Extremity Rhabdomyosarcoma: An Integrated Clinicopathologic and Genomic Study to Improve Risk Stratification

Authors

Henry de Traux de Wardin

Bin Xu

Josephine K. Dermawan

Mariel H. Smith

Suzanne L. Wolden

Cristina R. Antonescu

Leonard H. Wexler

Doi

10.1200/PO.22.00705

PMID: 37315267 · DOI: 10.1200/PO.22.00705 · Journal: JCO Precision Oncology (2023)

TL;DR

A single-center retrospective study of 61 patients with extremity rhabdomyosarcoma (RMS) treated at MSKCC between 2000 and 2021, integrating clinicopathologic features with MSK-IMPACT targeted DNA sequencing (performed in 40% of patients) to refine risk stratification. The authors confirm the dominance of FOXO1 fusion–positive alveolar RMS (ARMS) in this anatomic subset and identify CDK4 amplifications and CDKN2A deletions as mutually exclusive, recurrent events associated with poor overall survival PMID:37315267.

Cohort & data

Key findings

  • One-third of patients had localized disease; 18% had regional nodal disease; 51% had distant metastases at diagnosis PMID:37315267.
  • Metastatic disease, high-risk group, and age ≥10 years significantly affected OS (HR 2.68, P=.004; HR 2.78, P=.010; HR 2.26, P=.034) PMID:37315267.
  • 5-year EFS/OS for metastatic disease: 19% / 29%; for nodal involvement without distant metastases: 43% / 66% PMID:37315267.
  • PAX3::FOXO1 ARMS had worse prognosis and affected older children than PAX7::FOXO1 (HR 3.45, P=.016) PMID:37315267.
  • The most common genomic events in ARMS were MED12 alterations, CDK4 amplifications, and CDKN2A deletions (each 8%–17%) PMID:37315267.
  • CDK4 amplifications and CDKN2A deletions were mutually exclusive, enriched in acral and high-risk lesions, and correlated with poor OS (P=.02) PMID:37315267.

Genes & alterations

Clinical implications

  • The authors argue that CDK4 amplifications and CDKN2A deletions should be considered for integration into risk stratification for extremity RMS, given their correlation with poor OS PMID:37315267.
  • PAX3::FOXO1 vs PAX7::FOXO1 fusion subtype carries independent prognostic weight within alveolar RMS and may warrant fusion-partner–aware stratification PMID:37315267.
  • Nodal-only involvement, while adverse, has a substantially less dismal outcome than distant metastatic disease, supporting aggressive local/regional control in node-positive extremity RMS PMID:37315267.

Limitations & open questions

  • Single-institution retrospective cohort of 61 patients over 20 years; small sample limits multivariable power, especially for rare fusion-negative and MYOD1-mutant subtypes PMID:37315267.
  • MSK-IMPACT sequencing was available for only 40% of patients, biasing the genomic correlatives toward cases with residual material PMID:37315267.
  • Treatment regimens spanned multiple sequential COG/institutional protocols across two decades, complicating outcome comparisons PMID:37315267.
  • Whether therapeutic targeting of CDK4/6 in CDK4-amplified or CDKN2A-deleted extremity RMS improves outcomes remains untested PMID:37315267.

Citations from this paper used in the wiki

  • “Most (85%) patients had FOXO1 fusion–positive alveolar RMS (ARMS), with 70% having a PAX3::FOXO1 transcript.” (Abstract)
  • “Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [P = .004], 2.78 [P = .010] and 2.26 [P = .034], respectively).” (Abstract)
  • “PAX3::FOXO1 ARMS had worse prognosis and afflicted older children compared with PAX7::FOXO1 (HR = 3.45, P = .016).” (Abstract)
  • “The most common events in the ARMS group included MED12 alterations, CDK4 amplifications, and CDKN2A deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS (P = .02).” (Abstract)
  • “MSK-IMPACT, a targeted DNA-based sequencing panel (410-505 genes), was used in 40% of the patients with available material.” (Patients and Methods)

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