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Improving Outcomes in Pediatric Oncology: Q&A With Garrett Brodeur, MD
Editor's Note: The American Society of Pediatric Hematology/Oncology (ASPHO) honored Garrett Brodeur, MD, director of the Cancer Predisposition Program and the Audrey E. Evans Endowed Chair in Pediatric Oncology, with its 33rd Distinguished Career Award. The Distinguished Career Award is presented annually to a senior physician who during their career has had a major impact on the subspecialty, through some combination of research, education, patient care, and advocacy. Dr. Brodeur was the 2020 honoree and accepted the award virtually during the 2021 ASPHO Conference. When Cornerstone spoke with Dr. Brodeur about what this honor means to him, he greeted our writer with a Vulcan salute, familiar to fans of “Star Trek” as a hand signal that wishes the recipient to live long and prosper — a fitting gesture from a physician-scientist who helps children with cancer do just that.
What does the ASPHO Distinguished Career Award represent to you?
The awards I have received are all extremely important and meaningful, but it means a great deal to be nominated by my peers in pediatric hematology and oncology, which is the narrow sphere in which I work. To be listed among the other past recipients— veritable giants in the field of pediatric oncology like Teresa Vietti, MD; Audrey Evans, MD; Alfred Knudson, MD; Ann Meadows, MD — some of whom were my mentors or my inspiration to go into this field, is humbling to me. I am extremely grateful to have received this award.
What led you to choose a focus in pediatric oncology?
I did research related to neuromuscular function as a chemistry major, and so I planned to be a neurologist and study memory. I had the opportunity to study normal and malignant neurons, the latter being neuroblastoma cells, in a lab during medical school, and I spent time with a neurologist and with a pediatric oncologist Dr. Vita Land. When I looked at the research going on in each field, I decided that pediatric oncology held more promise to make an impact and for future improvements in treatment and outcome. I also enjoyed clinical interactions with children along the age spectrum from infancy to adolescence and their families.
What have you found most interesting about how science has evolved since you began your career?
In a word: genetics. Around the beginning of my career, scientists were just starting to do cytogenetics, looking at the chromosomes to determine whether there were gains, losses, and translocations, but there wasn’t yet an understanding of how that translated to which genes were affected. Molecular genetics allows us to dissect down to the base pair, figure out which particular gene was affected in a particular tumor, and then identify the gene, protein, and pathway that was turned on or turned off by a particular mutation. This gave us a great deal of insight into how a normal cell becomes malignant.
When I started in this field, we were curing 20 to 25 percent of children. Now we are curing more than 80 percent. Empirical trial and error approaches have brought us a long way. However, most clinical trials were designed either to iteratively add or subtract a therapy, with many having unacceptable toxicity.
With molecular insights, we can now choose therapy that is more likely to be effective for an individual patient, and we can even design drugs that target specific pathways. The evolution from purely empirical therapy based on stage and type of cancer, to targeted agents based on activation of a particular pathway, allows us to treat patients in a way that improves their outcome and/or reduces the treatment’s toxicity.
Is there a particular aspect of your work or a specific project you are most proud of?
I am particularly proud of my role in two areas of developing international consensus. I am grateful to have been able to play a role in the development of a standardized International Neuroblastoma Staging System (INSS). The system has evolved over time, and we have worked together to develop, modify, or update it into the International Neuroblastoma Risk Group staging system (INRG-SS). However, the inception of developing an international consensus on neuroblastoma staging began with this effort.
More recently, I became director of the Cancer Predisposition Program at CHOP, and I quickly realized that there was no consensus on surveillance for patients who had an increased risk of developing cancer based on an inherited, mutated gene. The Pediatric Cancer Working Group (PCWG) within the American Association for Cancer Research (AACR), of which I was chair at the time, convened a workshop to develop consensus screening recommendations for children with the most common cancer predisposition syndromes. We published the recommendations in 18 papers in Clinical Cancer Research in 2017, recommending surveillance protocols for the 60 most common predisposition syndromes.
Another point of pride is the identification of prognostic markers, particularly MYCN oncogene amplification, as a predictor of poor outcome in patients with neuroblastoma. Although I did not discover the MYCN gene, I participated in its discovery, and I demonstrated its clinical significance in neuroblastoma, in collaboration with Dr. Robert Seeger. That knowledge is still used today around the world by pediatric oncologists to predict the outcome and select therapy for patients with neuroblastoma.
What do you think is next for your field in the next five years and in the long term?
We have come a long way, from 20 percent to 80 percent survival for patients with pediatric cancers, but that success has plateaued, so we are not making much headway in curing the remaining 20 percent of patients. Also, for those patients we do cure, there is a significant amount of short- and long-term toxicity. We need more effective, less toxic therapy, and to move away from conventional delivery of generic drugs that have been used empirically to more targeted approaches. I see targeted therapy coming in at least three different types of approaches that are being actively pursued today:
- Targeted drugs, in which a gene, protein, or pathway is identified that is activated, and a drug is used that blocks that pathway downstream of the activation. This approach works very well for small subsets of patients. For others, it is effective for a short period of time, and then resistance develops. This is an area of great promise, and we will continue to build on and improve targeted agents.
- Targeted immunotherapy with antibodies or genetically modified T cells called chimeric antigen receptor (CAR) T cells is another very exciting area. The initial results with CART-19 activated T cells were miraculous, helping patients who, by everything we know, had essentially zero chance of survival. Harnessing the amazing power of our immune system is going to be very important going forward and will increasingly become part of our armamentarium.
- Targeted drug delivery utilizing nanoparticles takes advantage of leaky tumor vasculature to deliver commonly used chemotherapy drugs at dramatically higher concentrations than can be achieved with conventional drug delivery. It also permits the delivery of chemically modified agents that dramatically improve its potency. Optimizing the drug release kinetics is also essential and an exercise in artful timing — if the drug comes off the carrier too quickly, it becomes free drug that is no different than conventional administration (IV, PO); or if the drug is released too slowly, the targeted tumor will not receive enough of the drug to have an effect. When we get it just right, we have the ability to deliver 50 to 100 times more drug to the tumor in our animal models, effectively curing most cancers, such as neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma, with four weekly IV doses.
Genetic predisposition is also becoming increasingly important. We used to think only 1 or 2 percent of children with cancer were predisposed, and we could identify a few subsets who were at increased risk. However, now we know that at least 10 to 15 percent of children with cancer are predisposed to develop those cancers due to inherited or de novo mutations in predisposition genes. If we can identify those individuals before they get cancer, we can do surveillance and find tumors when they are small (like a grape) and easily curable, rather than large (like a grapefruit) when they present with clinical symptoms. Identifying predisposed individuals and using enhanced surveillance techniques are going to be essential for the future of pediatric cancer diagnosis and treatment.
I am sure there are some geniuses who can come up with exciting new ideas on their own, but most people succeed as a team, and we can make much more progress working together. I have been fortunate to have wonderful mentors who helped direct and inspire me, and work with some great trainees in my lab that have helped to move things forward. I joined CHOP 28 years ago. It is a terrific place to do pediatric research, and I have thoroughly enjoyed my career here. No one wants to see a child develop cancer but, in many cases, we can offer them a chance of a cure. However, I am now excited that we are developing much better treatment options that will be much more effective, and hopefully not be nearly as toxic as we have experienced in the past.