From Risk to Readiness: Takeaways From the Second AACR Childhood Cancer Predisposition Workshop

Over the past decade, the understanding of inherited cancer risk in children has shifted dramatically. Previously, experts thought that only 1% or 2% of childhood cancers were linked to inherited predispositions, but we now know that at least 15% to 20% carry a germline mutation in a cancer predisposition gene. This recognition has transformed what was once a relatively rare consideration into a central element of pediatric oncology.

In response to the growing need to understand these predisposition syndromes, the American Association for Cancer Research (AACR) Pediatric Cancer Working Group convened the first Childhood Cancer Predisposition Workshop, “Optimizing Pediatric Surveillance and Care Through Precision Genetics,” in October 2016. That meeting brought together clinicians and researchers from around the world to establish consistent surveillance protocols, often adapting approaches from adult oncology or related syndromes, and to begin building consensus recommendations where little data previously existed.

In 2023, a second AACR Childhood Cancer Predisposition and Surveillance International Workshop aimed to evaluate how those protocols developed in the first workshop were working in practice, explored how they might be improved, and expanded the scope to cover dozens of additional syndromes.

Garrett M. Brodeur, MD, FAACR, the chair of both the 2016 and 2023 workshops, underscored why surveillance is at the heart of this effort: “If someone has a cancer predisposition, it is very helpful to know what cancers they are likely to get, and in what age range they are likely to get them, particularly if you are focusing on pediatric patients.”

According to Brodeur—the Audrey E. Evans Endowed Chair in Pediatric Oncology and a professor of pediatrics at the University of Pennsylvania Perelman School of Medicine; and the director of the Cancer Predisposition Program at the Children’s Hospital of Philadelphia (CHOP)—early detection can make a profound difference. Small tumors caught through surveillance tend to be more manageable surgically, often allowing for organ preservation and excellent prognoses while minimizing the need for chemotherapy and radiation, which is especially relevant for children due to increased risk of developing secondary cancers and other health issues. By contrast, when tumors are detected clinically due to symptoms and have grown large, those advantages are no longer present.

Cancer Research Catalyst spoke with Brodeur to gain deeper insight into the most recent workshop and its influence on childhood cancer surveillance strategies.

What were the goals and scope of the 2023 workshop and how did these differ from the workshop hosted in 2016?

In 2016, the first workshop established consistent surveillance protocols, largely adapted from existing practices, to see if they would be effective. The 2023 workshop built on this foundation with three main goals: evaluate the effectiveness of those protocols, refine or eliminate unnecessary tests, and expand coverage from about 60 pediatric predisposition syndromes to nearly 100. There were about 60 to 70 participants from all over the world in each workshop, and they were split into working groups focused on specific syndromes, or groups of related syndromes.

This recent workshop cast a wider net and also reevaluated the protocols for the previous predisposition syndromes to identify if any potential improvements were needed. Are the existing protocols too much or too little? Should we add or change anything? Should we remove anything for the roughly 60 syndromes identified initially? In short, the first workshop focused on establishing appropriate surveillance protocols, whereas the second sought to minimize the burden on patients and maximize the likelihood of early detection.

Why was it important to include less common and rare predisposition syndromes in the second workshop?

The participants in the initial workshop thought focusing on the 60 most common predisposition syndromes was enough. However, some syndromes were not included and there were new syndromes that were identified in the interim, and so the second workshop aimed to include virtually every predisposition syndrome affecting children and adolescents for which there were any reasonable data or recommendations.

For the predisposition syndromes we had not included in the initial workshop, we looked to see if there were already surveillance guidelines for a similar syndrome that might be relevant. Even though they are different syndromes, they might still predispose children to the same types of cancer, such as Wilms tumor, hepatoblastoma, or leukemia. In that case, we would adapt the existing protocol to suit the new syndrome.

What were some of the key takeaways from the second workshop and the publications that stemmed from it?

