Patients and their doctors are counting on cancer screening to save lives, yet several large, controlled studies are showing disappointing results for mammography and other mass screening tests. This month, the New England Journal of Medicine published a controversial study that calls into question the widely accepted benefits of colonoscopy.
The take-home lesson from these disappointing trials is not that we should abandon early detection. It is still the best hope we have of reducing the high number of deaths and suffering caused by cancer, which claims about half a million lives a year in the US alone.
The correct lesson is that saving lives by detecting cancer in healthy people is more difficult than it seems. And years from now, healthy people will be faced with newer, more technologically sophisticated blood tests that promise to detect more cancers before it’s too late to cure them. While these are much easier than current colonoscopies or other screening methods, they will likely be introduced as an adjunct, rather than a replacement.
We need new tools, because our current cancer screening tests are limited. Intuitively, it seems that any test that can detect hidden tumors would save lives and do little harm beyond some inconvenience and discomfort. But overdiagnosis is an insidious side effect of mammography and thyroid cancer screening because these tests can detect tumors that grow so slowly that they pose no threat. However, people who discover these tumors may experience stress, additional tests, and sometimes even unnecessary chemotherapy and surgery. And yet, typical screening procedures may still be inadequate in detecting the most aggressive tumors early enough to treat them. The good news about the recent colonoscopy study was that overdiagnosis was not a risk. People in the unscreened control group were more likely to be diagnosed with colon cancer, which can lead to chemotherapy or loss of part of the colon. But doctors were disappointed that death rates were similar for the control group and those invited for colonoscopy. (However, the fact that this test prevents cancer is a good reason for people to continue having it; colonoscopy is not just a test, but an opportunity for doctors to remove precancerous polyps.)
The new blood tests, which are now in clinical trials and could soon be available for general use, aim to address the problem of overdiagnosis and the problem of early detection.
These blood tests are sometimes known as liquid biopsies. Although actual biopsies are often performed on known tumors, these tests would be performed on both suspected cases and perfectly healthy people. They work on the principle that when people get cancer, some abnormal DNA will be circulating in the blood.
One is being developed by Exact Sciences Corp. with the help of Bert Vogelstein, a researcher at Johns Hopkins University who is a longtime leader in cancer research. As Vogelstein explained to me, this test can screen blood samples for different types of abnormal DNA, as well as so-called epigenetic changes, alterations in the molecular packaging that surrounds DNA that can suppress or activate different genes.
These epigenetic changes are the objective of another similar test, developed by the GRAIL biotechnology company. “More than 70% of the cancers that kill Americans every year are not detectable by screening tests,” said GRAIL Medical Director and Oncologist Jeff Venstrom. “There is a huge unmet need for me as an oncologist. I want to see patients earlier in the course of their disease when it is curable.”
That’s where liquid biopsies could make a difference. In a 2020 study published in Science, Vogelstein and colleagues showed that by combining a blood test with a CT scan, they could detect early-stage ovarian and uterine cancers, among others. “That doesn’t wrap the whole thing up or show that the benefits outweigh the harms, but it’s fair to say that it’s promising enough to get these blood tests done,” he said.
GRAIL’s Venstrom says his company’s test actually provides information about the location of the cancer so some patients can get early warning without being subjected to the radiation exposure of a CT scan. The GRAIL blood test is currently being studied in a clinical trial of 140,000 people in the UK and is now available on prescription.
“This field is moving so fast that we really hope that these tests will become standard of care in the next couple of years,” he said, and they will be administered annually to everyone over the age of 50.
The technology is a big step forward, but there is much more work to be done to understand who should get these tests, how often, how much skill is required to interpret the results, and when people still need traditional screening tests. Only with large, independent clinical trials, like the ones that have tempered our expectations about mammography and colonoscopy, can we learn to use the old standard and emerging evidence to better help patients.
And the best strategy for patients may not coincide with what is most profitable for testing companies, doctors and medical centers. The GRAIL test is estimated to cost $949. Critics worry that the cost of annual screenings for everyone over 50 far exceeds the money saved by the small fraction of people who are screened a tumor early enough to avoid more intense treatment. Unless the cost comes down, people may end up paying for it in higher insurance premiums. The tests could be heavily marketed to doctors and their patients, but making the benefits worth the cost may be harder than it seems.
So it’s important to keep in mind the inflated expectations we’ve placed on our current cancer screening tests. We now know that the risks and benefits were not fully understood when testing became the standard of care. There is always much more to learn.