Key Takeaways:
- Molecular biomarkers have been used for more than two decades to guide cancer treatment and have transformed outcomes in many forms of cancer.
- For rare cancers like Ewing sarcoma, discovering clinically viable biomarkers has been a challenge — until recent research by Dana-Farber scientists.
In 2014, Dana-Farber pediatric oncologist Brian Crompton, MD, discovered that a gene called STAG2 is mutated in about 15 percent of patients with Ewing sarcoma, a form of bone cancer that largely occurs in children and adolescents. Now, that molecular insight could hold the keys to advancing treatment for the disease.
New research led by senior authors Crompton and pediatric oncologist Katherine Janeway, MD, Dana-Farber Pediatric Oncology Section Chief and Chair of the Children’s Oncology Group bone tumor committee, found that patients with STAG2 gene mutations in their tumor are more likely to relapse after treatment, enabling investigators to predict before treatment begins which patients are likely to be cured, and which are likely to have a recurrence.
The findings support the use of STAG2 as a biomarker in clinical trials to classify patients and tailor treatments based on their risk of relapse.
“Now, for the first time ever, we’ve created a molecularly based stratification biomarker that can be implemented immediately in upcoming clinical trials,” says Crompton.
The study was published in the Journal of Clinical Oncology and completed in collaboration with the Children’s Oncology Group, which brings investigators across the country together to advance treatment for children.
“This study was enabled by advances in our knowledge of the genomics of the disease, an accumulation of patients participating in clinical studies over time, and the availability of tissue samples,” says co-first author and pediatric oncologist Riaz Gillani, MD. “It’s special to see those ingredients coming together to make this advancement possible.”
Plans, led by co-first author and pediatric oncologist David Shulman, MD, are already underway for a clinical trial that leverages this new genetic biomarker to stratify patients into treatment groups.
For rare cancers like Ewing sarcoma, discovering clinically viable biomarkers has been a challenge — until recent research by Dana-Farber scientists.
A success story that isn’t over yet
Modern treatment for Ewing sarcoma cures approximately 78 percent of patients with localized tumors that have not spread. The remaining patients, however, typically relapse with disease that has spread and is difficult to treat.
Crompton and colleagues want to find ways to stave off or prevent relapse in the patients who aren’t cured. One approach might be to add more treatment to increase its intensity.
But treatment for Ewing sarcoma is already very intense, involving five forms of chemotherapy plus surgery or radiation. Adding intensity for every patient isn’t an option because existing treatments, while potentially curative, also result in long-term adverse effects including heart disease, the development of secondary leukemia, new sarcomas, renal disease, and infertility.
“It’s not just about figuring out which patients need more treatment so we can cure them. We also need to protect those kids who we know are already going to be cured with current therapy and prevent them from getting additional, unnecessary treatment,” says Crompton. “Having the ability to stratify patients based on relapse risk could help us design trials to test new agents or approaches to intensifying therapy for patients who need it without intensifying therapy for patients who are already extremely likely to be cured.”
The search for a stratification biomarker
Crompton was as a postdoc in the lab of Kimberly Stegmaier, MD, chair of the Department of Pediatric Oncology at Dana-Farber, when they discovered the prevalence of STAG2 mutations in Ewing sarcoma more than a decade ago. Follow-up research by the team showed that loss of STAG2 amps up cancer cell growth and makes the cells more likely to spread.
“This change makes the disease more micro-metastatic, creating metastatic lesions we can’t detect and making the cancer more likely to relapse,” says Crompton.
A later study of archival tissue collected from Ewing sarcoma patients led by Shulman and Crompton showed in 2022 that loss of STAG2 function was associated with worse outcomes.
This study validates that finding in three prospective Children’s Oncology Group clinical trials including patients with consistent diagnoses and treatments. While STAG2 mutations, TP53 mutations, and copy number alterations were all separately associated with poorer outcomes in this study, only STAG2 stood out as predictive of poor outcomes when these factors were tested together.
“When we controlled for all of the variables, STAG2 led the pack as the only independently prognostic molecular biomarker,” says Gillani.
Molecular biomarkers have been used for more than two decades to guide cancer treatment and have transformed outcomes in many forms of cancer. But for rare cancers like Ewing sarcoma, which affects just 400 – 500 children and adults per year in the U.S., discovering clinically viable biomarkers has been a challenge.
“It takes a long time and collaboration across different institutions to have enough patients involved in studies to make statistically significant conclusions,” says Gillani.
“This study would not have been possible without the Children’s Oncology Group project every child study, the associated National Clinical Trials Network biobank which collects samples from over 200 pediatric cancer hospitals and the generosity of the patients and families who agreed to participate in this research,” adds Janeway.
Written By: Beth Dougherty