The 2023 workshop marked a major step forward in refining how we approach surveillance for children at increased cancer risk. Building on the 2016 workshop, our group re-evaluated those recommendations with new data and expanded coverage to nearly 100 predisposition syndromes, more than 30 of which had not been addressed before. This effort created a far more comprehensive and consistent framework for clinicians managing children with inherited cancer risks.

Perhaps the clearest takeaway was that surveillance works. Tumors detected through structured screening protocols were typically smaller, more amenable to surgery, and associated with significantly better outcomes. For example, children with Li-Fraumeni syndrome who followed surveillance protocols had markedly higher survival compared with those who did not. Similar benefits were documented in children with Beckwith-Wiedemann syndrome and replication repair deficiency.

One of the primary goals was ensuring that no extra or unnecessary surveillance was being performed, considering the potential expenses and what young patients have to experience, especially with burdensome tests like long-duration imaging studies. Where possible, we wanted to prune tests that were redundant or poorly tolerated.

The workshop also highlighted how emerging technologies could transform surveillance. Liquid biopsy approaches that detect tumor material in blood may allow earlier, less invasive detection than extensive imaging. Additionally, advances in imaging technologies like rapid whole-body MRI, contrast-enhanced ultrasound, and metabolic or proteomic biomarkers, also promise to improve sensitivity while reducing burden on patients and families.

How are technological advances influencing surveillance approaches?

In patients who could be predisposed to developing tumors in multiple anatomical sites, such as those with Li-Fraumeni syndrome, whole-body MRI has been very valuable. Without it, patients instead have to undergo multiple, piecemeal MRIs for each of the various body parts, and could be in the scanner for a prolonged period, whereas rapid whole-body MRI can cover virtually everything in reasonable detail within one and a half to two hours.

Although whole-body MRI technology has been around for a while, not every center has the software and hardware capabilities to do those scans. Plus, MRIs are time-consuming and expensive. Therefore, we were interested in exploring approaches that might be as or more effective and maybe easier to tolerate for the patients and their families, both physically and financially, such as ultrasounds.

Although there was not any emerging technology that we thought was ready for prime time, there are several centers and groups that are exploring cell-free DNA, with the hope that as we get better at picking up abnormal DNA signals we will potentially be able to avoid the whole-body MRIs that are done every year and the ultrasounds that are done more regularly just by doing a blood test.

With respect to analyzing cell-free DNA, there are three dimensions that can be helpful.

One is if a patient harbors a mutation, for example in the TP53 tumor suppressor gene—meaning they have Li-Fraumeni syndrome—then detecting a different TP53 mutation or deletion, or a mutation in another gene like a RAS gene, would suggest a tumor may be developing.

The second approach looks at DNA copy number to examine for extra copies of parts of certain chromosomes, or if parts of certain chromosome sections were missing or underrepresented. That does not tell you what the tumor is or where it is, but it does suggest that there may be a developing neoplastic process, as unbalanced DNA in the circulation should not be evident otherwise.

The third approach involves DNA methylation assessment. Every cell in the body possesses the entire genome and all the same genes, and one way cells of a given tissue (e.g., liver) control which genes are activated and which proteins are produced is through methylation. Consequently, every tissue in the body has a characteristic methylation pattern. Normal blood has predictable patterns of methylation associated with the different blood cell lineages and precursors that are supposed to be there. However, if you see a methylation pattern that does not reflect those cells, that tells you something is off, and it may even offer clues about the tissue or origin of the abnormal cells.

What steps are being taken to improve the feasibility and accessibility of these tools in resource-limited settings?

Here, I think the onus is on the more developed countries to show that the approaches we are using work, and then we have to make them exportable and affordable. Whole-body MRI equipment cost millions of dollars, so it is not practical to have them everywhere, but it is practical in most places to have blood tests, so that is why there is special focus on the detection of circulating tumor material in the blood.

