Oncogenic driver mutations in Swiss never smoker patients with lung adenocarcinoma and correlation with clinicopathologic characteristics and outcome

PurposeLung cancer in never smokers is recognized as a distinct molecular, clinicopathologic and epidemiologic entity. The aim of the study was to investigate the molecular profile in Swiss never smokers with lung adenocarcinoma and to correlate the mutation status with clinicopathologic and demographic patient characteristics and outcome.MethodsOne hundred thirty-eight never smokers diagnosed with lung adenocarcinoma at the University Hospital Zurich between 2011–2018 were included in the study. Data from the electronic medical records were reviewed to characterize clinicopathologic and demographic features, molecular profile, treatment and outcome.ResultsThe majority of patients were female (58.7%) with a median age at diagnosis of 64.5 years (range, 27.1–94.2 years). The most common mutations were EGFR (58.7%) followed by ALK (12.3%), TP53 (5.8%), MET (5.8%), KRAS (4.3%), ERBB2 (4.3%), PIK3CA (2.9%), BRAF (2.2%), ROS1 (1.4%), RET (1.4%), CTNNB1 (0.7%), PARP1 (0.7%), TET1 (0.7%) and PIK3CG (0.7%). Median overall survival (mOS) was 51.0 months (mo). Early clinical stage (p = 0.002) and treatment with targeted therapy (HR 2.53, 95% CI 1.35–4.74, p = 0.004) were independently associated with longer mOS. Patients with oncogenic driver mutations had significantly longer mOS (52.2 mo) compared to patients without mutations (16.9 mo) (HR 3.38, 95% CI 1.52–7.55, p = 0.003). Besides, patients with EGFR mutated (57.8 mo) or ALK rearranged (59.9 mo) tumors had significantly longer mOS compared to the EGFR wildtype (35.0 mo), ALK wildtype (46.5 mo) and pan-negative (16.9 mo) cohorts (HR 2.35, 95% CI 1.37–4.04, p = 0.002; HR 7.80, 95% CI 3.28–18.55, p p = 0.023 and HR 34.78, 95% CI 3.48–34.65, p = 0.003).ConclusionNever smokers with lung adenocarcinoma display distinct clinicopathologic and molecular features and are characterized by a high incidence of targetable mutations. Never smokers with targetable mutations have significantly longer survival compared to patients without mutations.

研究目的：从不吸烟者所患的肺癌已被明确为一类独立的分子、临床病理及流行病学表型实体。本研究旨在探究瑞士从不吸烟肺腺癌患者的分子谱特征，并分析其突变状态与患者临床病理、人口统计学特征及预后的相关性。

研究方法：本研究纳入2011年至2018年间在苏黎世大学医院确诊为肺腺癌的138例从不吸烟者。通过回顾电子病历数据，对患者的临床病理与人口统计学特征、分子谱、治疗方案及预后进行分析。

研究结果：本队列中多数患者为女性（58.7%），确诊时中位年龄为64.5岁（范围：27.1~94.2岁）。最常见的突变类型为表皮生长因子受体（EGFR，58.7%），其次为间变性淋巴瘤激酶（ALK，12.3%）、肿瘤蛋白p53（TP53，5.8%）、肝细胞生长因子受体（MET，5.8%）、Kirsten大鼠肉瘤病毒癌基因同源物（KRAS，4.3%）、erb-b2受体酪氨酸激酶2（ERBB2，4.3%）、磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA，2.9%）、B-Raf原癌基因（BRAF，2.2%）、ROS1原癌基因（ROS1，1.4%）、转染过程中重排（RET，1.4%）、β-连环蛋白（CTNNB1，0.7%）、多腺苷二磷酸核糖聚合酶1（PARP1，0.7%）、TET原癌基因1（TET1，0.7%）以及磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基γ（PIK3CG，0.7%）。中位总生存期（median overall survival, mOS）为51.0个月。早期临床分期（p=0.002）及靶向治疗（风险比（Hazard Ratio, HR）=2.53，95%置信区间（Confidence Interval, CI）：1.35~4.74，p=0.004）与更长的中位总生存期独立相关。携带致癌驱动基因突变的患者中位总生存期为52.2个月，显著长于无突变患者的16.9个月（HR=3.38，95%CI：1.52~7.55，p=0.003）。此外，携带EGFR突变（中位总生存期57.8个月）或ALK重排（中位总生存期59.9个月）的患者，其中位总生存期显著长于EGFR野生型（35.0个月）、ALK野生型（46.5个月）及全阴性队列（16.9个月），对应的风险比分别为HR=2.35（95%CI：1.37~4.04，p=0.002）、HR=7.80（95%CI：3.28~18.55，p=0.023）及HR=34.78（95%CI：3.48~34.65，p=0.003）。

研究结论：从不吸烟的肺腺癌患者具有独特的临床病理与分子特征，且可靶向突变的发生率较高。携带可靶向突变的从不吸烟肺腺癌患者，其生存期显著长于无突变患者。