Supplementary Material for: Successful treatment with dabrafenib/trametinib of a malignantly transformed and metastasized BRAFV600E mutant pleiomorphic xanthoastrocytoma: a case report and review of the literature

Pleiomorphic xanthoastrocytoma (PXA) is considered a low grade glioma with a favorable prognosis following surgical resection. We present a case report of a BRAFV600E mutant malignantly transformed and disseminated PXA that was successfully treated with BRAF-/MEK-targeted therapy (dabrafenib/trametinib).
At the age of 16 years, our patient underwent an initial gross macroscopic resection of a right occipital PXA. Six months later, a reintervention for an asymptomatic tumor recurrence was performed; and complete resection was achieved. The patient was followed up by MRI for 14 years without arguments for recurrence. He was lost to follow-up thereafter. At the age of 38 years, he presented with a symptomatic local recurrence with extra-cerebral soft tissue extension for which a surgical resection was performed. Anatomopathological examination reported a grade 3 anaplastic PXA (aPXA); molecular analysis detected a BRAFV600E mutation. Three months later, before the initiation of radiotherapy, a local tumor recurrence was diagnosed for which he underwent a fourth surgical resection. Radiotherapy was performed following surgical debulking. One month after completion of radiotherapy, disease progression was documented including multiple sites of extra-cranial metastases (skeletal-, lung-, cervical lymph node and subcutaneous metastases). Systemic treatment with a combination of BRAF-/MEK-inhibitors (dabrafenib/trametinib) was initiated and resulted in a rapid and deep tumor response (partial response according to RECISTv1.1) and absence of BRAFV600E mutant ctDNA in plasma at 6 weeks after treatment initiation. A near-complete metabolic remission was documented on [18F]FDG PET/CT 3 months after starting systemic therapy.
In conclusion, we present a rare case of a malignant transformation and systemic dissemination of a BRAFV600E mutant PXA, occurring 20 year after the initial diagnosis. This case highlights the importance of long-term follow-up of patients diagnosed with these rare central nervous system (CNS) tumors that initially are considered benign, and also illustrates that BRAF/MEK inhibition can be an effective therapy for BRAFV600E -mutated PXA, underscoring the importance of performing molecular genetic profiling of these tumors.

多形性黄色星形细胞瘤（Pleiomorphic xanthoastrocytoma, PXA）被归类为低级别胶质瘤，手术切除后预后良好。本文报告1例BRAFV600E突变型恶性转化并发生播散的PXA病例，该患者经BRAF/MEK靶向治疗（达拉非尼/曲美替尼）后获得成功救治。

患者16岁时因右侧枕叶PXA接受首次肉眼全切术。术后6个月，因无症状肿瘤复发再次手术，并实现完整切除。此后患者接受磁共振成像（MRI）随访14年，未发现肿瘤复发迹象，之后失访。患者38岁时出现有症状的局部复发并伴颅外软组织侵犯，遂接受第三次手术切除。病理检查结果提示为3级间变性多形性黄色星形细胞瘤（aPXA）；分子检测检出BRAFV600E突变。术后3个月，在启动放射治疗前，患者再次被诊断为局部肿瘤复发，并接受第四次手术切除。肿瘤减瘤术后患者接受了放射治疗。放疗结束1个月后，确诊疾病进展，伴多处颅外转移（骨骼、肺、颈部淋巴结及皮下转移）。遂启动BRAF/MEK抑制剂（达拉非尼/曲美替尼）联合全身治疗，治疗后快速获得显著肿瘤应答（按RECISTv1.1标准评估为部分缓解），且治疗启动后6周的血浆样本中未检测到BRAFV600E突变循环肿瘤DNA（ctDNA）。启动全身治疗3个月后，经[18F]FDG PET/CT检查证实接近完全代谢缓解。

综上，本文报告1例罕见的BRAFV600E突变型PXA恶性转化并全身播散病例，该事件距初始诊断已过去20年。本案例凸显了对初始被认为良性的罕见中枢神经系统（CNS）肿瘤患者进行长期随访的重要性，同时证实BRAF/MEK抑制疗法可有效治疗BRAFV600E突变型PXA，强调了对这类肿瘤开展分子遗传学检测的必要性。