Recurrence/prognosis estimation using a molecularly positive surgical margin-based model calls for alternative curative strategies in pIIIA/N2 NSCLC

Mol Oncol. 2024 Jun;18(6):1649-1664. doi: 10.1002/1878-0261.13600. Epub 2024 Feb 7.

Abstract

Stage pIIIA/N2 non-small cell lung cancer (NSCLC) is primarily treated by complete surgical resection combined with neoadjuvant/adjuvant therapies. However, up to 40% of patients experience tumor recurrence. Here, we studied 119 stage pIIIA/N2 NSCLC patients who received complete surgery plus adjuvant chemotherapy (CT) or chemoradiotherapy (CRT). The paired tumor and resection margin samples were analyzed using next-generation sequencing (NGS). Although all patients were classified as negative resection margins by histologic methods, NGS revealed that 47.1% of them had molecularly positive surgical margins. Patients who tested positive for NGS-detected residual tumors had significantly shorter disease-free survival (DFS) (P = 0.002). Additionally, metastatic lymph node ratio, erb-b2 receptor tyrosine kinase 2 (ERBB2) mutations, and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) mutations were also independently associated with DFS. We used these four features to construct a COX model that could effectively estimate recurrence risk and prognosis. Notably, mutational profiling through broad-panel NGS could more sensitively detect residual tumors than the conventional histologic methods. Adjuvant CT and adjuvant CRT exhibited no significant difference in eliminating locoregional recurrence risk for stage pIIIA/N2 NSCLC patients with molecularly positive surgical margins.

Keywords: COX model; metastatic lymph node ratio; molecularly positive surgical margin; next‐generation sequencing; non‐small cell lung cancer.

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Carcinoma, Non-Small-Cell Lung* / surgery
  • Carcinoma, Non-Small-Cell Lung* / therapy
  • Disease-Free Survival
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Lung Neoplasms* / surgery
  • Male
  • Margins of Excision
  • Middle Aged
  • Mutation
  • Neoplasm Recurrence, Local* / genetics
  • Neoplasm Recurrence, Local* / pathology
  • Neoplasm Staging
  • Prognosis