Molecular Targets Making Headway in Pediatric Thyroid Cancer Research

Aime T. Franco, PhD

Findings on the genetic and molecular landscape of pediatric thyroid cancers has provided insight into how pediatric and adult tumors are comparable to one another. As a result experts have begun evaluating how a patient's cancer may evolve over their lifespan.

While a large number of available treatment options for thyroid cancer has contributed to low mortality rates among patients, according to Aime T. Franco, PhD, the space is still underrepresented in cancer research.

One of the key areas investigators must be knowledgable in is the difference between treating pediatric and adult patients with thyroid cancer and what mutations drive these cancers, explained Franco, an assistant professor and investigator with the Center for Childhood Cancer Research at Children's Hospital of Philadelphia.

Pediatric thyroid cancers can be classified into 3 groups, including BRAF mutations, RAS mutations, and oncogenic fusions. Various multicenter studies through collaborations and consortiums have enabled researchers to identify these 3 subtypes.

Comparatively, pediatric patients tend to have oncogenic fusions more frequently than adult patients with thyroid cancers. In pediatric patients, oncogenic fusions are typically more invasive and lead to a greater risk of recurrence and metastasis.

Additionally, studies have revealed more about the progression of thyroid cancer for pediatric and adult patients, yet further research is warranted to determine whether pediatric patients should be treated the same way as adult patients do as they mature.

“Thyroid cancer is underrepresented in the research spectrum in general, just because we can so successfully treat the disease in regard to having a very low mortality. We don't often enough address the morbidities that are associated with the disease and patients that need to be on lifelong thyroid hormone replacement. Starting to think about this disease not as just cut and dry, looking at death or not death, but looking at the entire lifespan of the patient and how this disease affects them, even after the cancer may be cured [is important],” Franco said, in an interview with Targeted Oncology^TM.

In the interview, Franco discussed the molecular landscape of pediatric patients with thyroid cancer.

Targeted Oncology: Can you your thoughts on the molecular landscape of pediatric thyroid cancer?

Franco: Study findings on the genetic and molecular landscape of pediatric thyroid cancers, and how this has really improved our understanding and provided insight into how pediatric tumors are similar, but also very dissimilar to adult tumors and how we can personalize and specialize our approach to our pediatric patients compared with our adult patients. Also, it gets us to start thinking about the fact that pediatric patients become adult patients, and how that is going to change over their lifespan. We don't have all those answers yet. I think this is something we really need to start thinking about in the clinical spectrum is not only the immediate diagnosis, but what are the long-term repercussions, and how do we start to think about pediatric thyroid cancer as a lifespan disease, and not just something that happens only during childhood?

What have been some of the most important changes in the molecular landscape for pediatric thyroid cancer in recent years?

In recent years, what's been so unique is for us to start to understand the fact that pediatric thyroid cancers tend to look like they are 3 main groups based on their mutations. [There are cancers] driven by BRAF mutations, which we see in adult tumors, whether they're driven by RAS mutations, which we also see in the adult tumors, but interestingly in pediatrics, we see a lot of fusion-driven tumors that are driven by oncogenic fusion events. Although we see these in the adult cases, they tend to be much rarer than they are in the pediatric space. In the pediatric space, they represent kind of their own bucket. These tumors we're seeing look like they behave differently. They can be more invasive; they tend to have a greater risk for recurrence and for metastasis. We're still working and collaborating within our group, but in many others to expand the number of samples we've looked at, because thyroid cancer in the pediatric setting is still a rare cancer. It is difficult to get real power in large studies without doing multiinstitutional studies, which is exactly what we're doing now in starting new collaborations and consortiums.

But really, it looks like pediatric tumors fall in these 3 buckets, whereas the adult tumors tend to fall into 2 buckets. This is going to change how we think about treating the disease as well as stratifying these patients for their long-term follow-up and how we think about it, again, as this lifespan disease as these pediatric patients start to become adults. Are their tumors going to continue if they have persistent disease and continue to act like pediatric tumors, or are they going to act like adult tumors? That is an open-ended question at this point.

