Stanford Cancer Institute/Stanford University School of Medicine, Stanford, CA.
Quantitative Sciences Unit, Stanford School of Medicine, Stanford, CA.
Clin Lung Cancer. 2022 May;23(3):264-272. doi: 10.1016/j.cllc.2021.09.004. Epub 2021 Oct 21.
In most studies, patients with EGFR L858R mutant non-small cell lung cancer (NSCLC) have a shorter duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy than do patients with EGFR exon 19 deletion NSCLC. The role that co-mutations play in this observation is unknown.
We performed a single-institution retrospective analysis of patients with EGFR-mutant NSCLC (exon 19 deletion or L858R mutation) who received frontline EGFR TKI for metastatic disease between 2014 and 2019, and who had STAMP next-generation sequencing (NGS), a 130-gene platform. Time to treatment failure (TTF) and overall survival were calculated using Cox models adjusted for age, race, and brain metastases. Co-mutations in key tumor suppressor genes (TP53, RB1, KEAP1, CDKN2A, or CTNNB1) were identified and their effects on outcomes were evaluated. Analyses were stratified according to receipt of osimertinib versus nonosimertinib as frontline EGFR TKI.
Of 137 patients, 72 (57%) had EGFR exon 19 deletions and 65 (43%) had EGFR L858R mutations. Median TTF and OS on frontline TKI was shorter for the L858R cohort versus the exon 19 deletion cohort in univariate analysis. In adjusted models, this difference persisted for TTF but was no longer significant for OS. The difference in TTF in L858R mutant tumors was driven by the presence of co-mutations in key tumor suppressor genes.
Patients with metastatic NSCLC with mutations in EGFR L858R had shorter TTF on frontline TKI compared to patients with EGFR exon 19 deletions. Co-mutations in tumor suppressor genes may play an important role in the differential response to TKI therapy.
在大多数研究中，与 EGFR 外显子 19 缺失型非小细胞肺癌（NSCLC）患者相比，携带 EGFR L858R 突变的 NSCLC 患者接受表皮生长因子受体酪氨酸激酶抑制剂（TKI）治疗的缓解持续时间更短。但目前尚不清楚共同突变在此观察结果中所起的作用。
我们对 2014 年至 2019 年间接受一线 EGFR TKI 治疗转移性疾病的 EGFR 突变型 NSCLC（外显子 19 缺失或 L858R 突变）患者进行了单机构回顾性分析，这些患者接受了 STAMP 下一代测序（NGS），这是一个包含 130 个基因的平台。使用 Cox 模型计算无进展生存期（PFS）和总生存期，该模型根据年龄、种族和脑转移进行了调整。确定了关键肿瘤抑制基因（TP53、RB1、KEAP1、CDKN2A 或 CTNNB1）中的共突变，并评估了它们对结果的影响。根据一线 EGFR TKI 是奥希替尼还是非奥希替尼进行了分层分析。
在 137 名患者中，72 名（57%）患者存在 EGFR 外显子 19 缺失，65 名（43%）患者存在 EGFR L858R 突变。单因素分析显示，L858R 队列的无进展生存期和总生存期在一线 TKI 治疗中短于外显子 19 缺失队列。在调整后的模型中，这一差异在无进展生存期方面仍然存在，但在总生存期方面不再显著。L858R 突变肿瘤的无进展生存期差异是由关键肿瘤抑制基因中的共突变引起的。
与 EGFR 外显子 19 缺失型 NSCLC 患者相比，携带 EGFR L858R 突变的转移性 NSCLC 患者在接受一线 TKI 治疗时的无进展生存期更短。肿瘤抑制基因中的共突变可能在 TKI 治疗的不同反应中起重要作用。
