New technologies are making it possible to detect cancer earlier than ever — but the field is still fiercely divided on whether these liquid biopsy tests are yet ready for prime time.
Those tensions are tangible among experts who continue to spar over the question of whether the cancer screening technology is actually beneficial. Among the most contentious points of debate: Do studies of liquid biopsies need to prove they can reduce mortality rates?
“You can’t make an asymptomatic person feel better,” said Rita Redberg, cardiologist and medicine professor at the University of California, San Francisco. “So then you should show that your test is going to help them to live longer.”
To Peter Bach, chief medical officer at early cancer detection company Delfi Diagnostics, that kind of research is essential — and it’s also possible, despite some pushback in the field on whether it’s a feasible outcome to study. In a discussion Wednesday at the STAT Breakthrough Summit, he ticked off a string of studies on cancer treatments that have examined mortality: a randomized trial of sigmoidoscopy, two ovarian cancer trials, three randomized trials of lung cancer screening.
“What am I forgetting?” he said at a panel on liquid biopsy at the STAT Breakthrough Summit in San Francisco on Wednesday. “We’ve had numerous randomized trials with cancer specific mortality as the outcome in screening.”
Bach used those studies to take aim at some of the research on liquid biopsy, including some studies run by the Grail, which developed the Galleri early cancer screening test. Tina Clarke, the company’s vice president of epidemiology, vigorously defended the company’s research, which includes an ongoing trial of Galleri with 140,000 people through the U.K.’s National Health System that is using “reduction in stage IV cancer” as a primary endpoint, with several secondary objectives, including mortality.
Bach criticized that study for using cancer stage shift as the primary outcome, because it “has been shown to not be a predictor of mortality benefit in lung cancer and in ovarian cancer and probably others.”
The debate reinvigorated long-running arguments about whether the benefits of liquid biopsy — screening for bits of DNA in the blood that indicate the presence of a cancer, often earlier than the cancer would otherwise be detected — have enough evidence behind them, and what data is sufficient to prove benefit.
Gautam Kollu, the former chief commercial officer at Grail, said that when Galleri was first launched, an insurance company executive told him “the correct amount of evidence that we need for your test will always be a little bit more than the evidence you have,” he said. Kollu is now the CEO of D2G Oncology.
Another key question is whether earlier detection will lead to over-diagnosis. Redberg said an issue is that such screening could catch what she called the “tortoises” — cancers so slow-growing that the person will die from another cause before the cancer becomes a problem — and the “birds,” cancers that would normally disappear before conventional detection methods found them.
“I mean, to have a test out there, if I was running a company and eager to make a profit, I would be in a big rush. But if I’m a patient or I’m going to be the one paying for the test, I first want to know that I’m better off having the test,” she said. “So we really need to know, is this a test where we are better off with that information than without it? And the only way to get that is a randomized trial with all-cause mortality.”
She praised the rigor behind a recent randomized colonoscopy trial which showed that getting an invitation for a colonoscopy reduced incidence of colon cancer but not death.
Kollu, however, called the trial a “flop.”
“As these trials read out, the idea that we can only rely on a RCT is worshiping a false god,” he said. “That’s not going to work for genomics. And we need to look at the preponderance of evidence which now is showing that these tests can be used in routine clinical care without inflicting a lot of harm,” he said.
The friction in the field comes down, in part, to the question of whether early cancer screenings have benefit that can be measured faster than waiting for mortality.
“Whereas previously, orthodoxy has said that [clinical trials have] got to read out at a cancer specific mortality endpoint or an all-cause mortality endpoint, we’re really trying to understand from previous screening trials and from other evidence bases, ‘what is a set of milestones that one sees before you can achieve a reduction in mortality,’ and can we leverage those to get to answers sooner and not have to wait decades for lifesaving technologies, for diseases like cancer?” Clarke said.
Based on the 10,000 cancer cases in Grail’s control study, “we do not get the sense that these signals are going to be associated with over-diagnosis or over-treatment,” she said. “If it was me and if I found out I had a cancer that was shedding the signal, I would want to get surgery to get this cancer out of my body as quickly as possible. I would not have concerns about it being nothing to worry about or over-diagnosed on the basis of that data.”
Correction: An earlier version of this story misstated the company for which Gautam Kollu works.