatic cancers since screening for breast and prostate cancer, studies:

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Autier P, Boniol M, Middleton R, Dore JF, Hery C, Zheng T, et al. Advanced breast cancer incidence following population- based mammographic screening. Ann Oncol 2011;22(8): 1726e35.

Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012; 367(21):1998e2005.

De Glas NA, de Craen AJ, Bastiaannet E, Op ’t Land EG, Kiderlen M, van de Water W, et al. Effect of implementation of the mass breast cancer screening programme in older women in The Netherlands: population based study. Bmj 2014;349:g5410.

Autier P, Boniol M. The incidence of advanced breast cancer in the West Midlands, United Kingdom. Eur J Cancer Prev 2012; 21(3):217e21.

Nederend J, Duijm LE, Voogd AC, Groenewoud JH, Jansen FH, Louwman MW. Trends in incidence and detection of advanced breast cancer at biennial screening mammography in The Netherlands: a population based study. Breast Cancer Res 2012;14(1):R10.

Lousdal ML, Kristiansen IS, Moller B, Stovring H. Trends in breast cancer stage distribution before, during and after intro- duction of a screening programme in Norway. Eur J Public Health 2014;24(6):1017e22.

Johnson RH, Chien FL, Bleyer A. Incidence of breast cancer with distant Involvement among women in the United States, 1976 to 2009. JAm Med Assoc 2013;309(8):800e5.

Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. Jama 2009;302(15):1685e92. [53] Jorgensen K, Gøtzsche PC, Kalager M, Zahl P. Breast cancer screening in Denmark: a cohort study of tumor size and over-diagnosis. Ann Intern Med 2017 Mar 7;166(5):313e23.

Welch HG, Gorski DH, Albertsen PC. Trends in metastatic breast and prostate cancer dlessons in cancer dynamics. N. Engl JMed 2015;373(18):1685e7.

Di Meglio A, Freedman RA, Lin NU, Barry WT, Metzger-Filho O, Keating NL, et al. Time trends in incidence rates and survival of newly diagnosed stage IV breast cancer by tumor histology: a population-based analysis. Breast Cancer Res Treat 2016;157(3):587e96.

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