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

Sep 21, 2026

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Stage pIIIA/N2 non-small cell lung cancer (NSCLC) is commonly managed with complete surgical resection plus neoadjuvant/adjuvant therapies, yet recurrence affects up to 40% of patients. In 119 patients receiving complete surgery and adjuvant chemotherapy or chemoradiotherapy, paired tumor and resection margin samples were assessed using next-generation sequencing (NGS). Although histology classified all margins as negative, NGS identified molecularly positive surgical margins in 47.1%, associated with significantly shorter disease-free survival. Additional independent predictors included metastatic lymph node ratio and ERBB2 and SMARCA4 mutations. A COX model built from these features effectively estimated recurrence risk and showed broad-panel NGS detected residual tumors more sensitively than conventional histology. Outcomes did not differ significantly between adjuvant CT and adjuvant CRT in eliminating locoregional recurrence risk for patients with molecularly positive margins.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Stage pIIIA/N2 NSCLC treatment context and rationale

Methods and NGS margin assessment

Patient cohort and treatment regimens

NGS analysis of paired tumor and resection margins

Results and prognostic model

Molecularly positive margins and DFS impact

Independent prognostic features

COX model for recurrence risk estimation

Comparison of adjuvant CT vs adjuvant CRT for locoregional control

Key abbreviations

Recurrence/prognosis estimation using a molecularly positive surgical margin-based model calls for alternative curative strategies in pIIIA/N2 NSCLC Li Li 1, Kewen He 1, Tao Zhou 1, Yang Xu2 , Jiaohui Pang2, Qingxi Yu 1, Yongsheng Gao3, Hongjin Shi 1, He Zhu 1, Mengke Li3, Jinming Yu 1,4,5 and Shuanghu Yuan 1,6 1 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China 2 Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., China 3 Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China 4 Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China 5 Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, China 6 Department of Radiation Oncology, The First Afﬁliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China Keywords COX model; metastatic lymph node ratio; molecularly positive surgical margin; nextgeneration sequencing; non-small cell lung cancer Correspondence J. Yu, Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No 440 Jiyan Road, Jinan, Shandong 250117, China Tel: +86 531 67626919 E-mail: [sdyujinming@163.com](sdyujinming@163.com) and S. Yuan, Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No 440 Jiyan Road, Jinan, Shandong 250117, China; Department of Radiation Oncology, The First Afﬁliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No 17 Lujiang Road, Hefei, Anhui 230001, China 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 nextgeneration 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, erbb2 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. Abbreviations ADC, adenocarcinoma; CNA, copy number alteration; CNV, copy number variant; CRT, chemoradiotherapy; CT, chemotherapy; DFS, disease-free survival; ExAC, exome aggregation consortium; FFPE, formalin-ﬁxed parafﬁn-embedded; GATK, genome analysis toolkit; H&E, hematoxylin and eosin; KPS, Karnofsky performance status; mDFS, median disease-free survival; MLNR, metastatic lymph node ratio; mOS, median overall survival; MRD, minimal residual disease; NCCN,

FAQs

Why can molecularly positive surgical margins matter in stage pIIIA/N2 NSCLC?

Even when histology labels margins as negative, NGS can detect molecularly positive surgical margins. Patients with NGS-detected residual tumors had significantly shorter disease-free survival.

How was molecularly positive margin status assessed?

Paired tumor and resection margin samples were analyzed using next-generation sequencing (NGS). NGS revealed molecular positivity in 47.1% of patients despite histologic negative margins.

Which features were used to build the recurrence risk COX model?

The model used metastatic lymph node ratio plus ERBB2 and SMARCA4 mutations, along with molecularly positive surgical margin-related information from NGS-detected residual tumors to estimate recurrence risk and prognosis.

Sep 21, 2026

Uploaded by Hazel