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

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.