NIH initiative to ‘rigorously evaluate’ benefits, harms of evolving cancer screening technologies

The prospect of screening for multiple cancer types simultaneously through a blood draw or other simple methods has generated tremendous excitement.

Multicancer detection tests — often called liquid biopsies — measure circulating tumor cells, tumor DNA or other substances in the blood, urine or other body fluids that can identify the presence of cancer.

The global market for these products — which also include breath tests and other AI- or machine learning-based platforms — is expected to reach $2.72 billion by 2030, according to 360iResearch, an India-based market research and business consulting company.

Multicancer detection tests may be offered under federal regulations known as Clinical Laboratory Improvement Amendments, which ensure quality of laboratory testing.

However, despite the potential of — and rapidly escalating financial investment in — these approaches, no multicancer detection test has received FDA approval. Further, no large-scale clinical trials have demonstrated use of these tests reduce cancer deaths, and no professional societies nor the U.S. Preventive Services Task Force have issued recommendations related to their use for cancer screening.

The NIH has launched a clinical trials network to further evaluate multicancer detection tests and other emerging screening technologies. The Cancer Screening Research Network (CSRN) — which includes eight funded sites so far — will conduct trials of large, diverse populations to better understand the potential clinical utility of or risks associated with these approaches and provide insights into if — and how — they can be incorporated into standard care.

“We’re at a pivotal time [in which] a lot of technologies are being developed for cancer screening. Relatively few are currently available, but a lot are coming,” Lori Minasian, MD, FACP, deputy director in NCI’s division of cancer prevention, told Healio. “We need to have a systematic way to rigorously evaluate them for screening, because screening is different than early detection. Population-based screening requires that we establish true benefits that outweigh the harms.”

Research framework

The CSRN aligns with core goals of the Cancer Moonshot by investigating strategies to identify cancer at an earlier stage, when they may be easier to treat.

Fred Hutch Cancer Center — the network’s coordinating and communications center — will be the hub for statistics and data management.

Other NCI-funded sites that will enroll participants include:

• Henry Ford Health + Michigan State University Health Sciences;
• Kaiser Permanente Northern California, Kaiser Permanente Southern California and Kaiser Permanente School of Medicine;
• OU Health Stephenson Cancer Center at University of Oklahoma Health Sciences;
• University of Colorado Cancer Center;
• UNC Lineberger Comprehensive Cancer Center at The University of North Carolina at Chapel Hill;
• Virginia Commonwealth University, Inova, and Sentara Health; and
• Washington University School of Medicine in St. Louis.

The Department of Veterans Affairs and Department of Defense Uniformed Services University also will participate, with funding from their respective agencies.

The initial research will be conducted through the Vanguard study, scheduled to launch this year.

This pilot study — expected to enroll up to 24,000 participants — will evaluate the feasibility of using multicancer detection tests in future randomized controlled trials.

Results will guide the design of a larger randomized controlled trial designed to assess the benefits and potential harms of these tests.

The CSRN will begin by evaluating multicancer detection tests. Future research will evaluate other emerging technologies for cancer screening.

“We are anticipating that, in the future, there may be screening tests that involve different types of or approaches to imaging than we’ve used in the past,” Christine Neslund-Dudas, PhD, associate scientist in epidemiology at Henry Ford Health, told Healio. “We may also be testing other biospecimens or emerging technologies that we can use to test for cancer.”

The research effort has been designed to be adaptable and facilitate the study of cancer screening approaches as they evolve, Minasian said.

“The network was started intentionally to be agnostic of the technology so that, over time, we can evaluate a variety of different technologies,” Minasian said. “We know that cancer is not one disease. We know there are multiple different pathways and that no one assay is going to detect everything.”

‘A measured approach’

In population-based screening, it is essential that the risks of a test do not exceed the potential benefits, Minasian said.

This determination typically is made through evaluating a test’s impact on cancer mortality.

“We get mammograms on a regular basis because we know from multiple randomized controlled trials that annual mammograms after age 50 do, in fact, reduce breast cancer mortality,” Minasian said. “The same goes for low-dose CT scans for lung cancer. We don’t screen the general population for ovarian cancer, because the largest trial looking at screening modalities showed there was no benefit.

“When we’re looking to screen healthy people for cancer, we want to make sure that it is effective and that the benefits to the population as a whole outweigh the harms,” she added. “We decided that we needed a network to evaluate this.”

