切除的非小细胞肺癌中单种和多种癌症相关体细胞突变的预后影响。

The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer.

机构信息

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Ontario, Canada.

Aix Marseille University, Assistance Publique Hôpitaux de Marseille. Multidisciplinary Oncology and Therapeutic Innovations department, Marseille, 13015, France.

出版信息

Lung Cancer. 2018 Sep;123:22-29. doi: 10.1016/j.lungcan.2018.06.023. Epub 2018 Jun 19.

DOI:10.1016/j.lungcan.2018.06.023

PMID:30089591

Abstract

INTRODUCTION

Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with non-small-cell lung cancer (NSCLC). The role of multiple somatic mutations in early-stage NSCLC is unclear.

METHODS

Tissue from 214 patients with resected NSCLC at the Princess Margaret Cancer Centre was analyzed by next-generation sequencing by Mi-SEQ or Sequenom multiplex platforms. Associations between mutation status, baseline patient characteristics and outcomes (disease-free survival (DFS) after surgical resection and overall survival (OS)) were investigated.

RESULTS

Somatic mutations were identified in 184 patients with resected stage I-III NSCLC: None (n = 30), single (n = 101) and multiple (≥2, n = 83). Multiple mutations were significantly associated with younger age (p = 0.0006), female sex (p = 0.012), smoking status (p = 0.002) and adenocarcinoma histology (p = 0.0001).TP53, KRAS and EGFR were the most common mutations. TP53 mutation was the most frequent co-mutation occurring in 72% of patients with multiple mutations. In resected stage I-III patients, multiple mutations were significantly associated with worse DFS (HR = 2.56, p = 0.003) but not OS on univariate analysis. Patients with KRAS and EGFR mutations were also associated with shorter DFS (HR = 2.52, p = 0.016 and HR = 4.37, p = 0.001 respectively) but no OS difference. TP53 mutation was associated with both shorter DFS (HR = 2.21, p = 0.02) and OS (HR = 3.08, p = 0.02). In subgroup univariate analysis, poorer DFS was associated with multiple mutations (p = 0.0015), EGFR (HR = 3.14, p = 0.006), and TP53 (HR = 2.46, p = 0.018) in patients with stage I disease.

CONCLUSION

The presence of known somatic mutations is associated with worse DFS in resected NSCLC. The differences are both statistically significant and clinically relevant. The presence of EGFR, KRAS and TP53 mutations was also associated with adverse outcomes. Larger datasets are required to validate whether mutational status is an independent prognostic factor in early stage NSCLC.

摘要

简介

体细胞突变在非小细胞肺癌（NSCLC）患者的治疗选择和预后中越来越重要。早期 NSCLC 中多种体细胞突变的作用尚不清楚。

方法

对 214 例在玛格丽特公主癌症中心接受手术治疗的 NSCLC 患者的组织进行了下一代测序，通过 Mi-SEQ 或 Sequenom 多重平台进行分析。研究了突变状态与基线患者特征和结果（手术切除后的无病生存期（DFS）和总生存期（OS））之间的关系。

结果

在 184 例 I-III 期 NSCLC 患者中发现了体细胞突变：无突变（n=30）、单突变（n=101）和多突变（≥2，n=83）。多个突变与年龄较小（p=0.0006）、女性（p=0.012）、吸烟状态（p=0.002）和腺癌组织学（p=0.0001）显著相关。TP53、KRAS 和 EGFR 是最常见的突变。TP53 突变是最常见的共突变，在 72%的多突变患者中发生。在 I-III 期患者中，多突变与较差的 DFS 显著相关（HR=2.56，p=0.003），但单变量分析时与 OS 无关。KRAS 和 EGFR 突变的患者DFS 也较短（HR=2.52，p=0.016 和 HR=4.37，p=0.001），但 OS 无差异。TP53 突变与 DFS（HR=2.21，p=0.02）和 OS（HR=3.08，p=0.02）均相关。亚组单变量分析显示，在 I 期疾病患者中，多个突变（p=0.0015）、EGFR（HR=3.14，p=0.006）和 TP53（HR=2.46，p=0.018）与较差的 DFS 相关。