July 5, 2022 | In recent months, Diagnostics World has explored the realm of pan-cancer testing, providing a big picture overview and looking at some of the different technology approaches that are being pursued. As research and development continue in efforts to build upon the progress made so far, there’s still plenty to be sorted out. Here we dig a bit deeper into some of the biggest lingering issues facing the future of this fledgling field, including economic considerations, thoughts on regulatory and payor support, and questions surrounding equitable access.
Big Unknowns and Great Debates
One of the central ideas behind pan-cancer tests, also known as multi-cancer early detection (MCED) tests, is the notion that the earlier we can detect, the better we can treat. But some have cautioned that earlier doesn’t always equate to better and that screening could cause more harm than good in some scenarios.
One example is the potential for overdiagnosis, or the identification of early-stage cancers that would not have impacted someone during their lifetime. Some say MCED tests may not be capable of distinguishing between the type of slow-growth cancers that never become harmful from those that do cause sickness.
“It’s still not clear whether we’re really detecting the bad acting cancers—those that are going to be more lethal,” said Christina Curtis, an associate professor of medicine and genetics at Stanford University. There are “great debates in the field around the challenges of overdiagnosis, wherein some tumors may remain indolent and may not really pose a major health burden.”
MCED tests also introduce the possibility of catching cancer in its earliest stages without providing enough information to enable actionable next steps. Imagine the possibility of discovering you have early markers of cancer without also learning what type of cancer or where it is located.
Another intriguing issue relates to the availability—or lack thereof—of treatments. What if we are capable of detecting more cancers sooner but do not have an effective therapeutic intervention for some of them?
Earlier detection might generally lead to more treatment options, and for some cancers, that involves surgery. But according to Curtis, who has served as a scientific advisor at GRAIL and Ravel Biotechnology, there are other therapies we need to be pushing to make it possible to eradicate cancer when found early on.
False Alarms and Other Potential Harms
In addition to these types of dilemmas related to MCED tests flagging cancers early on, stakeholders face the challenge of considering how to best address their inevitable shortcomings as they fail to find cancers that are present or set off the occasional false alarm.
False-negative test results could mean treatment delays and a false sense of security, leading to skipped standard-of-care screening for some people. And false positives could lead to needless anxiety and unnecessary medical procedures or treatments, along with any related risks and financial expenditures.
As multi-cancer tests roll out, experts say guidelines are needed to help doctors and patients determine a reasonable course of action and navigate any next steps when reacting to positive test results. What sort of diagnostic workup is needed—and feasible—following a positive result? And what should be done if additional testing does not confirm the presence of cancer?
One of the goals is to avoid lengthy, frustrating diagnostic odysseys that can stress patients out and rack up expenses along the way.
“There is a trade-off in terms of unnecessary confirmatory testing both to the individual—considering some of those tests will have risks associated with them—and also to the healthcare system,” Curtis explained. “Because of this, there needs to be careful thought given to how confirmatory testing is conducted in the event of a positive multi-cancer test result.”
Questions have also been raised regarding how often a person should repeat the test if it is positive over a certain interval. There’s a lot of thought that needs to be given to these types of issues, Curtis said, because this is new territory—it’s never been done before. Over the coming years, it will be interesting to work through the logistics with an eye to optimizing the harm/benefit trade-offs involved.
Regulatory Approval and Payor Support
Although some companies already offer their tests to physicians and consumers, none has been approved by the U.S. Food and Drug Administration (FDA) to date. For now, it isn’t clear just how effective MCED tests will need to become to secure regulatory approval or buy-in from payors.
According to Ron Andrews, president and CEO at precision diagnostics and monitoring company Oncocyte, the bottom line is that the better the predictive value of a test, the better the chances of approval and reimbursement.
But if the bar is set too high, he cautioned, there will be fewer interested investors and these powerful applications will not make it to market. On the other hand, some have emphasized the importance of setting lofty expectations.
Luca Quagliata, vice president and global head of medical affairs for clinical sequencing and oncology at Thermo Fisher Scientific, hopes this would involve specificity well over 95% and the highest possible true positive rate.
“Anything too far from that will generate more problems than benefits from a patient care perspective,” he said.
Although it is possible lower levels might be viewed as acceptable for approval by regulatory bodies considering no other solution exists to tackle this problem, Quagliata indicated that payors would be less likely to back tests with lower specificity.
Are Lives Saved? (And at What Cost?)
Proponents tend to view MCED testing as an innovative tool that could revolutionize cancer care as we know it. Skeptics, meanwhile, say the upsides have been overstated and the dangers largely overlooked. Sure, the tests are bound to find some deadly cancers sooner, but if rolled out to the general population, would they save lives?
“Ironically, screening will look like it helps—even when it doesn’t,” H. Gilbert Welch of the Center for Surgery and Public Health at Brigham and Women’s Hospital pointed out in a STAT op-ed. Oft-touted statistics like five-year survival rates rise with screening even if age of death remains unchanged because it is measured using time of diagnosis.
