Selfe Joanna, Olmos David, Al-Saadi Reem, Thway Khin, Chisholm Julia, Kelsey Anna, Shipley Janet
Sarcoma Molecular Pathology Team, Division of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, UK.
Spanish National Cancer Research Centre, Madrid, Spain.
Pediatr Blood Cancer. 2017 Jul;64(7). doi: 10.1002/pbc.26386. Epub 2016 Dec 30.
Long-term toxicities from current treatments are a major issue in paediatric cancer. Previous studies, including our own, have shown prognostic value for the presence of PAX3/7-FOXO1 fusion genes in rhabdomyosarcoma (RMS). It is proposed to introduce PAX3/7-FOXO1 positivity as a component of risk stratification, rather than alveolar histology, in future clinical trials.
To assess the potential impact of this reclassification, we have determined the changes to risk category assignment of 210 histologically reviewed patients treated in the UK from previous malignant mesenchymal tumour clinical trials for non-metastatic RMS based on identification of PAX3/7-FOXO1 by fluorescence in situ hybridisation and/or reverse transcription PCR.
Using fusion gene positivity in the current risk stratification would reassign 7% of patients to different European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) risk groups. The next European trial would have 80% power to detect differences in event-free survival of 15% over 10 years and 20% over 5 years in reassigned patients. This would decrease treatment for over a quarter of patients with alveolar histology tumours that lack PAX3/7-FOXO1.
Fusion gene status used in stratification may result in significant numbers of patients benefitting from lower treatment-associated toxicity. Prospective testing to show this reassignment maintains current survival rates is now required and is shown to be feasible based on estimated recruitment to a future EpSSG trial. Together with developing novel therapeutic strategies for patients identified as higher risk, this may ultimately improve the outcome and quality of life for patients with RMS.
当前治疗方法的长期毒性是儿童癌症中的一个主要问题。包括我们自己的研究在内，先前的研究已表明，横纹肌肉瘤（RMS）中PAX3/7-FOXO1融合基因的存在具有预后价值。建议在未来的临床试验中引入PAX3/7-FOXO1阳性作为风险分层的一个组成部分，而非肺泡组织学。
为评估这种重新分类的潜在影响，我们基于荧光原位杂交和/或逆转录PCR对PAX3/7-FOXO1的鉴定，确定了英国先前针对非转移性RMS的恶性间充质肿瘤临床试验中210例经组织学检查的患者风险类别分配的变化。
在当前风险分层中使用融合基因阳性会将7%的患者重新分配到不同的欧洲儿科软组织肉瘤研究组（EpSSG）风险组。下一项欧洲试验将有80%的把握度检测出重新分配患者在10年内无事件生存率有15%的差异以及在5年内有20%的差异。这将减少对超过四分之一缺乏PAX3/7-FOXO1的肺泡组织学肿瘤患者的治疗。
分层中使用融合基因状态可能会使大量患者受益于较低的治疗相关毒性。现在需要进行前瞻性测试以表明这种重新分配能维持当前生存率，并且根据预计纳入未来EpSSG试验的患者人数显示这是可行的。连同为确定为高风险的患者开发新的治疗策略一起，这最终可能改善RMS患者的治疗结果和生活质量。
