‘The complexities are staggering.’ U.S. plans huge trial of blood tests for multiple cancers | Science

Tests that detect many types of cancer in apparently healthy people by analyzing a blood sample are beginning to enter the clinic, worrying some doctors and scientists that they could do more harm than good. Now, as part of President Joe Biden’s relaunched Cancer Moonshot, the National Cancer Institute (NCI) is making plans to assess the promise of such tests.

Last week, NCI advisers backed a $75 million, 4-year pilot study that enrolled at least 24,000 people to evaluate the tests, which mostly detect trace amounts of DNA and proteins that tumors shed into the blood. What it shows about the feasibility of these tests, sometimes called liquid biopsies, will help NCI decide whether to launch a longer-term clinical trial, in up to 300,000 volunteers ages 45 to 70, to see if they save lives.

Companies such as GRAIL and Exact Sciences report that their tests can detect many tumors at an early stage, when they are easier to treat. GRAIL is already offering its $949 test, which requires a prescription, to people age 50 and older and others at elevated risk of cancer. It has also launched a trial of 140,000 people in the UK. But the tests can miss cancers and produce false positives, leading to unnecessary procedures.

As a first step toward the pilot study, the NCI intends to validate the companies’ claims using blood samples from people already known to have cancer, along with others thought to be cancer-free. Some tests will then become part of the pilot clinical study starting in 2023 or 2024. Some participants will have one of the multi-cancer blood tests along with standard cancer screening tests, such as mammograms, while a control group you will only receive routine tests. One concern is that because early detection of cancer with a blood test is such an attractive idea, it might be difficult to find people willing to be part of the control group. Only if the pilot study is a success will the NCI commit to the larger follow-up study to test whether earlier diagnoses actually reduce mortality.

“The complexities are quite staggering,” Philip Castle, director of the NCI’s Division of Cancer Prevention, told an agency advisory council last week. The advisors acknowledged the challenges but agreed on the importance of the effort. “I applaud the NCI. I think this is critical and they have to do it,” said Sylvia Plevritis, a biomedical data scientist at Stanford University.

SciencesInsider discussed the NCI’s ambitious plans with Castle recently; This interview has been edited for clarity and brevity.

Q: What does NCI hope to learn from the pilot study?

A: We need to understand things like blood handling and bringing blood into the business and getting the results back. We have to know if we can randomly assign people to a control arm, which is just the standard of care. It can be a deal breaker for people. [to receive only standard cancer screening]although we do not know if these tests really benefit anyone.

Q: How will you narrow down the 20+ tests that companies are developing?

A: They must have published, peer-reviewed data and demonstrate that they can replicate the results. They must be able to lock the test parameters, the algorithm [that judges whether blood biomarkers indicate cancer]. And they also have to have the ability to do enough testing. So we can really stick with two or three that will be ready for a clinical trial.

Q: Are there any obvious ones to include, like the GRAIL and Exact Science tests?

A: It is not clear that these two want to be chosen. There may be a disincentive for GRAIL to participate now since they have gone directly to consumers. [The company offers its test in a way that does not require U.S. regulatory approval.] I think Exact is considering his own trial. We could balance the market by evaluating some of the second generation technologies that are coming.

Q: What would the largest long-term clinical trial look like?

A: It will probably be around 75,000 people per study arm. So if it’s three tests and one standard care arm, that would bring it to 300,000. We were thinking [the trial would run for] around 7 to 8 years. You can get an idea of ​​the costs given the size. There has never been a cancer screening study this large that I know of in the United States.

Q: The estimate from previous studies is that 1% of participants will have a positive test indicating they have cancer, and then some subset will actually have cancer.

A: among the positive [in past studies], in a third, nothing is found. And in a third there is no cancer, there is some other benign condition that caused [the false alarm]. And a third of people have cancer.

Q: At the NCI meeting, advisors were concerned that the tests might not turn into another PSA. (The prostate-specific antigen test has become controversial because it often detects small prostate tumors that may ultimately be harmless.)

A: The damage is multiple. The test could reduce advanced-stage cancer but not reduce mortality. I could find indolent disease [slow-growing tumors] like the PSA does that you don’t want to treat. We are concerned about compliance with the diagnostic study. [that is, whether a person who has a positive liquid biopsy will keep medical appointments to confirm or rule out cancer]. Obviously there will be [continuing] anxiety in a person who has tested positive even if cancer has been ruled out. What is your future risk? Remember that all those diagnostic steps are also imperfect.

And conversely, when you get a negative test, are people not going to do their standard screening because they got this fancy cancer test that said, “I’m negative”? That could offset the benefits of these tests.

Q: Given the doubts, why proceed?

A: What’s exciting is that we don’t have screening tests for deadly cancers like pancreas and ovary. We are desperate. But we have to put our emotions aside and do our due diligence to evaluate these technologies so we can speak confidently about what this can and can’t do.

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