Weighing the risks vs. benefits of tests that screen for several cancer types will pose a formidable challenge, according to S. Patrick Nana-Sinkam, MD, pulmonologist and physician-scientist at VCU Massey Comprehensive Cancer Center and co-principal investigator on the institution’s CSRN initiative.

“Right now, we don’t even know for every single type of cancer whether detecting it early actually impacts mortality,” Nana-Sinkam told Healio. “We certainly know that this is the case with breast cancer and lung cancer, but there are other cancers for which have not shown whether early detection affects mortality.”

Downstream testing that may result from a positive screening may not necessarily be benign, added Alex Krist, MD, MPH, a specialist in family medicine and population health at VCU Massey Comprehensive Cancer Center and co-principal investigator on the institution’s CSRN initiative.

“Not only does early detection not necessarily change mortality, it can cause harms,” Krist said. “When we have positive results, there are follow up tests and procedures — perhaps CT scans or biopsies that may cause harms in themselves. If it doesn’t impact mortality and causes harms, that could be a net negative.”

Questions such as these support why the CSRN is starting its research with the Vanguard study, Minasian said.

“We’ve run large cancer screening trials with technology looking at a single cancer that we understand, where we know its natural history, even if it has multiple subtypes, like lung cancer,” she said. “However, we’re now looking at tests that screen for a basket of different cancer types that don’t behave the same way. With the Vanguard study, we’re basically saying, ‘OK, in the best possible world, this is how we would design this study. Are these assumptions going to be accurate assumptions? You want to do that in a pilot before you put huge amounts of money into a much larger study.”

The fact that the CSRN is being overseen by a government agency — independent of industry interests — should provide reassurance and confidence to investigators at trial sites, according to Jeffrey K. Lee, MD, MPH, research scientist at Kaiser Permanente Northern California Division of Research.

“We need to be able to evaluate emerging screening tests in a rigorous fashion that is not sponsored by or influenced by companies,” Lee told Healio. “It’s very important to have scientists who are able to contribute and design the study the way it should be, and to properly execute it.”

The appeal of multicancer detection tests hold for the general public makes it even more essential that research into their potential utility and value be free of commercial interests and company influence, Lee said.

“We’ve already witnessed certain blood diagnostic tests that have been hyped up, even by the darlings of Silicon Valley,” Lee said.

He cited Theranos Inc., a consumer health care startup that “overpromised” its potential to revolutionize blood tests. When the technology failed, customers received incorrect diagnoses, investors lost nearly $1 billion combined and the company founder — convicted of fraud and conspiracy — went to prison.

“As scientists, we’re always excited about new technologies, but we have to have a measured approach,” Lee said. “We have to temper our enthusiasm enough to ask whether a new technology can benefit our patients.”

Research timeline

CSRN investigators and the coordinating centers have begun to develop working groups to design a protocol for the Vanguard study.

Meanwhile, NCI has been working systematically to actively engage companies that manufacture multicancer detection assays.

“In May 2023, we had an open workshop for any company ... in the technology,” Minasian said. “One of our network groups, the Alliance for Oncology Clinical Trials, developed a reference collection of a little more than 2,000 participants, with a thousand who had cancer and a thousand who didn’t.”

These blood collections are being sent to multicancer detection assay companies, which will send back results. This will allow CSRN investigators to identify the lead contenders for the Vanguard study.

“We’re still in the process of doing this,” Minasian said. “The [multicancer detection] assays have not yet been chosen for the pilot study.”

The Vanguard study is expected to take 4 years, according to Neslund-Dudas.

The larger randomized controlled trial likely will have a 10-year to 12-year timeline.

“The Vanguard study will enroll about 2,000 patients at each site. They want to have a total of about 24,000 patients in the pilot study,” Neslund-Dudas said. “The pilot study will basically work out some of the kinks, figure out the best ways to follow patients and [identify] the best way to communicate results to patients, before they roll it out to a larger group.”

Focus on diversity

One major priority of the CSRN is to study emerging technologies in populations that are representative of real-world scenarios.

For this reason, the selection process for research sites took diversity of study populations into account.

“We need to make sure that our results are as generalizable as possible to the people who live in our country,” Minasian said. “The ways in which the individual sites are achieving this is unique to the different locations. In one site, the hiring staff is going out to rural clinics and will consent participants in rural areas and associated clinics that have agreed to participate. In other settings, they’ll do it slightly differently.”

The VA and Department of Defense will enable access to military populations, and both agencies are “very excited” to participate, Minasian said.

