Koscielniak Ewa, Stegmaier Sabine, Ljungman Gustaf, Kazanowska Bernarda, Niggli Felix, Ladenstein Ruth, Blank Bernd, Hallmen Erika, Vokuhl Christian, Blattmann Claudia, Sparber-Sauer Monika, Klingebiel Thomas
Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart, Stuttgart, Germany.
Medical Faculty, University of Tübingen, Tübingen, Germany.
Cancer Med. 2025 Jan;14(1):e70215. doi: 10.1002/cam4.70215.
The histologic classification of rhabdomyosarcoma (RMS) as alveolar (aRMS) or embryonal (eRMS) is of prognostic importance, with the aRMS being associated with a worse outcome. Specific gene fusions (PAX3/7::FOXO1) found in the majority of aRMS have been recognized as markers associated with poor prognosis and are included in current risk stratification instead of histologic subtypes in localized disease. In metastatic disease, the independent prognostic significance of fusion status has not been definitively established. The objective of this analysis was to evaluate survival outcomes of patients with localized and metastatic aRMS and its association with fusion status and subtype (PAX3/7::FOXO1, FOXO1 break), and clinical prognostic factors.
A total of 470 patients with aRMS ≤21 years of age enrolled in two CWS-trials and two registries was eligible for the analysis.
The 5-year event-free survival (EFS) and overall survival (OS) rates for all patients with localized vs. metastatic tumors were: 56% and 65% vs. 18% and 22%, respectively. Of the 368 (78%) tumors tested, specific fusion was found in 330 (90%), considered "fusion positive" FP (PAX3::FOXO1 in 280, PAX7::FOXO1 in 49, FOXO1 break in 59 tumors). In patients with localized tumors, univariate analysis revealed that clinical group, tumor invasiveness (T1 vs.T2), regional lymph node involvement (N0 vs. N1) and FOXO1 fusion were significantly associated with EFS and OS, tumor size and PAX variant with OS only. In patients with metastatic aRMS, age, bone/marrow (B/BM) metastases, FOXO1 fusion and PAX variant were associated with EFS and OS, T status with OS only. Multivariate analysis identified PAX3::FOXO1 fusion as an independent adverse prognostic factor for EFS in patients with localized disease and for EFS and OS in patients with metastatic disease, B/BM metastases for EFS.
PAX3::FOXO1 fusion should replace FOXO1 fusion as an adverse prognostic factor in risk stratification. The prognostic relevance of PAX7::FOXO1-positive and FOXO1 fusion negative aRMS, along with the clinical factors described in this report, allows further refinement of risk assessment of patients with localized and metastatic aRMS.
横纹肌肉瘤（RMS）的组织学分类为肺泡型（aRMS）或胚胎型（eRMS）具有预后意义，aRMS的预后较差。在大多数aRMS中发现的特定基因融合（PAX3/7::FOXO1）已被认为是与预后不良相关的标志物，在局限性疾病中被纳入当前的风险分层，而非组织学亚型。在转移性疾病中，融合状态的独立预后意义尚未明确确立。本分析的目的是评估局限性和转移性aRMS患者的生存结果及其与融合状态、亚型（PAX3/7::FOXO1、FOXO1断裂）和临床预后因素的关联。
共有470例年龄≤21岁的aRMS患者参加了两项儿童肿瘤研究组（CWS）试验和两个登记处，符合分析条件。
局限性肿瘤与转移性肿瘤患者的5年无事件生存率（EFS）和总生存率（OS）分别为：56%和65%对比18%和22%。在检测的368例（78%）肿瘤中，330例（90%）发现了特定融合，被认为是“融合阳性”（FP）（280例为PAX3::FOXO1融合，49例为PAX7::FOXO1融合，59例肿瘤为FOXO1断裂）。在局限性肿瘤患者中，单因素分析显示临床分组、肿瘤侵袭性（T1对比T2）、区域淋巴结受累（N0对比N1）和FOXO1融合与EFS和OS显著相关，肿瘤大小和PAX变异仅与OS相关。在转移性aRMS患者中，年龄、骨/骨髓（B/BM）转移、FOXO1融合和PAX变异与EFS和OS相关，T分期仅与OS相关。多因素分析确定PAX3::FOXO1融合是局限性疾病患者EFS以及转移性疾病患者EFS和OS的独立不良预后因素，B/BM转移是EFS的不良预后因素。
在风险分层中，PAX3::FOXO1融合应取代FOXO1融合作为不良预后因素。PAX7::FOXO阳性和FOXO1融合阴性aRMS的预后相关性，以及本报告中描述的临床因素，有助于进一步完善局限性和转移性aRMS患者的风险评估。
