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

Tests that screen seemingly healthy people for many kinds of cancer by analyzing a blood sample are starting to enter the clinic—worrying some physicians and scientists that they could do more harm than good. Now, as part of President Joe Biden’s reignited Cancer Moonshot, the National Cancer Institute (NCI) is laying plans to evaluate the promise of such tests.

Last week, NCI advisers endorsed a $75 million, 4-year pilot study enrolling at least 24,000 people to assess the tests, which mostly pick up 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 as many as 300,000 volunteers ages 45 to 70, to learn whether they save lives.

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

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

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

ScienceInsider discussed NCI’s ambitious plans with Castle recently; this interview had been edited for clarity and brevity.

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

A: We need to understand issues like handling of the blood and getting the blood to the company and getting the results back. We have to know whether we can even randomize people to a control arm, which is just standard of care. It may be a deal breaker for people [to receive only standard cancer screening], even though we don’t know whether these tests actually benefit anybody.

Q: How will you pare down the more than 20 tests companies are developing?

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

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

A: It’s not clear that those two want to be picked. There may be a disincentive for GRAIL now to participate given that they’ve gone directly to consumers. [The company offers its test in a way that does not require U.S. regulatory approval.] Exact, I think, is considering its own trial. We could balance the marketplace by evaluating some of the second-generation technologies coming along.

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

A: It’s going to be probably around 75,000 people per study arm. So if it’s three tests and a standard of care arm, that would bring you to 300,000. We’re thinking [the trial would run for] around 7 to 8 years. You can get a sense of the costs given the size. There’s never been a cancer screening study that big that I’m aware of in the United States.

Q: The estimate from past 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 positives [in past studies], in one-third, nothing is found. And in one-third there’s no cancer, there’s some other benign condition that caused [the false alarm]. And one-third of the people have cancer.

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

A: The harms are manyfold. The test could reduce advanced-stage cancer but not reduce mortality. It could find indolent disease [slow-growing tumors] like PSA does that you don’t want to treat. We’re worried about compliance with the diagnostic workup [that is, whether a person who has a positive liquid biopsy will keep medical appointments to confirm or rule out cancer]. Obviously, there’s going to be [continuing] anxiety in a person who got positive test even if you’ve ruled out cancer. What’s their future risk? Remember that all those diagnostic steps are imperfect as well.

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

Q: Given the doubts, why proceed?

A: The exciting thing is, we don’t have screening tests for the lethal cancers like pancreas and ovarian. We’re desperate. But we have to put our emotions aside and do our due diligence to evaluate these technologies and be able to speak with confidence about what this can and can’t do.

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