The network’s access hubs are geographically distributed to capture the most diverse study population possible.

“In biomedical research, we often end up having research evidence that reflects a less diverse population than we might want. For example, if you look at the population of the landmark National Lung Screening Trial, the population was largely white,” Daniel S. Reuland, MD, MPH, professor of medicine at UNC Lineberger Comprehensive Cancer Center, told Healio. “We want this evidence to reflect America and the diversity of our communities.”

A lack of diverse representation can result in recommendations that do not necessarily reflect the wider population, Neslund-Dudas said.

“The eventual guidelines for lung cancer [screening] weren’t as tailored to some races and ethnicities as they were to others,” she said. “They fit risk for white individuals better than they fit the risk for Black individuals.”

Henry Ford plans to recruit members of the Black community, as well as individuals from surrounding Hispanic and Arab populations.

“We will be reaching out to all of these communities to make sure that the patients we enroll reflect the community we serve,” Neslund-Dudas said.

UNC Lineberger also will aim to include patients from across North Carolina.

“We have ongoing partnerships with regions of eastern North Carolina, for example, which has a historically poor, largely African American population,” Reuland said. “We have a very trusting partnership with a large community health center [in that area], and those communities deserve to be represented in this research.”

Virginia Commonwealth University encompasses three institutions. That will enable their research site to reach a large swath of the population, Krist said.

“We care for one in five Virginians,” he said. “We are committed to ensuring that we are including people in communities that have historically not been included in trials.”

‘Logical next step’

Although the CSRN is in its early stages, the participating investigators are excited about the opportunities it creates for rigorously studying emerging technologies.

“Our hope is that this is the start of an ongoing process of answering these difficult questions about screening for — and ultimately preventing — cancer,” Krist said. “There are many evidence gaps and lots of questions that need to be addressed to try to improve the health of the communities we serve. This is a very big, audacious project.”

Neslund-Dudas said she hopes the work of the CSRN will advance the science of cancer screening and improve various aspects of patient care in the oncology space.

“We hope it reduces the number of cancer deaths, and we also hope it could even reduce the cost of cancer screening,” she said. “It would be wonderful if we could have a blood test that could screen for cancer, rather than requiring the patient to drive to a specific facility that has a particular type of CT scanner or another specific device. This could potentially improve access.”

This research represents an essential early step for developing tests that ideally will inform clinical decision-making, Nana-Sinkam said.

“One of the most important stages of evaluating these tests is clinical utility. Can it work in the community? Will patients and physicians be receptive to it?” he said. “This represents the logical next step in developing a test with the hope that, eventually, it becomes common practice.”

This research comes at a crucial time, Reuland said, noting the inherent appeal of early cancer detection could drive premature uptake among the public before these technologies are fully understood and investigated.

Ultimately, Reuland said he is hopeful these innovations will reach their full potential.

“In the long run, I’m optimistic that cancer screening is undergoing some important revolutions,” he said. “If you think about what we’re doing now, it’s relatively crude. Couldn’t we find easier, better ways in the long run? I think we can — and we should.”

References:

• 360iResearch. Multicancer screening market projected to reach $2.72 billion by 2030 — exclusive report by 360iResearch (press release). Available at: https://www.marketwatch.com/press-release/multicancer-screening-market-projected-to-reach-2-72-billion-by-2030-exclusive-report-by-360iresearch-7e011375#. Published April 15, 2024. Accessed May 15, 2024.
• NCI. NIH launches research network to evaluate emerging cancer screening technologies (press release). Available at: https://www.cancer.gov/news-events/press-releases/2024/cancer-screening-research-network-launches. Posted Feb. 21, 2024. Accessed May 15, 2024.
• NIH. Multi-cancer detection (MCD) research. Available at: https://prevention.cancer.gov/major-programs/multi-cancer-detection-mcd-research. Accessed May 15, 2024.

For more information:

Alex Krist, MD, MPH, can be reached at alexander.krist@vcuhealth.org.

Jeffrey K. Lee, MD, MPH, can be reached at jeffrey.k.lee@kp.org.

Lori Minasian, MD, FACP, can be reached at lori.minasian@nih.gov.

S. Patrick Nana-Sinkam, MD, can be reached at patrick.nana-sinkam@vcuhealth.org.

Christine Neslund-Dudas, PhD, can be reached at mediarelations@hfhs.org.

Daniel S. Reuland, MD, MPH, can be reached at daniel_reuland@med.unc.edu.