One of his concerns is that multi-cancer testing could lead to people living for a longer duration of time with the awareness that they have an incurable disease—without actually extending their lives. He also takes issue with the expense involved. Test makers have a financial incentive to push for widespread testing, but screening the masses could come with an enormous price tag.
To help illustrate, Welch pointed out that GRAIL’s Galleri costs nearly $1,000 per test and is recommended annually for those at a heightened risk for cancer, like adults ages 50 and up. With roughly 100 million Americans in this group, the yearly cost would amount to about $100 billion, surpassing the Centers for Disease Control and Prevention (CDC) budget many times over. And that doesn’t even factor in the expense of all additional testing and treatment.
Along with Barnett Kramer, a former director of the National Cancer Institute’s Division of Cancer Prevention, Welch has also explained why Congress will need to weigh some crucial questions in light of a bipartisan bill that could pave a pathway for Medicare coverage.
Where is the Biggest Bang for the Buck?
From an economic standpoint, “what you don’t want is millions of healthcare dollars being poured into needle-in-haystack searches,” said Michael J. Hall, professor of medicine and chair of the Department of Clinical Genetics at Fox Chase Cancer Center. Because this type of testing is expensive, there is a need to consider which populations may be best suited for them.
Deploying MCED testing approaches in high-risk populations, like those with a family history of cancer, makes the most sense to some.
Others have proposed the possibility of introducing this form of testing in conjunction with a woman’s age 50 mammogram. They are already in the doctor’s office, they are already getting screened for cancer, and there is an opportunity to screen for other cancers at this same point in time.
“Maybe that’s a good way, but you have to think about how many millions of women are getting a mammogram every year. That’s going to be a lot of tests, and there’s going to be a lot of expense that piles up,” Hall said. Moving forward, there is still a need to figure out where the bang will be greatest for the buck.
Economic analyses are beginning to emerge. Among those highlighted in a 2021 paper (DOI: 10.37765/ajmc.2021.88801) are a modeling study that explores drivers of the range of value-based price for an MCED test and a health economic model that examines the outcomes of adding an MCED test to current screening.
“Naturally, all of these economic analyses are preliminary and built on a set of assumptions that will need to be further confirmed within clinical trials and real-world evidence-gathering efforts,” Oregon Health & Science University’s Tomasz Beer pointed out in the paper.
Still another example can be found in a paper published earlier this year (DOI: 10.1002/cncr.33980) that details three hypothetical MCED-detectible cancers and calls for additional efforts to build, validate, and apply decision modeling approaches to further examine the potential impact.
“The time is ripe for additional, prospective investigations of the clinical value of MCED testing, the benefits versus the risks for screened populations, and the overall projected impact on health outcomes and costs over time,” the researchers noted.
Equitable Access Considerations
Meanwhile, equitable access has surfaced as another pressing issue within the larger discussion of target populations and overall cost considerations.
Oftentimes those who are better educated, better insured, and have a higher socioeconomic status tend to benefit from new technologies that are just being rolled out, Hall explained. But it could be argued that a pan-cancer screen might make more sense for those less likely to get in for regular exams and screenings.
“We have to always think about how to do our best to make sure that if we’re rolling something out that there is some degree of equitable access to people who want to engage in that technology,” he said.
A group of researchers spoke to this same issue from an international perspective in a paper published earlier this year (DOI: 10.1002/cncr.33927). They remind that it isn’t early detection alone that saves lives but early and effective treatment. With this in mind, they wonder if an MCED test can be appropriately introduced into settings with limited access to cancer treatments, including surgery.
If the answer is no, they wrote, then how do we dodge the ethical conundrum of developing a universal cancer screening test that is only available to wealthier nations or well-to-do patients?
While the implementation of MCED testing would inevitably look different in different countries and parts of the world, they argued for the need to come up with a business model for its introduction into low- and middle-income countries in addition to the high-income countries that industry will likely target initially.
Some continue to see the hope and possibility through the fog of questions, concerns, and challenges swirling around this field and its uncertain future.
The possibility of detecting multiple cancers from a single blood draw, including some that do not currently have screening modality, “has a huge amount of appeal,” Curtis said, and it is “potentially transformative.”
She balances her optimism with a dose of caution, though, emphasizing that the field is still emerging and evolving. Although technologies have come a long way, she pointed out that there is still plenty to be learned about how early we can detect, how well we can detect, and how this type of testing might be deployed in real-world settings.
Ultimately, the impact of these tests will depend upon not only their performance characteristics but also factors like disease characteristics, the ability to deploy, and the efficacy of early treatment, Curtis explained.
Testing is a critical piece of that overall puzzle, but it is also very much a work in progress. “I don’t think the assays are all where they ultimately will land,” she added. “It’s very much a continued process, so it’s still early days.”
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.