Stool samples are another type of biological material that hold some promise for use in surveillance in lower resource settings because samples can be acquired easily and may shed light on the microbiome of the gastrointestinal (GI) tract, especially the specific bacteria found there. This information could be very useful, particularly in patients predisposed to tumors of the GI tract, but also for other syndromes with identifiable GI tract manifestations. Our breath and urine also may also hold clues because of the volatile organic compounds, proteins, or other molecules that can be found in them.

My team and the other experts involved in the workshop are very interested in advancing these types of approaches and extending their applications to more settings. However, they are still not going to be cheap, and they will require expertise to perform and interpret the tests. However, if blood samples could be taken at the point of care and then sent to a central lab for processing, we could serve many more patients in countries with fewer health care-related resources.

How do you balance the potential benefits of early tumor detection against the medical and psychosocial burdens of surveillance, especially in young children?

Having a predisposition syndrome is sort of a Damocles’ sword, since the potential of something bad happening is hanging over the patient all the time. The sword may never fall, but it may fall, and you do not know when. To improve how doctors confront this dilemma, many institutions employ psychologists whose clinical investigations are also helping us to better understand the patients’ and parents’ feelings on the matter. Ultimately, it is the family’s decision and no one is forced to undergo testing or to do the surveillance. Psychologists can help patients and families to deal with the stress and anxiety, and most large programs offer these services.

Regarding predisposition syndromes that carry lifetime cancer risks, how do you address the transition from pediatric to adult care?

Once patients start to age out when they get to be 18 and older, doctors cannot just tell them to go find somebody else. It is the physician’s responsibility to identify potential options for them based on where they live and what their insurance is and so forth, and we will work to connect them with cancer centers or recommended individuals who can continue their surveillance and specialized care. With most cancer predisposition disorders, some risk remains in adulthood, either of developing the same cancer or different cancers, so there needs to be a continuum and continuity of care.

What do you consider to be the most pressing research priorities to address moving forward with respect to childhood cancer predispositions and surveillance?

Moving forward, I would say there are at least four main areas of focus at cancer research centers that manage these patients.

The first priority is the discovery of new cancer-causing genes. There are cancers that run in families that are not yet linked to any known genetic mutation or aberration, so we cannot do genetic testing to determine who is at risk and who is not. Some cases of childhood cancer may be due to mutations in genes that do not cause cancer by themselves, but they may still contribute, likely in combination with other genes. The discovery of more genes with the potential to cause cancer, at least down to a certain threshold level, will be increasingly important.

The second priority is to identify what are called genotype-phenotype correlations, which means how likely a patient with a given mutation is to get cancer, or which cancers, or how early they are likely to occur. This will become more feasible as data on more patients are pooled from more centers. We need more data to see the whole picture because predisposition syndromes manifest differently in different families, and sometimes even within a single family, due to the way predisposition genes interact with other genes in each person’s unique genetic landscape or environment. With a more detailed understanding of these connections, doctors could provide more accurate predictions as far as one’s likelihood of getting certain cancers.

The third priority is enhanced surveillance, which may be achievable as more progress is made in various diagnostic areas, including blood-based tests, analysis of the microbiome, and advanced imaging methods like high-resolution ultrasound.

And the fourth priority is prevention. I never thought in my lifetime that I would think seriously about potentially preventing childhood cancer. Also, to be clear, preventing cancer in all children is still not a feasible short-term goal. However, in children with these well-defined predisposition syndromes, there is hope on the horizon. If you know the gene, the protein, and the pathway that are affected by a certain predisposition syndrome, and you either have an existing drug or you can develop a drug that influences that pathway in a favorable way, perhaps it might be possible to delay, reduce, or even prevent cancer developing in some of these children.

Members of the 2023 AACR Childhood Cancer Predisposition and Surveillance International Workshop published a series of articles in the AACR journal Clinical Cancer Research, which are freely available to readers online: