Department of Dermatology, University Hospital Essen, Essen, Germany & German Cancer Consortium (DKTK), partner site Essen, Düsseldorf, Germany; Department of Dermatology, University Hospital Bonn, Bonn.
Institute for medical informatics, biometry and epidemiology, University Hospital Essen, Essen, Germany.
Eur J Cancer. 2024 Sep;208:114208. doi: 10.1016/j.ejca.2024.114208. Epub 2024 Jul 6.
Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date.
Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV.
184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2).
While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.
缺乏 BRAF、NRAS 和 NF1 突变的黑色素瘤通常被称为“三野生型”（tWT）黑色素瘤。它们占所有黑色素瘤的 5-10%，关于其临床特征和对治疗的反应仍描述不足。本研究调查了迄今为止最大的 tWT-黑色素瘤多中心集合。
对前瞻性多中心 ADOREG/TRIM 研究的 3109 份黑色素瘤组织样本进行靶向下一代测序，该研究揭示了 292 名患有 tWT-黑色素瘤的患者。分析了临床特征和突变模式。作为亚组分析，我们分析了 141 名接受抗 CTLA4 联合抗 PD1 或抗 PD1 单药治疗作为 AJCC 分期 IV 一线治疗的 tWT-黑色素瘤患者。
共纳入 184 例皮肤黑色素瘤患者、56 例黏膜黑色素瘤患者、34 例肢端黑色素瘤患者和 18 例来源不明的黑色素瘤（MUP）患者。所有黑色素瘤中，TERT 启动子突变的检出率为 33.2%，所有 tWT-黑色素瘤中，每例样本携带的突变少于 3 个。对于 141 例 IV 期疾病患者，无论黑色素瘤类型如何，mPFS 为 6.2 个月（95%CI：4-9），mOS 为一线抗 CTLA4 联合抗 PD1 治疗后 24.8 个月（95%CI：14.2-53.4）。一线抗 PD1 单药治疗后，mPFS 为 4 个月（95%CI：2.9-8.5），mOS 为 29.18 个月（95%CI：17.5-46.2）。
虽然 TERT 启动子突变和 TMB 等已知的预后因素在接受抗 CTLA4 联合抗 PD1 联合治疗或抗 PD1 单药治疗作为一线治疗的患者中分布均匀，但我们没有发现这两种治疗方法的 mPFS 或 mOS 延长。对于这两种治疗方案，mPFS 和 mOS 都明显短于已知有致癌基因突变的黑色素瘤。
