Germline Genetic Testing and Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From the Children's Oncology Group

Authors

Bailey A Martin-Giacalone
He Li
Michael E Scheurer
Dana L Casey
Shannon Dugan-Perez
Deborah A Marquez-Do
Donna Muzny
Richard A Gibbs
Donald A Barkauskas
David Hall
Douglas R Stewart
Joshua D Schiffman
Matthew T McEvoy
Javed Khan
David Malkin
Corinne M Linardic
Brian D Crompton
Jack F Shern
Stephen X Skapek
Rajkumar Venkatramani
Douglas S Hawkins
Aniko Sabo
Sharon E Plon
Philip J Lupo

Publication Date

3-4-2024

Journal

JAMA Network Open

DOI

10.1001/jamanetworkopen.2024.4170

PMID

38546643

PMCID

PMC10979319

PubMedCentral® Posted Date

3-28-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Child, Humans, Female, Male, Cohort Studies, Prospective Studies, Rhabdomyosarcoma, Neoplasms, Second Primary, Genetic Testing, Germ Cells

Abstract

IMPORTANCE: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma.

OBJECTIVE: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023.

EXPOSURE: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set of 63 autosomal-dominant CPGs.

MAIN OUTCOMES AND MEASURES: Overall survival (OS) and event-free survival (EFS) were the main outcomes, using the Kaplan-Meier estimator to assess survival probabilities and the Cox proportional hazards regression model to adjust for clinical covariates. Analyses were stratified by tumor histology and the fusion status of PAX3 or PAX7 to the FOXO1 gene.

RESULTS: In this study of 580 individuals with rhabdomyosarcoma, the median patient age was 5.9 years (range, 0.01-23.23 years), and the male-to-female ratio was 1.5 to 1 (351 [60.5%] male). For patients with CPVs in rhabdomyosarcoma-associated CPGs, EFS was 48.4% compared with 57.8% for patients without a CPV (P = .10), and OS was 53.7% compared with 65.3% for patients without a CPV (P = .06). After adjustment, patients with CPVs had significantly worse OS (adjusted hazard ratio [AHR], 2.49 [95% CI, 1.39-4.45]; P = .002), and the outcomes were not better among patients with embryonal histology (EFS: AHR, 2.25 [95% CI, 1.25-4.06]; P = .007]; OS: AHR, 2.83 [95% CI, 1.47-5.43]; P = .002]). These associations were not due to the development of a second malignant neoplasm, and importantly, patients with fusion-negative rhabdomyosarcoma who harbored a CPV had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma without CPVs (EFS: AHR, 1.35 [95% CI, 0.71-2.59]; P = .37; OS: AHR, 1.71 [95% CI, 0.84-3.47]; P = .14). There were no significant differences in outcome by CPV status of the 63 CPG set.

CONCLUSIONS AND RELEVANCE: This cohort study identified a group of patients with embryonal rhabdomyosarcoma who had a particularly poor outcome. Other important clinical findings included that individuals with TP53 had poor outcomes independent of second malignant neoplasms and that patients with fusion-negative rhabdomyosarcoma who harbored a CPV had outcomes comparable to patients with fusion-positive rhabdomyosarcoma. These findings suggest that germline CPV testing may aid in clinical prognosis and should be considered in prospective risk-based clinical trials.

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