MBD4 缺乏可预测转移性葡萄膜黑素瘤患者对免疫检查点抑制剂的反应。
MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients.
机构信息
Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France; INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par La Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, Paris, France.
INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par La Ligue Nationale Contre le Cancer, Institut Curie, PSL Research University, Paris, France.
出版信息
Eur J Cancer. 2022 Sep;173:105-112. doi: 10.1016/j.ejca.2022.06.033. Epub 2022 Jul 19.
BACKGROUND
MBD4 mutations have been reported in uveal melanomas, acute myeloid leukemias, colorectal adenocarcinomas, gliomas, and spiradenocarcinomas and cause a hypermutated phenotype. Although metastatic uveal melanomas (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI.
METHODS
Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients.
RESULTS
Three hundred mUM patients were included. Median follow-up was 17.3 months. Ten patients with an objective response and 20 cases with stable disease for >12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (i.e., responder patients and stable disease) rate of 10%. Of the 131 tumors sequenced for MBD4, five (3.8%) were mutated. MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded (p < 0.001). Of these five responders, three presented progressive disease at 2.8, 13.9, and 22.3 months. Median PFS was 4.0 months in MBD4 wild-type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median OS in MBD4def patients was unreached as compared to 16.6 months in MBD4pro (HR = 0.11; 95% CI: 0.02-0.86; log-rank p-test = 0.04; Fig. 2e).
CONCLUSIONS
In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.
背景
MBD4 突变已在葡萄膜黑色素瘤、急性髓系白血病、结直肠腺癌、神经胶质瘤和螺旋腺瘤中报道，并导致超突变表型。虽然转移性葡萄膜黑色素瘤（mUM）通常对免疫检查点抑制剂（ICI）有抗性，但首例报道的 MBD4 突变（MBD4m）患者对 ICI 有反应，这表明 MBD4 突变可能预测对 ICI 的反应。
方法
对接受 ICI 治疗的 mUM 患者进行回顾性队列研究。对这些患者中的一部分进行了 MBD4 测序。
结果
共纳入 300 例 mUM 患者。中位随访时间为 17.3 个月。观察到 10 例患者有客观缓解，20 例患者疾病稳定超过 12 个月，客观缓解率为 3.3%，临床获益（即应答患者和疾病稳定）率为 10%。在 131 例测序的肿瘤中，有 5 例（3.8%）发生突变。MBD4 突变与更好的客观缓解率相关，5 例 MBD4m 中有 3 例（60%）与 4%的 MBD4 野生型患者（p<0.001）应答。在这 5 名应答者中，有 3 名在 2.8、13.9 和 22.3 个月时出现进展性疾病。MBD4 野生型患者的中位 PFS 为 4.0 个月，MBD4m 患者为 22.3 个月（HR=0.22；p=0.01）。与 MBD4pro 患者的 16.6 个月相比，MBD4def 患者的中位 OS 未达到（HR=0.11；95%CI：0.02-0.86；对数秩检验 p 测试=0.04；图 2e）。
结论
在 mUM 患者中，MBD4 突变高度预测对 ICI 的反应、PFS 和总生存获益。MBD4 可以作为一种组织非特异性生物标志物，应在 mUM 及其他报道有 MBD4 突变的肿瘤类型中进行测序。
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