A study suggests that sequencing TP53 and MYOD1 can improve risk stratification for patients with rhabdomyosarcomas. It suggests that sequencing should be completed for each patient to determine which treatment regimen will most likely be effective.

Mutations in TP53 and MYOD1 correlate with shortened survival for patients with rhabdomyosarcoma, a recent study reveals (J Clin Oncol 2021 June 24 [Epub ahead of print]). The findings suggest that sequencing these genes should be part of the diagnostic workup to determine the most effective treatment regimen for each patient.

“This is a seminal paper in the field,” says Timothy Cripe, MD, PhD, of Ohio State University and Nationwide Children's Hospital in Columbus, who wasn't connected to the study.

Risk stratification is critical for rhabdomyosarcoma, which is the most common soft-tissue tumor in children. High-risk patients typically endure a year of intensive chemotherapy, often with radiation and surgery. However, some patients may not need aggressive treatment, either because their tumors have a low risk of spreading or because they are unlikely to benefit from it. The only molecular marker currently incorporated into risk evaluations is a PAXFOXO1 fusion indicative of serious disease.

To determine whether other mutations could improve risk stratification, Jack Shern, MD, of the NCI, and colleagues obtained tumor samples from 641 patients in the United States and the UK. The team then sequenced 39 genes linked to rhabdomyosarcoma. The mutations patients carried depended on their FOXO1 fusion status: The most common alterations in the fusion-positive group were CDK4 and MYCN amplifications, which occurred in 13% and 10% of patients, respectively. Only 4% of these patients had TP53 mutations. In contrast, 56% of patients lacking FOXO1 fusions had mutations in RAS pathway genes. In this group, TP53 mutations were also more common, occurring in 15% of patients.

Because the researchers had access to patients' clinical data, they assessed the effect of the mutations on survival. Previous work suggested that fusion-negative patients with RAS pathway mutations were more likely to have severe disease. However, the team found that these mutations did not correlate with shorter overall survival or event-free survival (EFS)—the time until the original tumor recurs, a new tumor emerges, or the patient dies.

TP53 mutations, on the other hand, diminished EFS in fusion-negative patients. Only five fusion-positive patients carried TP53 mutations, all of whom died, suggesting that the mutations may reduce overall survival in this group too.

For those with normal FOXO1, mutations in MYOD1 had a profound effect on survival. Patients with these alterations have been considered at low or intermediate risk for disease progression. However, less than 10% of patients in the United States with these mutations had 5 years of EFS, whereas 75% of patients with a wild-type gene did. The UK cohort showed a similar pattern.

“Genomic and molecular techniques can help us determine subgroups of patients who are going to do poorly,” says Shern. “Every one of these kids [with rhabdomyosarcoma] deserves to have this kind of analysis done on their tumors.” He notes that two upcoming clinical trials of rhabdomyosarcoma treatments will test patients for TP53 and MYOD1 mutations.

“We are probably undertreating some patients and overtreating others” under the current risk-stratification criteria, Cripe says. “These data are quite believable and should be incorporated into our risk stratification.”

The study also provides insight into the biology of the disease, adds Anton Henssen, MD, of Charité-Universitätsmedizin Berlin in Germany, who was not involved in the research, by explaining why tumors in the extremities often respond poorly to treatment: TP53 mutations were abundant in fusion-negative patients with tumors in these locations.

Overall, this is “a landmark study,” Henssen says, because it integrates clinical and genomic data, a difficult feat considering the cancer's rarity.–Mitch Leslie