Molecular typing of stage IB non-small-cell lung cancer for precision medicine

Background The optimal postoperative management of stage IB non-small-cell lung cancer (NSCLC) remains controversial due to significant heterogeneity. This study aimed to establish a molecular classification for stage IB NSCLC to guide precision medicine. Methods We performed consensus clustering of transcriptomic profiles from TCGA-NSCLC (training set, n=119) and validated in GSE31210 (n=53). Molecular subtypes were compared with stage IA/II patients for clinical significance. Differentially expressed genes were analyzed using LASSO regression to identify biomarkers. Functional studies were conducted using patient-derived organoids (PDOs), cell lines, and tissue specimens. Results Stage IB NSCLC was divided into two subtypes (IB1 and IB2) with significantly different disease-free survival (DFS). IB1 patients showed DFS similar to stage IA, while IB2 patients exhibited DFS comparable to stage II (especially IIB). Carboxypeptidase D (CPD) was identified as a key biomarker capable of distinguishing high- and low-risk patients (AUC=0.874 in validation). CPD was overexpressed in tumor tissues and promoted proliferation and migration in PDOs and cell lines. Conclusion This molecular classification effectively stratifies stage IB NSCLC into low-risk (IB1, observation suitable) and high-risk (IB2, adjuvant therapy warranted) subgroups. CPD serves as a promising biomarker for clinical risk stratification.