Data-Driven Research Improves Clinical Care: Interview with Jeffrey Dome, MD, PhD
The TARGET datasets are huge. In Wilms Tumor alone, hundreds of tumors were sequenced in our effort to define the genetic landscape of this pediatric cancer. There is so much in that dataset that there are bound to be more discoveries in the future. Additional knowledge comes out as researchers go back to “re-mine” the data. That’s why it is so important to make these datasets publicly available.
Jeffrey Dome, MD, PhD, recently spoke with the CRDC team about his work and that of his peers in the Children’s Oncology Group (COG)/Wilms Tumor program, as well as with the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program. Their work is focused on the intersection of clinical care informed by an understanding of the genetic and ‘omics’ landscape of Wilms Tumor.
Dr. Dome is Senior Vice President of the Center of Cancer and Blood Disorders and Division Chief, Oncology, Children’s National Hospital, Washington, DC.
Wilms Tumor (WT; nephroblastoma) is the most common pediatric kidney tumor. Approximately 90-95% of tumors in patients are of a so-called “favorable” histology (FHWT). Patients with this histology have an overall survival rate of 90% but that comes with difficult side effects from current “mainline” drugs. Although included in the “favorable” histology group, a small percent of WT patients has a genetic change in their cancer cells called loss of heterozygosity [LOH] at chromosomes 1p and 16q, which is associated with unfavorable prognosis.
The landmark paper, A Children's Oncology Group and TARGET Initiative Exploring the Genetic Landscape of Wilms Tumor, published in 2017, documents the work done to define biomarkers that support risk stratification for better diagnosis and prognosis.
As Dr. Dome notes:
I used to be skeptical about making a difference with very rare subtypes in Wilms Tumor patients. I thought they were just too rare, and we’d never be able to demonstrate any change in outcomes. But what I’ve seen over the years is that it is worth pursuing.
Dr. Dome’s work with hundreds of pediatric cancer specialists has changed the standard of care for treating Wilms Tumor as outlined in the 2021 paper, Impact of the First Generation of Children’s Oncology Group Clinical Trials on Clinical Practice for Wilms Tumor.
We also see that patients without specific biomarkers benefit from lower dosing with mainline drugs. This is also an important outcome of this work – improved treatment and outcomes for a larger percent of Wilms Tumor patients.
Scroll further down for more detail about genetic mutations in Wilms Tumor patients and how those mutations are informing tailored clinical care.
These landmark studies are grounded in the work of two NCI-funded research consortia, for which Dr. Dome plays an integral role: Children’s Oncology Group and the TARGET program. The Wilms tumors that have been genetically sequenced for the TARGET program were obtained from patients enrolled in Children’s Oncology Group studies.
Data from two Wilms Tumor TARGET studies are accessible through the Genomic Data Commons (GDC): High Risk Wilms Tumor and Molecular Profiling to Predict Response to Treatment - Wilms Tumor.
It pays to bank samples – tumor samples and patient blood, to assess germline mutations. Just as we can go back to the data, we can go back to the samples, especially as 'omics technology advances and becomes more affordable. This is important in all diseases, but especially important in rare diseases.
It also pays to annotate the genetic data with clinical outcomes – to correlate biology and outcomes. That takes an investment. It requires major infrastructure for both banking and clinical data collection and entry. But that is how we are going to learn about rare subtypes of cancer. You don’t know what you might find as you are banking these samples, but you need to amass this bank to identify distinct subsets.
Reflecting on his ongoing clinical care and research, Dr. Dome notes:
It is important to discover ways to target the genetic mutations uncovered through TARGET research, many of which are currently not considered “druggable.” In the meantime, we will fine-tune treatment with existing agents based on the genetic landscape and novel prognostic markers– and that’s an important advance.
Scroll further down for Dr. Dome’s comments about early career researchers and how they can make an impact.
Wilms Tumor data from the TARGET studies are also available through the CRDC cloud resources; all require that you create an account and log in, even to browse data informally.
Wilms tumor: Specific genetic mutations now serving as biomarkers to tailored treatment
As noted above, pediatric patients with FHWT are typically treated with the current “mainline” chemotherapy drugs, vincristine and dactinomycin, for stage I and II, with the addition of doxorubicin for stage III and IV.
Although included in the “favorable” histology group, a small percent of WT patients has a genetic change in their cancer cells called loss of heterozygosity [LOH] at chromosomes 1p and 16q, which is associated with unfavorable prognosis. Recent clinical trials have demonstrated that additional chemotherapy (doxorubicin for stage I and II and cyclophosphamide and etoposide for stage III and IV) improves outcomes in this uncommon group. These studies demonstrate the benefit of using biomarkers alongside traditional prognostic factors, such as stage and histology, in determining treatment regimens.
Between 5-10% of WT patients have anaplastic histology (AHWT), which is associated with acquisition of TP53 mutations within the tumor cells. Outcomes for patients with AHWT have improved over time with more intensive chemotherapy regimens, yet remain suboptimal, particularly for patients with metastatic disease. As Dr. Dome notes, novel therapies are desperately needed for these and other high-risk Wilms Tumors, as summarized in Advances in the clinical management of high-risk Wilms Tumors, published in Pediatric Blood Cancer, in May 2023.
Advice for early career researchers
Dr. Dome took a few moments to reflect on the early career researchers with whom he has collaborated and mentored over the years. His advice:
In the early stages of your career, find a mentor with depth and breadth of experience in your area of interest who can help you navigate the specifics of your research, as well as the landscape of relevant research consortia, and how to secure grants. The science as well as the politics and funding of the work are important – navigating all of this is essential throughout your career.
And then, in working with your mentor, come up with specific questions – for example, query specific molecular pathways. Don’t start off too broadly, although you need to be well-imbued in what has been done. But for your own work and career, ask specific questions and bring something new to the table.
Your mentor can help you define where your specific questions fit into the landscape of work underway and how you can best make a difference in the field. Your mentor might know if these questions have already been asked, or who within various research consortia might be interested. Your mentor can point you to peers with whom you can collaborate. Or your mentor can help you forge your own path if your questions are truly unique.