How and when should an oncologist be testing these patients?

In my opinion, it would be wonderful if oncologists and endocrinologists could treat this at time of diagnosis, even before a patient goes into surgery. Unfortunately, this isn't going to be available to everyone. This is a real concern of mine, especially as a basic scientist. I'm not a practicing clinician, but the more we learn, we introduce a lot of disparities into the system because not everyone is going to be seen, especially at the very beginning of their care at a major cancer center, at a large institutional, or educational institution, and they may not have access to this. I am a thyroid cancer survivor, and my initial diagnosis was done at our community hospital. Even though it was done 20 years ago, I never would have had access to the latest and greatest care just because of where I was seen. I think we have to be very cognizant as we make these discoveries and continue to advance medicine that we also don't introduce or inadvertently introduce additional disparities into the way we deliver care so that it becomes so specialized, and it's inaccessible to patients that are continuing to be seen at community hospitals and in rural settings.

Are you aware of anything in preclinical or clinical trial research that may impact the landscape for pediatric patients in the near future?

I think that there's going to be a lot that will be on the landscape. There's been a lot of developments in trying to make new mouse models utilizing data, different mouse models using patient derived xenografts, and samples. I think as we become more adept in the laboratory setting of incorporating those models, we're going to start to see pediatric specific models. Now, we don't have pediatric cell lines, but there's a lot of active work in many groups, including our own, to establish pediatric-specific models so that we can start to dissect what we've seen clinically for years, that these tumors behave differently.

Now with this genomic and molecular data suggesting that these tumors are different, we need those models in the laboratory so we can understand the mechanisms that are driving these differences. We also have just started a multi-institutional clinical trial looking at how we can use these molecularly targeted therapies, specifically to attract RET fusions, and how some of these therapies can be used in the pediatric setting for redifferentiation of thyroid cancers, and maybe also just as a cytotoxic type of therapy towards these tumors.

Can you talk specifically about NTRK fusion-positive thyroid cancers? What are the unmet needs for this population?

The unmet need for the NTRK is for us to better understand the biology of this disease, specific to pediatric thyroid cancers. We've had great success across many other malignancies using larotrectinib [Vitrakvi] and some of these very specific and NTRK inhibitors. But what we don't understand is what are going to be the long-term repercussions. How long can we use these types of inhibitors in our pediatric patients? We need those long-term studies, and especially those preclinical models to understand how long we can leave patients safely on these therapies and what other nonspecific effects may have on other systems. But also, we need to understand more about the mechanism of how these inhibitors are working, again, so we can better understand what the long-term repercussions and potential adverse events may be. Also, so that we can begin to try to predict what those resistance mechanisms are. As we become more mainstream and utilize these therapies more often in pediatric patients and across a wider batch of tumors, the likelihood of developing resistance, especially using them long-term, increases significantly. The quicker we can get ahead of that and try to model this in the laboratory and start to anticipate what some of these resistance mechanisms may be, we can start to develop some of the second- and third-line therapies if we need them.

What questions do you anticipate still need to be addressed?

A lot of my discussion [focused] on, what are the differences between pediatrics and adults and what should we be looking at differently? Also, this concept in this idea of looking at thyroid cancer as a lifespan disease. Thyroid cancer is underrepresented in the research spectrum in general, just because we can so successfully treat the disease in regard to having a very low mortality. We don't often enough address the morbidities that are associated with the disease and patients that need to be on lifelong thyroid hormone replacement. Starting to think about this disease not as just cut and dry, looking at death or not death, but looking at the entire lifespan of the patient and how this disease affects them, even after the cancer may be cured [is important]. There's a lot of lifelong monitoring and disease management that needs to take place. As we get better and more curative therapies, we need to think about this, and put the patient back at the center of the equation and discuss how this is going to affect a patient across their entire lifespan.