Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
Neuro Oncol. 2021 Nov 2;23(11):1872-1884. doi: 10.1093/neuonc/noab081.
Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.
We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.
Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM.
TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.
对于新诊断的 IDH 突变型低级别胶质瘤（LGG）患者，化疗可改善手术和放疗后的总体生存率，但一部分接受替莫唑胺（TMZ）治疗的患者会出现 TMZ 诱导的高度突变的复发性肿瘤。我们旨在确定复发时 TMZ 诱导的高度突变的流行率及其预后意义。
我们对 82 例最初患有 IDH 突变型低级别胶质瘤且接受再次手术的患者的复发性肿瘤进行了测序，并将高度突变状态与复发时的分级和随后的临床结果相关联。
高度突变与再次手术时的高级别疾病相关（OR 12.0，95%CI 2.5-115.5，P=.002），并且在先前接受 TMZ 治疗的复发性 LGG 中，有 57%的患者在发生转化时出现了高度突变。在发生间变（III 级）转化后，在单变量和多变量分析中，高度突变与较短的生存时间相关（HR 3.4，95%CI 1.2-9.9，P=.024），控制了肿瘤分级、亚型、年龄和先前的放疗。在一个独立的、已发表的数据集，高度突变对转化后的生存影响得到了验证。高度突变（HM）肿瘤更有可能在大脑和脊柱中出现不连续的病灶（P=.003）。为了估计 IDH 突变型低级别肿瘤中高级别转化的总体发生率，对 TMZ 治疗 LGG 的 II 期临床试验的数据进行了分析。8 年无复发生存率为 53.8%（95%CI 42.8-69.2），分析的转化病例中有 61%是 HM。
TMZ 诱导的高度突变是先前接受 TMZ 治疗的 LGG 转化后的常见事件，与预后不良和复发后不连续疾病的发展相关。这些发现影响了复发性肿瘤的分类、预后和临床试验设计。
