SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication

ESMO Open. 2024 Jun;9(6):103472. doi: 10.1016/j.esmoop.2024.103472. Epub 2024 Jun 3.

Abstract

Background: SWItch/Sucrose NonFermentable (SWI/SNF) mutations have garnered increasing attention because of their association with unfavorable prognosis. However, the genetic landscape of SWI/SNF family mutations in Chinese non-small-cell lung cancer (NSCLC) is poorly understood. In addition, the optimal treatment strategy has not yet been determined.

Patients and methods: We collected sequencing data on 2027 lung tumor samples from multiple centers in China to comprehensively analyze the genomic characteristics of the SWI/SNF family within the Chinese NSCLC population. Meanwhile, 519 patients with NSCLC from Sun Yat-sen University Cancer Center were enrolled to investigate the potential implications of immunotherapy on patients with SWI/SNF mutations and to identify beneficial subpopulations. We also validated our findings in multiple publicly available cohorts.

Results: Approximately 15% of Chinese patients with lung cancer harbored mutations in the SWI/SNF chromatin remodeling complex, which were mutually exclusive to the EGFR mutations. Patients with SWI/SNFmut NSCLC who received first-line chemoimmunotherapy had better survival outcomes than those who received chemotherapy alone (median progression-free survival: 8.70 versus 6.93 months; P = 0.028). This finding was also confirmed by external validation using the POPLAR/OAK cohort. SWI/SNFmut NSCLC is frequently characterized by high tumor mutational burden and concurrent TP53 or STK11/KEAP mutations. Further analysis indicated that TP53 and STK11/KEAP1 mutations could be stratifying factors in facilitating personalized immunotherapy and guiding patient selection.

Conclusions: This study provides a step forward in understanding the genetic and immunological characterization of SWI/SNF genetic alterations. Moreover, our study reveals substantial benefits of immunotherapy over chemotherapy for SWI/SNF-mutant patients, especially the SWI/SNFmut and TP53mut subgroups.

Keywords: SWI/SNF; co-occurring mutation; immune checkpoint inhibitors; non-small-cell lung cancer.

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • China
  • Chromosomal Proteins, Non-Histone / genetics
  • DNA Helicases
  • DNA-Binding Proteins
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Nuclear Proteins
  • Prognosis
  • SMARCB1 Protein / genetics
  • Transcription Factors* / genetics

Substances

  • Immune Checkpoint Inhibitors
  • Transcription Factors
  • Chromosomal Proteins, Non-Histone
  • SMARCB1 Protein
  • ARID1A protein, human
  • SMARCA4 protein, human
  • SMARCB1 protein, human
  • SWI-SNF-B chromatin-remodeling complex
  • ARID1B protein, human
  • SMARCA2 protein, human
  • DNA Helicases
  • DNA-Binding Proteins
  • Nuclear Proteins