病例报告：转移性非小细胞肺癌中体细胞EGFR、BRCA1和BRCA2突变共表达

文献信息

中文摘要

背景： 过去十年间，随着广泛基因检测、免疫治疗和靶向治疗的出现，非小细胞肺癌（NSCLC）的治疗发生了巨大变化。针对表皮生长因子受体（EGFR）及其他驱动突变的治疗降低了毒性，并提高了特定患者的疗效。
病例介绍： 我们报告一名59岁男性转移性NSCLC患者，其同时携带EGFR、BRCA1和RNA结合基序蛋白10（RBM10）突变，并具有高程序性死亡配体1（PD-L1）表达。随后在外周血检测中发现BRCA2突变。患者因致残性卒中就诊，表现为吞咽困难和偏瘫。在治疗过程中，他接受了奥希替尼治疗，之后外周血检测显示EGFR和RBM10变异等位基因频率（VAF）升高。他还接受了免疫治疗和奥拉帕利。尽管文献报道的缓解率较高，但他对这些药物均无应答。他对化疗有应答，但耐受性差。最终，鉴于缺乏持久缓解且无法耐受化疗，患者选择了姑息治疗。
讨论： 携带EGFR、BRCA1/2或PD-L1升高等可靶向靶点的患者，通常在接受靶向及联合治疗时较无可靶向选择者预后更优。然而，共存突变之间可能相互作用并提供逃逸机制。本例患者缺乏应答，这与显示在RBM10功能缺失（LOF）改变存在时EGFR靶向治疗疗效降低的研究一致。需要对携带多个同时突变患者开展进一步研究，以改善该群体的治疗选择。

英文摘要

BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) has evolved dramatically over the past decade with the advent of widespread genetic testing, immunotherapy, and targeted therapies. Treatments directed against epidermal growth factor receptor (EGFR) and other driver mutations have reduced toxicity and improved efficacy for selected patients.
CASE PRESENTATION: We present a 59-year-old man with metastatic NSCLC harboring coexisting EGFR, BRCA1, and RNA-binding motif protein 10 (RBM10) mutations and high programmed death-ligand 1 (PD-L1) expression. A BRCA2 mutation was later detected on peripheral blood testing. The patient presented with a debilitating stroke that included dysphagia and hemiparesis. During his course of care, he received osimertinib, after which EGFR and RBM10 variant allele frequencies (VAFs) increased on peripheral blood testing. He also received immunotherapy and olaparib. Despite high response rates reported in the literature, he did not respond to these agents. He had a response to chemotherapy but tolerated it poorly. Ultimately, given the lack of durable response and his inability to tolerate chemotherapy, the patient opted for palliative care.
DISCUSSION: Patients with actionable targets such as EGFR, BRCA1/2, or elevated PD-L1 generally have superior outcomes with targeted and combination therapy compared with patients who lack targetable options. However, coexisting mutations can interact and provide escape mechanisms. The lack of response in our patient is consistent with studies showing reduced efficacy of EGFR-directed therapy in the presence of RBM10 loss-of-function (LOF) alterations. Further research in patients with multiple concurrent mutations is needed to improve treatment options for this group.